are adolescents more vulnerable to drug addiction than ... · times (alcohol and cigarettes in late...

REVIEW

Are adolescents more vulnerable to drug addictionthan adults? Evidence from animal models

Nicole L. Schramm-Sapyta & Q. David Walker &

Joseph M. Caster & Edward D. Levin & Cynthia M. Kuhn

Received: 7 February 2008 /Accepted: 26 May 2009 /Published online: 23 June 2009# Springer-Verlag 2009

AbstractBackground and rationale Epidemiological evidence sug-gests that people who begin experimenting with drugs ofabuse during early adolescence are more likely to developsubstance use disorders (SUDs), but this correlation doesnot guarantee causation. Animal models, in which age ofonset can be tightly controlled, offer a platform for testingcausality. Many animal models address drug effects thatmight promote or discourage drug intake and drug-inducedneuroplasticity.Methods We have reviewed the preclinical literature toinvestigate whether adolescent rodents are differentiallysensitive to rewarding, reinforcing, aversive, locomotor,and withdrawal-induced effects of drugs of abuse.Results and conclusions The rodent model literature con-sistently suggests that the balance of rewarding andaversive effects of drugs of abuse is tipped toward rewardin adolescence. However, increased reward does notconsistently lead to increased voluntary intake: age effectson voluntary intake are drug and method specific. On theother hand, adolescents are consistently less sensitive towithdrawal effects, which could protect against compulsivedrug seeking. Studies examining neuronal function haverevealed several age-related effects but have yet to linkthese effects to vulnerability to SUDs. Taken together, thefindings suggest factors which may promote recreationaldrug use in adolescents, but evidence relating to patholog-ical drug-seeking behavior is lacking. A call is made for

future studies to address this gap using behavioral modelsof pathological drug seeking and for neurobiologic studiesto more directly link age effects to SUD vulnerability.

Keywords Addiction . Alcohol . Cocaine . Amphetamine .

Nicotine . Cannabinoids

Introduction

Drugs such as cocaine, amphetamine, nicotine, alcohol, andmarijuana are commonly used for their mood- and mind-altering properties. These substances also have the potentialto be addictive. In some people, regular use leads to“addiction” or “dependence,” i.e., compulsive and repeti-tive drug-seeking behavior despite negative health andsocial consequences. However, this type of behavior doesnot occur in all users (see Fig. 1). Many people whoexperiment with drugs do not find the effects rewarding andavoid them in the future. Some people enjoy the effects ofthe drugs and use them recreationally without everbecoming dependent. For others, however, the drugs gainpowerful control over their lives and may replace all otherhealthy pursuits (see Fig. 1). The majority of people whoself-administer drugs of abuse begin during adolescence.Epidemiological studies have shown that earlier onset ofdrug intake is associated with greater likelihood ofdevelopment of substance use problems. However, there isdebate about whether early onset uniquely affects braindevelopment in such a way as to promote pathologicalbehavior or whether the same genetic and environmentalfactors that make an individual likely to develop drugproblems also make them likely to initiate early. Thisreview summarizes results from animal models in which theeffect of age of onset has been examined.

Psychopharmacology (2009) 206:1–21DOI 10.1007/s00213-009-1585-5

N. L. Schramm-Sapyta (*) :Q. D. Walker : J. M. Caster :E. D. Levin : C. M. KuhnDuke University,Durham, NC, USAe-mail: [email protected]

The terms “addiction,” “drug abuse,” and “drug depen-dence” are used interchangeably in the vernacular and havevarying definitions in psychological, sociological, andneuroscience literature. For the sake of clarity, we willrefer to the two substance use disorders (SUDs), drugdependence and drug abuse, as they are defined by theDiagnostic and Statistical Manual of Mental Disordersversion IV (DSM-IV 1994).

For a diagnosis of drug abuse, a patient must present atleast one of the following four characteristics:

1. Recurrent substance use resulting in the failure to fulfillmajor role obligations at work, school, or home

2. Recurrent substance use in situations in which it isphysically hazardous

3. Recurrent substance-related legal problems4. Continued substance use despite having persistent or

recurrent social or interpersonal problems caused orexacerbated by the effects of the substance

For a diagnosis of drug dependence, a patient mustpresent three of the following seven characteristics:

1. Tolerance2. Withdrawal3. The substance is taken in larger amounts or over a

longer period than was intended4. There is a persistent desire or unsuccessful efforts to cut

down or control substance use5. A great deal of time is spent in activities necessary to

obtain the substance, use the substance, or recover fromits effects

6. Important social, occupational, or recreational activitiesare given up or reduced because of substance use

7. The substance use is continued despite knowledge ofhaving a persistent or recurrent physical or psycholog-

ical problem that is likely to have been caused orexacerbated by the substance

Two of the criteria for drug dependence, withdrawal andtolerance, relate to physiological phenomena that ensuefrom repeated drug taking and are relatively easy tomeasure in animal models. New behavioral methods areapproaching success at modeling increased intake, intakedespite negative consequences, and the choice betweendrug intake and other activities, as described below.

The DSM-IV criteria provide a “snapshot” that clinicianscan use when a patient requires diagnosis or treatment.However, drug dependence is actually a progressivedisease, with several defined stages that often overlap withadolescence (Kreek et al. 2005; see Figs. 1 and 2). Drugdependence necessarily begins as experimental drug use; noperson can become dependent without first taking a drug.Most people try drugs (at least alcohol or tobacco) at somepoint in their lives, typically experimenting during the lateteenage years and early 20s (Chen and Kandel 1995). Someusers repeat drug use under recreational circumstances.Recreational drug use can vary widely but is defined by thefact that the user has control over it. Recreational users seekdrugs for their rewarding properties and not out ofcompulsion (Kalivas and Volkow 2005). Drug abuse anddependence begin to emerge when use becomes compul-sive. The likelihood of progression from experimentation torecreational use to dependence varies by drug. Figure 1provides a visual interpretation of this point by depictingthe percentage of the population of the USA over age 12that has ever taken a particular drug, uses regularly, or isdependent. Although the percentage that develops depen-dence varies by drug and is likely influenced by culturaland legal factors, the dependent population represents asmall subset of those who have experimented with a drug.

Fig. 1 Percentages of the USpopulation over the age of12 years who have ever tried theindicated drug (top number, lightgray circle); who used the indi-cated drug in the past month(middle number, darker graycircle); who meet criteria fordependence on the indicateddrug (bottom number, black cir-cle). Numbers in the center ofeach diagram represent the per-centage of people who have evertried the indicated substance whoare currently dependent. Dataobtained from the NSDUH 2007,lifetime use, past month use,DSM-IV dependence criteria (forall drugs except tobacco), anddaily cigarette use (for tobacco)

2 Psychopharmacology (2009) 206:1–21

A key research question, therefore, is why do some drugusers develop SUDs, while others can remain purelyrecreational?

Epidemiological studies have provided insight into somefactors that explain the difference between recreationalusers and those with SUD. One frequently observedcorrelation is that people who begin use at a young ageare more likely to develop SUDs (Robins and Przybeck1985; Meyer and Neale 1992; Lewinsohn et al. 1999;Prescott and Kendler 1999; DeWit et al. 2000; Lynskey etal. 2003; Brown et al. 2004; Patton et al. 2004) and tend toprogress faster from experimentation to problem use (Chenand Kandel 1995; Chen et al. 1997). This correlation is thefocus of the present review. Other contributing factorsinclude family history of SUDs (Hoffmann and Su 1998;Hill et al. 2000) and psychopathology such as depression,anxiety, attention deficit disorder, schizophrenia, andconduct disorder (Deykin et al. 1987; Russell et al. 1994;Burke et al. 1994; Abraham and Fava 1999; Compton et al.2000; Shaffer and Eber 2002; Costello et al. 2003). All ofthese factors are associated with increased risk of develop-ment of SUDs, but causality is difficult to address in humanpopulations. In this review, we will examine attempts inanimal models to address the question of whether drugtaking at a young age is causal or merely coincidental inSUD development.

It is crucial at this point to define what we mean by“young.” Experimentation with alcohol, tobacco, andmarijuana typically begins during the teenage years(SAMHSA 2008). Use of alcohol peaks around age 18–20and declines into adulthood (Chen and Kandel 1995).Marijuana and tobacco use peaks slightly later, betweenages 19 and 22 (Chen and Kandel 1995). Cocaine use peaksin the early to mid-20s and also declines into adulthood(Chen and Kandel 1995). The typical age-related pattern ofdrug use involves experimentation in the late teens andearly 20s, so those who experiment before these typicaltimes (alcohol and cigarettes in late childhood or the early

teens or illegal drugs in the teens) are the most at risk.While many studies use an age of onset before 15 years asthe cutoff for “early onset,” there is, in general, an inversecorrelation: younger users are more likely to develop SUDs.

While the inverse correlation between age of onset andSUD liability is well established in humans, it does not tellus whether early use is causal. Epidemiological studies totest causality require twin or longitudinal studies which aredifficult and rare. Two twin studies have resulted inconflicting results, albeit with different substances. Onelarge study examining the risk for alcohol abuse anddependence reported that age of onset was correlated withbut not causal in development of alcohol use disorders(Prescott and Kendler 1999). In contrast, a smaller study oftwins who were discordant for early-onset marijuana usereported that age of onset was causal in development oflater drug use and abuse problems (Lynskey et al. 2003).Thus, there is sparse evidence and lingering debate withinthe epidemiological literature regarding the causality ofearly-onset drug use as it relates to later drug problems.Human studies show that family history and psychopathol-ogy both increase the likelihood of early initiation (Tarter etal. 1999; Franken and Hendriks 2000; McGue et al. 2001a,b). Do these biological and environmental effects, therefore,operate through early initiation to increase vulnerability toSUDs? Or would users with a family history and/orpsychopathology develop SUDs no matter when theyinitiate? These questions are difficult to address in humanstudies. To fully address the causality of early drugexposure on later SUD, animal models are necessary.

Animal models have the distinct advantage of experi-mental control. Experimenters can randomly assign the ageof initial exposure, as well as the drug, dose, duration, andtiming of exposure, whereas, in human studies, theseconditions are determined by the user. For this reason,animal models have provided much valuable information.However, one drawback to animal use is that no modelcompletely recapitulates the stages in development of SUD.

Fig. 2 Stages in the progressionto drug dependence (rectangles)and animal models related toeach stage (ovals; self-admin,self-administration)

Psychopharmacology (2009) 206:1–21 3

For this reason, we must integrate results from multiplebehavioral and neurobiological models to achieve a fullunderstanding.

Rodent behavioral models of substance use disorders

Rodent behavioral tasks model basic processes that arecomponents of SUD pathology but cannot completelymimic the disease. Multiple models have been used whichvary in validity and relevance to the human condition andare summarized below and in Fig. 2.

Conditioned place preference

Conditioned place preference (CPP) is designed to assesswhether a drug is rewarding. The animal is trained toassociate a place with the rewarding effects of experimenter-injected drug-induced sensations. If the animal later freelyapproaches the drug-associated place, then the drug isdeemed rewarding (Carr et al. 1989; Bardo and Bevins2000). Rewarding drugs, it is assumed, are more likely tobe sought than nonrewarding drugs. This test is useful inmeasuring the level and persistence of drug-inducedreward. It is not a useful model of pathological drugseeking or taking. This test is also highly dose sensitive:drugs of abuse are typically rewarding at low to moderatedoses and aversive at high doses.

Conditioned place and taste aversion

These tests are designed to assess aversive effects of drugsof abuse. It is assumed that aversive effects discourageintake. In these tasks, the animals are trained to associate aplace or an otherwise palatable flavor with the sensationsensuing from an experimenter-injected drug (Welzl et al.2001). Subsequent avoidance of the place or flavorindicates aversive effects. These tests measure the use-limiting effects of drugs of abuse but do not modelpathological drug seeking or taking.

Withdrawal

Withdrawal is a constellation of affective and physiologicalchanges that occurs after cessation of intake of some drugsof abuse. Symptoms vary based on the drug consumed,duration, and extent of exposure and generally reflect thereversal of initial drug effects. Many of these behaviors areeasily quantified in animal models. For example, ethanolwithdrawal is marked by signs of autonomic arousal andbehavioral activation such as piloerection, locomotoractivation, tremor, and seizures (Majchrowicz 1975).Withdrawal from opiates elicits both behavioral andautonomic activation as indicated by ptosis, teeth chatter,

lacrimation, wet dog shakes, and jumping (Rasmussen et al.1990). Withdrawal from nicotine includes autonomic andbehavioral signs such as body shakes, tremors, writhing,escape attempts, chewing, gasping, ptosis, teeth chattering,and yawning (O’Dell et al. 2007b). All of these signs areanalogous to effects in humans (DSM-IV 1994). Forpsychostimulants such as cocaine and amphetamine, phys-iological withdrawal signs such as these are rarely observed(DSM-IV 1994). Withdrawal from the psychostimulantsand most other drugs of abuse elicits a generalized“negative motivational state” characterized by elevatedreward threshold which can be assessed using intracranialself-stimulation (O’Dell et al. 2007b). Withdrawal alsoelicits an anxiety-like state which can be assessed usingmultiple models such as the social interaction test, elevatedplus maze, light–dark task, and others (see below).

Locomotor behaviors

Most abused drugs stimulate locomotor behavior throughactivation of the dopaminergic circuits that contribute totheir reinforcing effects (Wise 1987; Di Chiara 1995).Cocaine and amphetamine typically increase motor activityin two ways. At lower doses, ambulatory activity isincreased, which is most often measured as an increase inmatrix crossings or distance traveled. At higher doses,locomotion falls and stereotypic behavior can emerge,which is manifested as an increase in sniffing, grooming,head bobbing, or other repetitive behaviors and a conse-quent decrease in distance traveled. Ethanol, in humans,tends to be activating at low doses (which may result fromreduced inhibitions) and sedating at high doses (DSM-IV1994). In rats, ethanol has been reported to either increaseor decrease locomotion, but dose effects do not consistentlyparallel the human pattern (see below). Similarly, nicotinecan either increase or decrease locomotion in rodents (seebelow). Opiates can also cause locomotor activation(Buxbaum et al. 1973; Pert and Sivit 1977; Kalivas et al.1983). Mu opioid agonists cause locomotor stimulation inboth mice and rats, and repeated treatment causes sensiti-zation (Rethy et al. 1971; Babbini and Davis 1972; Stinuset al. 1980; Kalivas and Stewart 1991; Gaiardi et al. 1991).In summary, acute motor responses are one indicator ofdrug sensitivity but are highly variable.

Repeated exposure to any of these drugs can lead to aphenomenon called sensitization, in which the ambulatoryor stereotypic response to a repeated low dose is augmented(Shuster et al. 1975a, b, 1977, 1982; Aizenstein et al. 1990;Segal and Kuczenski 1992a, b). Sensitization is a manifes-tation of neuroplastic changes in response to repeatedexposure, and some researchers have hypothesized that it isa behavioral correlate of increased drug craving anddevelopment of dependence (Robinson and Berridge


1993, 2000, 2001, 2008), although others debate thisassertion (Di Chiara 1995). Clearly, sensitization representsa lasting neuroplastic change that is easily measured. Itsrelevance to drug dependence is still debated.

Self-administration

Since humans who become drug addicts voluntarilyconsume drugs, it is important to examine animal modelsin which drugs are voluntarily administered (or “self-administered”) by the animal. For drugs such as cocaineand nicotine, self-administration (SA) in rodents is achievedvia intravenous administration through indwelling jugularcatheters (since rodents will not reliably snort or smokethese compounds). Admittedly, while most adolescenthumans do not use the intravenous route to administercocaine and nicotine, they do utilize routes which result inrapid absorption of the drugs into the blood (insufflation ofcocaine, smoking of crack cocaine and nicotine). Ethanolpresents a much simpler model because oral ingestion iseasily performed in rodents, as long as taste, caloric intake,and fluid balance are properly controlled. Both oral andintravenous approaches have been used to assess the agedependence of voluntary intake in animal models.

Animals that acquire drug-seeking behavior more quick-ly or perform it more frequently are thought to resemblehuman drug addicts. However, drug taking, even when it isacquired quickly, is not equivalent to drug dependence.Experimental animals will also work to obtain food andother environmental conditions in the absence of any abuseliability. Dependence-like behaviors require more complextesting, and there are several more sophisticated operantconditioning methods currently in use that provide bettermodels of SUDs. One such example is progressive ratioresponding, in which each successive infusion requiresmore lever presses than the previous one. This schedule isdesigned to assess motivation to seek the drug (Hodos1961; Roberts et al. 1989; Depoortere et al. 1993).Extinction and reinstatement paradigms are used to modelrelapse (de Wit and Stewart 1981; Shaham et al. 2003).Timeout and punished responding are used to model com-pulsive use (Vanderschuren and Everitt 2004; Deroche-Gamonet et al. 2004). Extended access or long-access(LgA) training schedules are used to model high-level orbinge use (Knackstedt and Kalivas 2007; O’Dell et al.2007a; George et al. 2008; Mantsch et al. 2008). In a com-prehensive self-administration model, Deroche-Gamonet etal. (2004) combined several of these measures andobserved that a small percentage of self-administering ratsexhibited multiple dependence-like behaviors, similar to theresults obtained in the human population shown in Fig. 1.These models are just beginning to appear in studiescomparing adolescents and adults.

Ranking the behavioral models

The relevance of each of these rodent models to humanSUD can be debated. In the analysis that follows, we assigngreater weight to methods which come closest to modelinghuman SUD and less weight to models which are notclearly linked to pathological drug intake. Therefore,studies using the more complex methods of self-administration (progressive ratio, extinction, reinstatement,punishment, LgA, etc.) are likely to be the most informativeregarding vulnerability to SUD. However, these are thenewest techniques, are the most difficult to employ indevelopmental studies, and consequently are the leastexamined in adolescent vs. adult rodents. Next, we assignapproximately equal weight to studies examining thereinforcing, rewarding, aversive, and withdrawal-relatedeffects of these drugs (simple self-administration, condi-tioned place preference, conditioned taste/place aversion,and withdrawal measures, respectively). All of thesemeasures are related to the phenomena which promote ordiscourage drug taking and are therefore useful indirectmeasures of propensity for drug intake. We rank thelocomotor effects of drugs of abuse as less compelling intheir validity. Acute locomotor effects are useful indicatorsof drug sensitivity, and sensitization is widely used as asurrogate for reinforcement. However, locomotion andreinforcement involve overlapping but nonidentical pro-cesses (Di Chiara 1995; Robinson and Berridge 2008;Vezina and Leyton 2009).

In addition to varying relevance to human SUD, thesemodels vary in the phase of development of SUD that theymodel. Self-administration models both early and latephases of the disease. CPP, conditioned place aversion(CPA), conditioned taste aversion (CTA), and acutelocomotor effects model early drug intake, sensitizationmodels repeated intake, and withdrawal model long-termuse and attempted abstinence. See Fig. 2.

In this review, we will summarize results from animalmodels in which the effects of age of onset of drugexposure have been examined in adolescent vs. adultrodents. This comparison is crucial: many studies haveexamined effects in adolescents only or in adults whichwere preexposed as adolescents, but such studies do not testfor age specificity of the findings. The review focuses onnicotine, ethanol, marijuana, and psychostimulants, as thereis a significant literature comparing the effects of thesedrugs in adolescents and adults. Unfortunately, there areonly a few studies which examine narcotics in adolescents(for example, see Zhang et al. 2008). The outline of thereview will follow the path from initial use throughaddiction. We will begin by examining the effects of asingle or a few drug administrations in which therewarding, aversive, and locomotor effects have been


examined. We will then discuss the effects of long-termvoluntary intake via oral and intravenous self-administration.Finally, we will discuss evidence from withdrawal studieswhich model the likely consequences of attempts to quit.

In general, the results obtained from rodent modelssuggest that:

1. Adolescents find some addictive drugs more rewardingthan adults

2. Adolescent rodents are consistently less likely todemonstrate aversive effects of drugs of abuse

3. Adolescent rodents may self-administer higher doses ofsome drugs of abuse under some conditions

4. Adolescent rodents consistently experience less severewithdrawal effects

These conclusions, for which we will provide evidencebelow, suggest that the developmental stage of adolescenceitself could increase early drug taking because addictivedrugs are on balance more rewarding and less aversive.However, these studies do not provide any support for thepossibility that progression to compulsive use is more likelywhen drug use begins in adolescence: the critical studieshave not been done.

The review will begin with a description of adolescentdevelopment in rodents as compared to humans. We willthen examine results from studies in which each model hasbeen used to compare adolescent and adult exposure.

Adolescent rodents as models of adolescent humans

We have focused on rodent models of addiction-relatedbehavior because of the extensive data published usingthese models and the relative simplicity of comparingadolescent and adult rodents. While primate models wouldbe very informative, we found only one study directlycomparing drug effects in adolescent vs. adult primates(Schwandt et al. 2007). Based on data that are reviewedextensively elsewhere (Spear 2000), we will consider theage range of 28–42 days to be “adolescence” in rodents. Byhormonal, physical, and social maturation criteria, thisphase of development corresponds to age 12–18 years inhumans (Spear 2000). It is critical to mention that animalsare not uniform through this time period. In fact, somebehavioral measures discussed below differ markedlybetween 28- and 42-day-old rodents, much as addictionvulnerability differs markedly between 12- and 18-year-oldhumans.

Growing evidence suggests that adolescent humans androdents experience many similar structural and functionalchanges in the brain as they progress to adulthood. Forexample, forebrain dopamine innervation is still maturingin both humans (Seeman et al. 1987) and rodents.Dopamine D1 and D2 receptor levels reach a peak and

then decline over adolescence (Gelbard et al. 1989; Teicheret al. 1995; Andersen and Teicher 2000). In addition,connections between the amygdala and prefrontal cortexmature during this phase, as demonstrated by microscopystudies in rodents (Cunningham et al. 2002, 2008) andfunctional magnetic resonance imaging studies in humans(Ernst et al. 2005; Eshel et al. 2007). Thus, braindevelopment during adolescence is likely similar in manyways between humans and rodents.

Early drug exposure

As shown in Fig. 2, the necessary first step towarddevelopment of drug dependence is drug intake. Thequality of the first drug experience is crucial in determiningfuture intake: for most drugs, people who enjoy their initialexperiences are more likely to repeat drug intake (Haertzenet al. 1983). Drugs of abuse exert both rewarding andaversive effects (Wise et al. 1976), and the overall balancebetween these experiences during early drug use determineswhether an individual will repeat drug taking in the future.In rodents, as described above, CPP, CPA, and CTA areused to assess initial reward and aversion and haveprovided valuable insight into the age dependence of sucheffects.

Rewarding effects

Some have speculated that elevated drug use in adolescenceoccurs because younger users find drugs more rewarding(Vastola et al. 2002; Belluzzi et al. 2004; Badanich et al.2006; O’Dell 2009). There is some evidence that youngerpeople and rodents derive greater reward from naturalsubstances (Vaidya et al. 2004), which could generalize toaddictive substances. If so, then younger users would likelytake a drug more frequently or at higher doses, which couldexplain the faster progression to dependence seen inadolescents. Evidence to address this crucial question ismixed but indicates that adolescents are more sensitive tothe rewarding effects of at least some drugs.

Nicotine is consistently more rewarding in adolescents(Vastola et al. 2002; Belluzzi et al. 2004; Torrella et al.2004; Shram et al. 2006; Kota et al. 2007; Brielmaier et al.2007; Torres et al. 2008). One study has shown that ethanolis more rewarding in adolescents (Philpot et al. 2003).Studies of psychostimulant reward (cocaine, amphetamine,methamphetamine) are more mixed but tend to indicategreater reward sensitivity in adolescents, particularly atlower doses (Badanich et al. 2006; Brenhouse andAndersen 2008; Brenhouse et al. 2008; Zakharova et al.2008a, b; but see Aberg et al. 2007; Adriani and Laviola2003; Balda et al. 2006; Campbell et al. 2000; Schramm-


Sapyta et al. 2004; Torres et al. 2008). Tetrahydrocannab-inol (THC) does not elicit strong conditioned placepreferences in rodents. See Table 1. Overall, conditionedplace preference studies suggest that adolescents are likelyto find many drugs of abuse more rewarding, especially atthreshold doses. More systematic dose–effect comparisonsare needed in the literature.

Aversive effects

There is a clear consensus in the literature that adolescentrodents are less susceptible to aversive effects of everyabused drug that has been tested. This is true for nicotine(Wilmouth and Spear 2004; Shram et al. 2006), ethanol(Philpot et al. 2003; and Schramm-Sapyta et al., unpub-lished observations), THC (Schramm-Sapyta et al. 2007;Quinn et al. 2008), amphetamine (Infurna and Spear 1979),and cocaine (Schramm-Sapyta et al. 2006); see Table 1. Infact, conditioned taste aversion for a nonaddictive sub-stance, lithium chloride, is also reduced in adolescent rats(Schramm-Sapyta et al. 2006), suggesting that insensitivityto aversive effects may be a generalized feature ofadolescence. In addition to these direct tests of aversiveeffects, other potentially use-limiting effects of many drugsof abuse are reduced in adolescents compared to adults. Forexample, nicotine is anxiolytic in adolescent male rats butanxiogenic in adults (Elliott et al. 2004). Adolescent rats areless sensitive to ethanol’s social inhibitory effects (Varlinskayaand Spear 2004b), hangover-induced anxiety (Doremus et al.2003; Varlinskaya and Spear 2004a), and sedative effects(Little et al. 1996; Swartzwelder et al. 1998). The anxiogenicand sedative effects of THC are also reduced in adolescence(Schramm-Sapyta et al. 2007). Overall, either the severity ofaversive effects or the ability to learn from an aversiveexperience is globally reduced in adolescence, which mayfacilitate higher or more frequent drug intake in adolescentscompared to adults.

Locomotor effects

As described above, the locomotor effects of drugs of abusecan be used to examine age-related effects on drugsensitivity and drug-induced neuroplasticity. A large num-ber of published studies have examined these phenomena,which we will now summarize.

Acute locomotion

The acute locomotor effects of drugs of abuse are highlyvariable and age, drug, and laboratory specific. Nicotine caneither increase or decrease locomotion. There is debate inthe literature as to what determines the direction ofnicotine’s locomotor effects (Jerome and Sanberg 1987),

so it is not surprising that the role of age is also debated.Two studies observed increased locomotion in adolescentsbut decreased locomotion in adults (Vastola et al. 2002; Caoet al. 2007a). Another study observed decreased locomotionin adults and midadolescents (45 days old) but no effect inyoung adolescents (28 days old; Belluzzi et al. 2004). Twostudies observed decreased locomotion in both ages, withgreater effects in adolescents (Lopez et al. 2003; Rezvaniand Levin 2004). Four other studies have observedincreased locomotion in both ages to an equal extent(Faraday et al. 2003; Schochet et al. 2004; Collins et al.2004; Cruz et al. 2005). One study reported greater acutelocomotion in adolescents (Collins and Izenwasser 2004).These conflicting results were obtained despite a similarrange of nicotine doses across the studies. Reports forethanol are similarly inconclusive despite similar dosesexamined across studies. One study reported greater motorreduction in adult mice (Lopez et al. 2003), while anotherstudy reported equal locomotor reduction in the two ages(Rezvani and Levin 2004). Another study reported loco-motor activation in both ages, with a greater effect onadolescents (Stevenson et al. 2008). In primates, ethanol’sataxic effects decrease with age, while impairment ofjumping ability and motor stimulation increased with ageacross adolescence (Schwandt et al. 2007). Amphetamineand cocaine both increase locomotion. Adolescents areconsistently hyporesponsive (in terms of both ambulatoryand stereotypic activity) to amphetamine and methamphet-amine compared to adults (Lanier and Isaacson 1977;Bolanos et al. 1998; Laviola et al. 1999; Zombeck et al.2009). However, in response to cocaine, studies comparingrats in the third or fourth week of life (preadolescence toearly adolescence) to rats in the fifth or sixth week of life(midadolescence to late adolescence) generally reportgreater ambulation and stereotypy in the early adolescents(Spear and Brick 1979; Snyder et al. 1998; Caster et al.2005; Parylak et al. 2008). Most investigators then observeno change from late adolescence to adulthood (Laviola etal. 1995; Maldonado and Kirstein 2005; Caster et al. 2005;Parylak et al. 2008), while others have observed a slighttrend toward reduced ambulation and stereotypy in adoles-cents compared to adults (Laviola et al. 1995; Frantz et al.2007), particularly in females (Laviola et al. 1995).Morphine stimulates greater locomotor activation in ado-lescents than adults (Spear et al. 1982). Overall, there is noconsensus in the literature regarding the relationship of ageto acute locomotor effects of drugs of abuse.

Sensitization

Many reports have examined the effect of age on locomotorsensitization to psychostimulants. Sensitization clearlychanges developmentally. It is absent in the early neonatal


Tab

le1

Age

depend

ence

ofreward,

aversion

,self-adm

inistration,

andwith

draw

al

Cocaine

Amph

etam

ine

Nicotine

Ethanol

THC

Rew

ard

Rew

ardgreaterin

adolescents

Badanichet

al.20

06;Brenh

ouse

etal.20

08;Brenh

ouse

and

And

ersen20

08;Zakharova

etal.20

08a,

b

Belluzziet

al.20

04;Brielmaier

etal.20

07;Shram

etal.20

06;

Torrella

etal.20

04;Vastola

etal.20

02;Kotaet

al.20

07;

Torreset

al.20

08

Philpot

etal.20

03

Rew

ardgreaterin

adults

Aberg

etal.20

07;Balda

etal.20

06Adriani

and

Laviola

2003

Noageeffect

onreward

Schramm-Sapytaet

al.20

04;

Cam

pbellet

al.20

00Torreset

al.20

08

Aversion

Aversiongreaterin

adults

Schramm-Sapytaet

al.20

06Infurnaand

Spear

1979

Shram

etal.20

06;Wilm

outh

andSpear

2004

Philpot

etal.20

03;

Schramm-Sapyta,

unpu

blished

Schramm-Sapyta

etal.20

07;Quinn

etal.20

08

Self-administration

Ado

lescentsself-adm

inister

more,

acqu

irefaster,exhibit

moremotivation,

orexhibit

greaterrelapse

Perry

etal.20

07(LoS

rats)

Levin

etal.20

03,20

07;

Chenet

al.20

07BrunellandSpear

2005;

Dorem

uset

al.20

05;

Vetteret

al.20

07;

Fullgrabe

etal.20

07;

Siegm

undet

al.20

05

Adu

ltsself-adm

inistermore,

acqu

irefaster,exhibitmore

motivation,

orexhibit

greaterrelapse

Shram

etal.20

07b

Noageeffect

onself-adm

inistration

Perry

etal.20

07(H

iSrats);

Belluzziet

al.20

05;Frantz

etal.20

07;Kantaket

al.

2007;KerstetterandKantak

2007;Leslie

etal.20

04

Bellet

al.20

06;

Siegm

undet

al.20

05

With

draw

alAdo

lescentshave

less

severe

with

draw

alO’D

ellet

al.20

07a,

b;Wilm

outh

andSpear

2006

;O’D

ellet

al.

2006

;Kotaet

al.20

07

Varlin

skayaandSpear

2004

a,b;

Dorem

uset

al.20

03;Acheson

etal.19

99

Adu

ltshave

less

severe

with

draw

alSlawecki

etal.20

06;

Ristuccia

andSpear

2005

Studies

cited(see

text)demon

stratin

gtheindicatedeffect

fortheindicatedsubstance


period and emerges as animals mature (Kolta et al. 1990;McDougall et al. 1994; Ujike et al. 1995). For cocaine,amphetamine, methamphetamine, and phencyclidine, de-tectable levels of sensitization become apparent during lateneonatal development and early adolescence, between thethird and fourth postnatal week (Tirelli et al. 2003). Oncesensitization is detectable, there is debate about whether itchanges in adolescence.

For nicotine, some experimenters have observed reducedsensitization in adolescents (Schochet et al. 2004; Collins etal. 2004; Collins and Izenwasser 2004; Cruz et al. 2005);some have observed greater sensitization in adolescents(Belluzzi et al. 2004; Adriani et al. 2006); and others haveobserved no age effect (Faraday et al. 2003), particularly infemales (Collins et al. 2004; Collins and Izenwasser 2004).Therefore, the literature indicates that nicotine is notglobally more sensitizing in adolescents than adults. Onestudy has examined sensitization in response to ethanol andfound that adolescent mice are less sensitive (Stevenson etal. 2008).

For amphetamine, two reports have concluded thatadolescents sensitize more than adults (Adriani et al.1998; Laviola et al. 2001). For cocaine, three studies havereported reduced sensitization in adolescent rats (Laviola etal. 1995; Collins and Izenwasser 2002; Frantz et al. 2007).Other studies have reported greater sensitization in adoles-cent rats (Caster et al. 2005, 2007) and mice (Schramm-Sapyta et al. 2004). Two of the studies which reportedgreater cocaine sensitization in adolescents (Caster et al.2005, 2007) utilized rapid assessments of sensitization(within a repeated-dose binge and 24 h after a single highdose). Thus, adolescents might develop sensitization faster.

Behavioral plasticity to these drugs is clearly possible inboth adolescent and adult rodents, but the relative magni-tude in the two ages may depend on drug, dose, andduration of exposure. Overall, the weight of evidenceshows that adolescents are not more vulnerable than adultsto neuroplastic changes in the locomotor behavioralcircuitry in response to intermittent repeated exposures tothese drugs.

Prolonged drug exposure

Self-administration

SA of psychostimulants, nicotine, and ethanol has thepotential to be an excellent model of human drug takingand the progression to dependence (THC is not reliablyself-administered by rodents). Much of the researchpublished to date has focused on the initial acquisition ofSA, which is indicative of the reinforcing effects of thedrugs examined. A few studies have examined long-term

SA and the permutations, such as progressive ratio, LgA,extinction, and reinstatement, which are most informativeabout the progression to dependence.

The frequency of nicotine self-administration may begreater in adolescence, though results vary. Levin et al.(2003, 2007) have shown that adolescent rats take morenicotine (more infusions per hour) under a continuousreinforcement schedule (one infusion per lever press) thanadult rats. This effect is highly dependent on the age ofinitial training within adolescence. The average number ofinfusions per session decreases with increasing age of onsetwithin the adolescent age range and into early adulthood.With multiple weeks of self-administration as the animalsmature, sex differences emerge. Male adolescent-onset ratsshow higher rates of nicotine self-administration initiallybut decrease their intake to adult-onset levels as they age(Levin et al. 2007). In contrast, adolescent-onset female ratsshow higher levels of nicotine self-administration which aremaintained as they become adults (Levin et al. 2003).Another group has also shown that adolescent female ratsacquire nicotine self-administration more rapidly than adultfemales (Chen et al. 2007). In contrast, Shram et al. haveshown that at a high response ratio (five lever presses perinfusion) adolescent male rats self-administer less nicotinethan adults (Shram et al. 2007b). The adolescent rats in thisstudy also exhibited less motivation to seek the drug undera progressive ratio schedule and were less resistant toextinction when saline was substituted for nicotine. Takentogether, these studies suggest that adolescents might bemore likely to engage in high levels of initial intake but areless likely to exhibit nicotine dependence-like behavior. SeeTable 1.

For ethanol, there are a number of studies comparingvoluntary drinking in adolescent vs. adult rodents. There issome evidence that adolescent rats consume more ethanol(Doremus et al. 2005; Brunell and Spear 2005; Vetter et al.2007), but this is not evident in all studies (Siegmund et al.2005; Bell et al. 2006; Truxell et al. 2007) or in mice(Tambour et al. 2008). Two studies examined the effect ofage on relapse and found that adolescent-onset drinkers aremore susceptible to stress-induced reinstatement of drinkingwhen examined in adulthood after long-term drinking(Siegmund et al. 2005; Fullgrabe et al. 2007), dependingon the stressor used (Siegmund et al. 2005). Unlikenicotine, ethanol may induce more dependence-like behav-iors in adolescent rats, regardless of the level of intake. SeeTable 1.

Most studies have observed no differences betweenadolescents and adults in levels of cocaine self-administration (Leslie et al. 2004; Belluzzi et al. 2005;Kantak et al. 2007; Kerstetter and Kantak 2007; Frantz etal. 2007). However, one study revealed that age differencesmay be dependent on genetics. Perry et al. (2007) observed


that adolescent rats bred for low saccharin intake acquiredself-administration faster than adults bred for low saccharinintake. In contrast, adolescents and adults bred for highsaccharin intake self-administered cocaine at equivalentrates. At this point, the evidence suggests that cocaine is notself-administered at higher levels by adolescents than adultsbut that genetic differences may interact with age todetermine the level of cocaine self-administration. SeeTable 1. Preliminary studies from our laboratory suggestthat progressive ratio, extinction, and reinstatement ofcocaine seeking do not differ between adolescent and adultrats.

These conflicting reports on the self-administration ofcocaine, nicotine, and ethanol suggest that the level ofvoluntary intake of these drugs is not consistently agedependent. Depending on the drug examined, adolescentsmay be more (ethanol) or less (nicotine, cocaine) suscep-tible to dependence-like behaviors. Detailed studies ofdependence-like self-administration behavior are key tounderstanding whether adolescents progress faster tocompulsive patterns of drug intake. Future work shouldplace a greater emphasis on progressive ratio, LgA,resistance to extinction, and punished or compulsive drugseeking. Such techniques have the potential to revealwhether adolescents are more prone to addiction-likebehavior, distinct from their propensity for drug taking.

Withdrawal

Withdrawal is a constellation of behavioral and physiolog-ical changes that occur after cessation of intake of manyabused drugs. As described above, it is characterized byphysiological (diarrhea, seizures, etc.) and psychologicalresponses (anxiety, dysphoria, craving, etc.) which caninclude both drug-specific responses and behaviors whichmay reflect a “core” aversive response (Koob 2009). Theeffect of withdrawal on subsequent drug taking and theprogression to SUDs varies with the duration of drug intakeand the experience of the user. After a single episode ofdrug taking, withdrawal can either reduce or increase futureuse. A bad hangover causes some people to avoid alcoholtemporarily (Prat et al. 2008), but people who consistentlyhave more severe hangovers and drink to alleviate hangoversymptoms are more likely to progress to alcohol depen-dence (Earleywine 1993a, b). After repeated intake of manydifferent drugs of abuse, symptoms such as negative affect,elevated reward threshold, and craving perpetuate contin-ued drug taking (Koob 1996; Koob and Le Moal 1997).Several studies suggest that adolescent rodents experiencereduced withdrawal symptoms for nicotine and ethanolcompared to adults, as summarized below. Withdrawalfrom cocaine, amphetamine, and THC has not beencompared in adolescent vs. adult rodents.

Many symptoms of nicotine withdrawal are reduced inadolescent rats, such as withdrawal-associated conditionedplace aversion (O’Dell et al. 2007b), anxiety-like behavior(Wilmouth and Spear 2006; but see Kota et al. 2007), anddecrements in reward (O’Dell et al. 2006). Adolescents alsoshow fewer somatic symptoms of nicotine withdrawal(O’Dell et al. 2006; Kota et al. 2007). See Table 1.

Most ethanol withdrawal symptoms are also reduced inadolescent compared to adult rodents. These includewithdrawal-induced social inhibition (Varlinskaya andSpear 2004a, b), anxiety-like behavior (Doremus et al.2003), and seizures (Acheson et al. 1999). In contrast, atleast two measures of withdrawal, cortical electroencepha-logram activity (Slawecki et al. 2006), and hypothermia(Ristuccia and Spear 2005) are more pronounced inadolescents if ethanol is delivered by vapor inhalation. SeeTable 1.

It is difficult to infer from these data how the effectswould generalize to human drug taking. The relativeabsence of withdrawal signs after prolonged exposurewould be expected to slow the progression to compulsiveuse. In contrast, the absence of withdrawal symptoms afterinitial experimentation might motivate increased use due tothe perception that the drug is not harmful.

Cognitive effects

There are many effects of drugs that could have a strongrelationship to their abuse potential which have not yetbeen fully explored. For example, addicts are known tohave cognitive impairments which affect their success indrug treatment (Volkow and Fowler 2000; Kalivas andVolkow 2005; Moghaddam and Homayoun 2008). It iscurrently unclear whether the cognitive impairments pre-cede or result from drug taking. In addition, clinical datasuggest that executive function may be impaired in bothadolescents and drug addicts, facilitating the appearance ofthe link between the two (Chambers et al. 2003; Volkow etal. 2007; Beveridge et al. 2008; Pattij et al. 2008). Some ofthese effects have been examined in adolescent vs. adultrodents, which we will now summarize.

Learning and memory

Drugs of abuse can affect learning and memory acutely andcould also cause persistent effects which are evident in thedrug-free state. This impairment is important for severalreasons which may differentially affect adolescents andadults. First, while people are under the influence ofdepressants such as alcohol and THC, their reaction timeand judgment can be impaired (DSM-IV 1994), whichcould place the individual and others in their vicinity indanger. In contrast, stimulants such as nicotine and


amphetamine can acutely enhance memory (Martinez et al.1980; Provost and Woodward 1991; Levin 1992; Soetens etal. 1993, 1995; Le Houezec et al. 1994; Lee and Ma 1995;Levin and Simon 1998). After long-term use, addictivedrugs may diminish cognitive ability, making recovery andtreatment efforts more difficult (although it is also possiblethat people with preexisting diminished cognitive abilitymight be the most difficult to treat; Aharonovich et al.2006; Teichner et al. 2001). Several studies in rodents havecompared adolescents and adults in cognitive tasks, bothacutely and after long-term exposure and abstinence.Acutely, the depressant drugs seem to impair adolescentsmore than adults. After long-term exposure, the effect ofage of onset is drug and task specific.

Acute intoxication with ethanol or THC impairs spatiallearning in the Morris Water Maze to a greater extent inadolescents (Acheson et al. 1998, 2001; Cha et al. 2006,2007; Markwiese et al. 1998; Obernier et al. 2002; Sircarand Sircar 2005; White et al. 2000; White and Swartzwelder2005; but see Rajendran and Spear 2004). Adolescents arealso more impaired than adults by ethanol in appetitivelymotivated odor discrimination (Land and Spear 2004). Long-term impairment also seems to be greater after adolescentpreexposure than adult preexposure. One study showed thatimpairment induced by ethanol persisted in adolescents butnot adults for up to 25 days following cessation of ethanolexposure (Sircar and Sircar 2005). Similarly, performance inobject recognition is more impaired after adolescent pre-exposure to THC (Quinn et al. 2008) and syntheticcannabinoids (Schneider and Koch 2003; O’Shea et al.2004) than adult preexposure. There is one contrasting studyshowing that the impairments caused by THC in spatiallearning dissipate upon 4 weeks of abstinence in both ages(Cha et al. 2007).

Long-term effects of adolescent exposure have beenexamined in response to some psychostimulants. Afterextended cocaine self-administration and abstinence,amygdala-dependent learning is impaired to a lesser extentin adolescent-onset than adult-onset rats (Kerstetter andKantak 2007), suggesting that adolescents may be protectedfrom some long-term cognitive effects. In a separate study,administration of cocaine in early adolescence produceddeficits in Morris Water Maze learning which were reversedupon long-term cocaine abstinence (Santucci et al. 2004).This study did not, however, compare the effects of adultexposure. In contrast, neurotoxic doses of methamphet-amine produce small but long-lasting deficits in spatiallearning in both the Morris Water Maze and CincinnatiWater Maze if administered between 41 and 50 days of age(late adolescence). Administration at 51–60 days had noeffect (Vorhees et al. 2005).

In summary, the depressant drugs ethanol and THCacutely impair adolescents more than adults. This may

affect decision making while users are under the influenceof the drugs. Studies of the acute effects of stimulants oncognitive ability would be informative. Long-lasting effectsseem to be drug specific: persistent effects of alcohol, THC,and neurotoxic doses of methamphetamine have beendescribed, although there are conflicting reports. Thesestudies raise the concern that long-lasting cognitive impair-ment from adolescent drug exposure, particularly depres-sants, could raise vulnerability to future drug use.

Impulsivity and executive function

SUDs are often conceptualized as a failure of impulsecontrol or executive function: addicts fail to control theimpulse to take drugs despite adverse consequences. Theyalso fail to plan ahead and make decisions in their bestinterests (Kalivas and Volkow 2005). The loss of executivecontrol in addiction is thought to result from reducedglutamatergic drive from the prefrontal cortex to thenucleus accumbens in response to natural rewards and anexcess drive in response to drug-associated stimuli (Kalivasand Volkow 2005). Adolescents are known to have reducedactivity of the “supervisory system,” the prefrontal cortex(Ernst et al. 2006), and adolescent humans have immatureprefrontal cortical circuitry (Lenroot and Giedd 2006). Inthis sense, adolescents may have deficient executivefunction, even without drug exposure. THC has beenshown to impair executive functioning (Egerton et al.2005, 2006) in tasks dependent upon the prefrontal cortex(McAlonan and Brown 2003), but no experiments pub-lished to date have examined whether this effect is agespecific.

Impulsivity is a complex concept, and most researchersdivide it into multiple domains (Evenden 1999). In rodents,impulsivity is most often modeled using three types oftasks. First, delay discounting procedures require the animalto choose between a small immediate reinforcer and a largerdelayed one. In such models, cocaine and amphetamineincrease impulsive choice (Paine et al. 2003; Helms et al.2006; Roesch et al. 2007), and rats bred for high alcoholconsumption tend to exhibit greater impulsivity (Wilhelmand Mitchell 2008). Adolescents are more impulsive insuch tasks at baseline (Adriani and Laviola 2003). Nicotineexposure during adolescence does not adversely affect per-formance in this task when tested in adulthood (Counotte etal. 2009). Another aspect of impulsivity is modeled by thefixed consecutive number (FCN) task and Go/No-go task.These tasks assess the ability to inhibit an improperresponse while performing an appropriate one. Ethanoland amphetamine increase impulsivity in the FCN task(Evenden and Ko 2005; Bardo et al. 2006). Cocaine doesnot influence behavior in the Go/No-go task (Paine et al.2003). Mice bred for high alcohol consumption exhibit


greater impulsivity in the Go/No-go task (Wilhelm et al.2007). A third type of impulsivity is modeled in thedifferential reinforcement of low rates of responding (DRL)task. It models the ability to wait before seeking reinforce-ment. Cocaine (Wenger and Wright 1990; Cheng et al.2006), amphetamine (Wenger and Wright 1990), andethanol (Popke et al. 2000; Arizzi et al. 2003) increaseimpulsivity in the DRL task. The effect of adolescence onthe response to drugs in all of these tasks is a critical areafor future study, as developmental stage itself may be asignificant vulnerability in this domain.

Role of pharmacokinetics in behavioral measures

Several pharmacokinetic properties of drugs of abuse couldcontribute to development of dependence. The rates ofappearance and clearance of the drug in the brain (and at itsmolecular targets), the peak concentration, and the durationof exposure can affect the addictive effects of drugs (Sellerset al. 1989; de Wit et al. 1992; Gossop et al. 1992).Euphorigenic effects of drugs are enhanced by rapidaccumulation in brain (de Wit et al. 1992; Abreu et al.2001; Nelson et al. 2006). Although less studied, theaversive, reinforcing, and cognitive effects of drugs ofabuse could be similarly affected by these pharmacokineticvariables. Rate of drug delivery is determined by the drugitself, the formulation, and the chosen route of administra-tion. Studies comparing adult and adolescent pharmacoki-netics of common drugs of abuse are sparse and not yetcomprehensive with respect to dose, route of administra-tion, and timing. The most informative studies haveexamined behavioral effects and pharmacokinetics inparallel and generally demonstrated that age differences inbehavior are not related to varying drug levels.

Nicotine and its metabolite, cotinine, which may also bebiologically active (Terry et al. 2005), are metabolizedfaster in adolescent than in adult rats (Slotkin 2002).However, in two studies in which nicotine dosing wasadjusted to achieve comparable plasma levels, adolescentsstill exhibited reduced signs of withdrawal (O’Dell et al.2006, b). Ethanol seems to enter the brain and blood atsimilar rates and extents in adolescents and adults (over arange of 5–30 min; Varlinskaya and Spear 2006) but it iscleared more rapidly from adolescent than from adultrodents, over a range of 2–18 h (Doremus et al. 2003).However, differences in sedation are not attributable to thedifference in clearance. Little et al. (1996) showed thatadolescent rats lose their righting reflex for a shorterduration than adults but, upon awakening, have higherblood alcohol levels. Similarly, age differences in locomo-tor sensitization to ethanol are independent of blood alcohollevels (Stevenson et al. 2008). Methamphetamine stimulates

locomotor activity to a lesser extent in adolescent than adultmice despite achieving comparable brain concentration(Zombeck et al. 2009). For cocaine, one group hasobserved that adolescent mice have lower levels in bloodand brain at 15 min postinjection than adults (McCarthy etal. 2004). In contrast, another group has shown higherlevels at 5 min (Zombeck et al. 2009) despite observingreduced locomotor stimulation. Our group has measuredequivalent levels in brain tissue and lower levels in blood inadolescents compared to adults despite the fact that weobserved increased locomotor responses in adolescent rats(Caster et al. 2005). In summary, there are reports ofdiffering pharmacokinetic profiles in adolescent vs. adultrodents, but they do not account for age-related behavioraldifferences.

Neurobiological considerations

The behavioral studies summarized above point to theconclusion that adolescents may tolerate higher and morefrequent drug exposures, but there are not yet enough datato show whether they are more likely to develop compul-sive patterns of drug taking and dependence-like behavior.Additional studies with more comprehensive models ofdrug dependence are necessary to confirm or refute thisspeculation. In addition, an understanding of the molecularand neurophysiological basis of drug dependence is key todetermining whether the process happens more rapidly orextensively in adolescents. A large body of research isaimed at understanding the physiological basis of drugdependence. These findings have been extensivelyreviewed elsewhere (Robinson and Berridge 1993; 2000;Nestler 1994; Fitzgerald and Nestler 1995; Nestler et al.1996; Volkow and Fowler 2000; Koob and Le Moal 2001;Hyman and Malenka 2001; Shalev et al. 2002; Winder et al.2002; Goldstein and Volkow 2002; Kalivas and Volkow2005; Yuferov et al. 2005; Grueter et al. 2007; Kalivas andO’Brien 2008). They provide a framework for evaluatingmolecular and neurophysiologic mechanisms that mightmediate substance abuse vulnerability in adolescents.

Several studies have tested whether there are molecularand physiological differences between adolescents andadults that might underlie differential vulnerability to drugdependence (see (Schepis et al. 2008) for review). Ingeneral, molecular and physiological studies have revealedmechanisms that could be related to age differences insensitivity to drug reward, but evidence about neuroplasticevents related to the transition to compulsive drug use doesnot yet exist. The initial rewarding effects of drugs of abuseare dependent upon dopaminergic signaling. Adolescentshave rapidly maturing dopaminergic neurocircuitry in theareas related to drug reward, in terms of presynaptic and


postsynaptic function such as dopamine transporter andreceptor expression (Seeman et al. 1987; Palacios et al.1988; Teicher et al. 1995; Tarazi et al. 1998a, b, 1999;Meng et al. 1999; Montague et al. 1999; Andersen et al.2002; Andersen 2003, 2005) and dopamine content in braintissue (Andersen 2003, 2005). These studies have shownthat innervation of the forebrain continues through adoles-cence, with levels of terminal markers such as dopaminecontent, transporters, and synthetic enzymes reaching apeak in late adolescence. Postsynaptic receptor numberpeaks and then declines to adult levels as innervationbecomes complete. Most studies show that basal levels ofsynaptic dopamine are lower during this phase of develop-ment (Andersen and Gazzara 1993; Badanich et al. 2006;Laviola et al. 2001; but see Camarini et al. 2008; Cao et al.2007b; Frantz et al. 2007) which is consistent withincomplete innervation. Adolescents also differ from adultsin the amount of dopamine released in response toamphetamine and cocaine: the percentage change inextracellular dopamine level is greater in adolescents thanadults (Laviola et al. 2001; Walker and Kuhn 2008; but seeBadanich et al. 2006; Frantz et al. 2007), and the rate ofincrease may be faster in adolescents (Badanich et al. 2006;Camarini et al. 2008). In these studies, one criticaldeterminant of the experimental results is the age at whichthe experiment was conducted: dopamine systems in earlyadolescence (day 28) are very different from those in lateadolescence (day 42) and at the beginning of adulthood(day 60).

These neurobiologic differences between adolescentsand adults are often not concordant with behavioralmeasures. For example, psychostimulant sensitization isreduced in adolescents despite greater increases in dopa-mine (Laviola et al. 2001; Frantz et al. 2007), whileconditioned place preference is greater in adolescentsdespite comparable increases in dopamine (Badanich et al.2006). One study that did observe concordance betweendopamine release and intravenous self-administrationreported no age difference in either measure (Frantz et al.2007).

Similarly inconclusive findings have also been reportedregarding the molecular and physiological responses toprolonged drug taking. Prolonged exposure leads to adecrease in the induction of immediate early genes (such asc-fos), upregulation of other genes, and the accumulation oflong-lived proteins like delta Fos B, which persist for daysor weeks (Kalivas and O’Brien 2008). These changesaccompany and may mediate synaptic rearrangement incortical circuitry and dysregulated glutamatergic signalingwhich are thought to underlie pathological drug seeking. Afew studies have examined induction of c-fos in response todrugs of abuse in adolescents vs. adults, and the results arehighly variable and dependent upon the brain region

examined, stimulant used, and dose. Shram et al. observedthat after low-dose (0.4 mg/kg) but not high-dose (0.8 mg/kg)nicotine, adolescents expressed greater c-fos in the medialnucleus accumbens shell (Shram et al. 2007a). Similar dosespecificity of age effects has been reported for cocaine.Three studies have shown that adults generate more c-fosexpression than adolescents in a few striatal subregions afterhigh-dose (30–40 mg/kg) cocaine (Kosofsky et al. 1995;Cao et al. 2007b; Caster and Kuhn 2009). In contrast,adolescents have greater responses throughout the dorsalstriatum and medial shell of the nucleus accumbens inresponse to lower-dose cocaine (10 mg/kg; Caster and Kuhn2009). In many brain regions, however, fos induction issimilar between the two ages (for nicotine amygdala, locuscoeruleus, lateral septum, superior colliculus (Cao et al.2007a; Shram et al. 2007a) and for cocaine bed nucleus ofthe stria terminalis (Cao et al. 2007b), cortex, and cerebellum(Kosofsky et al. 1995)). The stable protein product of the fosgene, delta Fos B, is also regulated in a drug- and region-specific manner. Upon treatment with nicotine, one grouphas reported no age effect (Soderstrom et al. 2007). Aftercocaine or amphetamine, adolescents express more delta FosB in the nucleus accumbens and caudate putamen (Ehrlich etal. 2002). In general, the current studies are inconclusiveabout whether the molecular changes thought to beimportant for the transition to compulsive drug taking areexaggerated in adolescents.

The long-term behavioral effects of repeated drug takingare likely mediated by altered synaptic efficacy broughtabout by structural and biochemical mechanisms. Dendriticarbors in the nucleus accumbens and prefrontal cortex arealtered after long-term cocaine and amphetamine exposure(Robinson and Kolb 2004), but these alterations have notyet been compared in adolescents vs. adults. After exposureto nicotine, dendritic length is differentially affected inadolescent vs. adult rats in the prelimbic cortex (Bergstromet al. 2008) and nucleus accumbens (McDonald et al.2007). The functional significance of these differencesremains to be elucidated.

Electrophysiological responses can also be altered bydrugs of abuse. For example, studies in adult rodents haveshown that repeated self-administration or experimenteradministration of cocaine reduces glutamatergic synapticstrength in the nucleus accumbens (Thomas et al. 2001;Schramm-Sapyta et al. 2005) and reduces long-termdepression in the bed nucleus of the stria terminalis(Grueter et al. 2006). These alterations parallel alteredexpression levels of α-amino-3-hydroxyl-5-methyl-4-iso-xazole-propionate and N-methyl-D-aspartic acid receptors(Lu et al. 1997, 1999; Lu and Wolf 1999). Adolescent ratsare generally more susceptible to plasticity in the nucleusaccumbens (Schramm et al. 2002) and in many other brainregions (Kirkwood et al. 1995; Izumi and Zorumski 1995;


Crair and Malenka 1995; Liao and Malinow 1996;Partridge et al. 2000) in response to electrical stimulationand could therefore be more susceptible to the effects ofcocaine. The electrophysiological response of this circuit todrugs of abuse presents a potential mechanism forenhancing adolescent susceptibility to SUD but has notbeen directly compared in adolescent vs. adult animals.Many other potential mechanisms remain unexplored inadolescents vs. adults at this time, such as glutamatereceptor expression (Lu et al. 1999; Lu and Wolf 1999)and chromatin remodeling (Kumar et al. 2005). If behav-ioral studies conclusively reveal that adolescent onset iscausal in the progression to compulsive drug seeking, thenthese mechanisms should be explored.

Future studies should focus on linking molecular andphysiological studies with relevant behavioral models toaddress which molecular alterations are most relevant todrug dependence and asking whether the currently identi-fied differences between adolescents and adults might causedifferences in behaviors related to SUD.

Summary

In this review, we have addressed the question of whetheradolescents are more vulnerable to drug addiction thanadults by summarizing results from animal studies. Thesestudies suggest four conclusions:

1. The balance of rewarding vs. aversive effects of drugsof abuse is tipped toward reward in adolescents, asshown in place preference, place aversion, and tasteaversion studies. This could increase consumption ofdrugs of abuse by adolescents.

2. Adolescents are consistently less sensitive to withdraw-al effects. This could both promote drug use in earlystages and protect against development of compulsivedrug seeking after long-term use.

3. Adolescents are not consistently more sensitive toreinforcing or locomotor effects of drugs of abuse asshown in self-administration and sensitization studies.

4. Adolescents are undergoing changes in neuronalstructure and function in brain areas related to rewardand habit formation, which could influence suscepti-bility to drug dependence, although studies demon-strating causality are currently lacking.

These studies suggest that adolescents experience adifferent “balance” of rewarding and aversive effects ofdrugs of abuse. This balance could represent a potentialvulnerability for increased experimentation. However, onecritical element is missing in our ability to evaluate the riskof adolescent vulnerability to SUD. There are few dataabout the progression to compulsive drug seeking, the

hallmark of drug dependence. It is imperative to more fullyexplore animal models of the progression to drug depen-dence to address whether adolescents develop compulsiveuse more frequently or rapidly than adults and whetheradolescents are more or less resistant to extinction andreinstatement of drug taking. Second, more studies of theeffects of adolescent exposure on cognitive function,particularly related to executive control, are warranted.Third, studies of molecular alterations in response to drugsof abuse in adolescents vs. adults are incomplete andinconclusive. As animal models of the progression toaddiction become better understood and developed, molec-ular alterations underlying this transition can be explored ingreater depth and the functional implications of theseeffects can be determined.

Finally, a key direction for future research is theintersection between age-related and individual differences.Human studies (Dawes et al. 2000) and some animalstudies (Barr et al. 2004; Perry et al. 2007) suggest thatgenetics, environment, and psychopathology contribute toearly drug taking and development of addiction. A betterunderstanding of this relationship will greatly benefitprevention and treatment efforts: when we can determinewho is most likely to become addicted and why, then wecan prevent and treat drug problems in those individualsmost successfully, regardless of when they initiate drug use.

References

Aberg M, Wade D, Wall E, Izenwasser S (2007) Effect of MDMA(ecstasy) on activity and cocaine conditioned place preference inadult and adolescent rats. Neurotoxicol Teratol 29:37–46

Abraham HD, Fava M (1999) Order of onset of substance abuse anddepression in a sample of depressed outpatients. ComprPsychiatry 40:44–50

Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect ofintravenous injection speed on responses to cocaine and hydro-morphone in humans. Psychopharmacology (Berl) 154:76–84

Acheson SK, Stein RM, Swartzwelder HS (1998) Impairment ofsemantic and figural memory by acute ethanol: age-dependenteffects. Alcohol Clin Exp Res 22:1437–1442

Acheson SK, Richardson R, Swartzwelder HS (1999) Developmentalchanges in seizure susceptibility during ethanol withdrawal.Alcohol 18:23–26

Acheson SK, Ross EL, Swartzwelder HS (2001) Age-independent anddose-response effects of ethanol on spatial memory in rats.Alcohol 23:167–175

Adriani W, Laviola G (2003) Elevated levels of impulsivity andreduced place conditioning with d-amphetamine: two behavioralfeatures of adolescence in mice. Behav Neurosci 117:695–703

Adriani W, Chiarotti F, Laviola G (1998) Elevated novelty seekingand peculiar d-amphetamine sensitization in periadolescent micecompared with adult mice. Behav Neurosci 112:1152–1166

Adriani W, Deroche-Gamonet V, Le Moal M, Laviola G, Piazza PV(2006) Preexposure during or following adolescence differentlyaffects nicotine-rewarding properties in adult rats. Psychophar-macology (Berl) 184:382–390


Aharonovich E, Hasin DS, Brooks AC, Liu X, Bisaga A, Nunes EV(2006) Cognitive deficits predict low treatment retention incocaine dependent patients. Drug Alcohol Depend 81:313–322

Aizenstein ML, Segal DS, Kuczenski R (1990) Repeated amphet-amine and fencamfamine: sensitization and reciprocal cross-sensitization. Neuropsychopharmacology 3:283–290

American Psychiatric Association (1994) Diagnostic and statisticalmanual for mental disorders (DSM-IV). American PsychiatricAssociation, Philadelphia

Andersen SL (2003) Trajectories of brain development: point ofvulnerability or window of opportunity? Neurosci Biobehav Rev27:3–18

Andersen SL (2005) Stimulants and the developing brain. TrendsPharmacol Sci 26:237–243

Andersen SL, Gazzara RA (1993) The ontogeny of apomorphine-induced alterations of neostriatal dopamine release: effects onspontaneous release. J Neurochem 61:2247–2255

Andersen SL, Teicher MH (2000) Sex differences in dopaminereceptors and their relevance to ADHD. Neurosci BiobehavRev 24:137–141

Andersen SL, Thompson AP, Krenzel E, Teicher MH (2002) Pubertalchanges in gonadal hormones do not underlie adolescentdopamine receptor overproduction. Psychoneuroendocrinology27:683–691

Arizzi MN, Correa M, Betz AJ, Wisniecki A, Salamone JD(2003) Behavioral effects of intraventricular injections of lowdoses of ethanol, acetaldehyde, and acetate in rats: studieswith low and high rate operant schedules. Behav Brain Res147:203–210

Babbini M, Davis WM (1972) Time–dose relationships for locomotoractivity effects of morphine after acute or repeated treatment. Br JPharmacol 46:213–224

Badanich KA, Adler KJ, Kirstein CL (2006) Adolescents differ fromadults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi. Eur JPharmacol 550:95–106

Balda MA, Anderson KL, Itzhak Y (2006) Adolescent and adultresponsiveness to the incentive value of cocaine reward in mice:role of neuronal nitric oxide synthase (nNOS) gene. Neurophar-macology 51:341–349

Bardo MT, Bevins RA (2000) Conditioned place preference: whatdoes it add to our preclinical understanding of drug reward?Psychopharmacology (Berl) 153:31–43

Bardo MT, Cain ME, Bylica KE (2006) Effect of amphetamine onresponse inhibition in rats showing high or low response tonovelty. Pharmacol Biochem Behav 85:98–104

Barr CS, Schwandt ML, Newman TK, Higley JD (2004) The use ofadolescent nonhuman primates to model human alcohol intake:neurobiological, genetic, and psychological variables. Ann N YAcad Sci 1021:221–233

Bell RL, Rodd ZA, Sable HJ, Schultz JA, Hsu CC, Lumeng L,Murphy JM, McBride WJ (2006) Daily patterns of ethanoldrinking in peri-adolescent and adult alcohol-preferring (P) rats.Pharmacol Biochem Behav 83:35–46

Belluzzi JD, Lee AG, Oliff HS, Leslie FM (2004) Age-dependenteffects of nicotine on locomotor activity and conditioned placepreference in rats. Psychopharmacology (Berl) 174:389–395

Belluzzi JD, Wang R, Leslie FM (2005) Acetaldehyde enhancesacquisition of nicotine self-administration in adolescent rats.Neuropsychopharmacology 30:705–712

Bergstrom HC, McDonald CG, French HT, Smith RF (2008)Continuous nicotine administration produces selective, age-dependent structural alteration of pyramidal neurons fromprelimbic cortex. Synapse 62:31–39

Beveridge TJ, Gill KE, Hanlon CA, Porrino LJ (2008) Review.Parallel studies of cocaine-related neural and cognitive impair-

ment in humans and monkeys. Philos Trans R Soc Lond B BiolSci 363:3257–3266

Bolanos CA, Glatt SJ, Jackson D (1998) Subsensitivity to dopami-nergic drugs in periadolescent rats: a behavioral and neurochem-ical analysis. Brain Res Dev Brain Res 111:25–33

Brenhouse HC, Andersen SL (2008) Delayed extinction and strongerreinstatement of cocaine conditioned place preference in adoles-cent rats, compared to adults. Behav Neurosci 122:460–465

Brenhouse HC, Sonntag KC, Andersen SL (2008) Transient D1dopamine receptor expression on prefrontal cortex projectionneurons: relationship to enhanced motivational salience of drugcues in adolescence. J Neurosci 28:2375–2382

Brielmaier JM, McDonald CG, Smith RF (2007) Immediate and long-term behavioral effects of a single nicotine injection in adolescentand adult rats. Neurotoxicol Teratol 29:74–80

Brown TL, Flory K, Lynam DR, Leukefeld C, Clayton RR (2004)Comparing the developmental trajectories of marijuana use ofAfrican American and Caucasian adolescents: patterns, antece-dents, and consequences. Exp Clin Psychopharmacol 12:47–56

Brunell SC, Spear LP (2005) Effect of stress on the voluntary intakeof a sweetened ethanol solution in pair-housed adolescent andadult rats. Alcohol Clin Exp Res 29:1641–1653

Burke JD Jr, Burke KC, Rae DS (1994) Increased rates of drug abuseand dependence after onset of mood or anxiety disorders inadolescence. Hosp Community Psychiatry 45:451–455

Buxbaum DM, Yarbrough GG, Carter ME (1973) Biogenic aminesand narcotic effects. I. Modification of morphine-inducedanalgesia and motor activity after alteration of cerebral aminelevels. J Pharmacol Exp Ther 185:317–327

Camarini R, Griffin WC 3rd, Yanke AB, Rosalina dos Santos B, OliveMF (2008) Effects of adolescent exposure to cocaine onlocomotor activity and extracellular dopamine and glutamatelevels in nucleus accumbens of DBA/2J mice. Brain Res1193:34–42

Campbell JO, Wood RD, Spear LP (2000) Cocaine and morphine-induced place conditioning in adolescent and adult rats. PhysiolBehav 68:487–493

Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, Leslie FM(2007a) Acetaldehyde, a major constituent of tobacco smoke,enhances behavioral, endocrine, and neuronal responses tonicotine in adolescent and adult rats. Neuropsychopharmacology32:2025–2035

Cao J, Lotfipour S, Loughlin SE, Leslie FM (2007b) Adolescentmaturation of cocaine-sensitive neural mechanisms. Neuropsy-chopharmacology 32:2279–2289

Carr GD, Fibiger HC, Phillips AC (1989) Conditioned placepreference as a measure of drug reward. In: Liebman JM, CooperSJ (eds) The neuropharmacological basis of reward. Clarendon,Oxford, pp 264–319

Caster JM, Kuhn CM (2009) Maturation of coordinated immediateearly gene expression by cocaine during adolescence. Neurosci-ence 160:13–31

Caster JM, Walker QD, Kuhn CM (2005) Enhanced behavioralresponse to repeated-dose cocaine in adolescent rats. Psycho-pharmacology (Berl) 183:218–225

Caster JM, Walker QD, Kuhn CM (2007) A single high dose ofcocaine induces differential sensitization to specific behaviorsacross adolescence. Psychopharmacology (Berl) 193:247–260

Cha YM, White AM, Kuhn CM, Wilson WA, Swartzwelder HS(2006) Differential effects of delta9-THC on learning inadolescent and adult rats. Pharmacol Biochem Behav 83:448–455

Cha YM, Jones KH, Kuhn CM, Wilson WA, Swartzwelder HS (2007)Sex differences in the effects of delta9-tetrahydrocannabinol onspatial learning in adolescent and adult rats. Behav Pharmacol18:563–569


Chambers RA, Taylor JR, Potenza MN (2003) Developmentalneurocircuitry of motivation in adolescence: a critical period ofaddiction vulnerability. Am J Psychiatry 160:1041–1052

Chen K, Kandel DB (1995) The natural history of drug use fromadolescence to the mid-thirties in a general population sample.Am J Public Health 85:41–47

Chen K, Kandel DB, Davies M (1997) Relationships betweenfrequency and quantity of marijuana use and last year proxydependence among adolescents and adults in the United States.Drug Alcohol Depend 46:53–67

Chen H, Matta SG, Sharp BM (2007) Acquisition of nicotine self-administration in adolescent rats given prolonged access to thedrug. Neuropsychopharmacology 32:700–709

Cheng RK, MacDonald CJ, Meck WH (2006) Differential effects ofcocaine and ketamine on time estimation: implications forneurobiological models of interval timing. Pharmacol BiochemBehav 85:114–122

Collins SL, Izenwasser S (2002) Cocaine differentially alters behaviorand neurochemistry in periadolescent versus adult rats. Brain ResDev Brain Res 138:27–34

Collins SL, Izenwasser S (2004) Chronic nicotine differentially alterscocaine-induced locomotor activity in adolescent vs. adult maleand female rats. Neuropharmacology 46:349–362

Collins SL, Montano R, Izenwasser S (2004) Nicotine treatmentproduces persistent increases in amphetamine-stimulated loco-motor activity in periadolescent male but not female or adultmale rats. Brain Res Dev Brain Res 153:175–187

Compton WM 3rd, Cottler LB, Phelps DL, Ben Abdallah A,Spitznagel EL (2000) Psychiatric disorders among drug depen-dent subjects: are they primary or secondary? Am J Addict9:126–134

Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A (2003)Prevalence and development of psychiatric disorders in child-hood and adolescence. Arch Gen Psychiatry 60:837–844

Counotte DS, Spijker S, Van de Burgwal LH, Hogenboom F,Schoffelmeer AN, De Vries TJ, Smit AB, Pattij T (2009) Long-lasting cognitive deficits resulting from adolescent nicotineexposure in rats. Neuropsychopharmacology 34:299–306

Crair MC, Malenka RC (1995) A critical period for long-termpotentiation at thalamocortical synapses. Nature 375:325–328

Cruz FC, Delucia R, Planeta CS (2005) Differential behavioral andneuroendocrine effects of repeated nicotine in adolescent andadult rats. Pharmacol Biochem Behav 80:411–417

Cunningham MG, Bhattacharyya S, Benes FM (2002) Amygdalo-cortical sprouting continues into early adulthood: implications forthe development of normal and abnormal function duringadolescence. J Comp Neurol 453:116–130

Cunningham MG, Bhattacharyya S, Benes FM (2008) IncreasingInteraction of amygdalar afferents with GABAergic interneur-ons between birth and adulthood. Cereb Cortex 18:1529–1535

Dawes MA, Antelman SM, Vanyukov MM, Giancola P, Tarter RE,Susman EJ, Mezzich A, Clark DB (2000) Developmental sourcesof variation in liability to adolescent substance use disorders.Drug Alcohol Depend 61:3–14

de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforcedresponding in the rat. Psychopharmacology (Berl) 75:134–143

de Wit H, Bodker B, Ambre J (1992) Rate of increase of plasma druglevel influences subjective response in humans. Psychopharma-cology (Berl) 107:352–358

Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW (1993)Parameters of self-administration of cocaine in rats under aprogressive-ratio schedule. Pharmacol Biochem Behav 45:539–548

Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence foraddiction-like behavior in the rat. Science 305:1014–1017

DeWit DJ, Hance J, Offord DR, Ogborne A (2000) The influence ofearly and frequent use of marijuana on the risk of desistance andof progression to marijuana-related harm. Prev Med 31:455–464

Deykin EY, Levy JC, Wells V (1987) Adolescent depression, alcoholand drug abuse. Am J Public Health 77:178–182

Di Chiara G (1995) The role of dopamine in drug abuse viewed fromthe perspective of its role in motivation. Drug Alcohol Depend38:95–137

Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxio-genic effects during withdrawal from acute ethanol in adolescentand adult rats. Pharmacol Biochem Behav 75:411–418

Doremus TL, Brunell SC, Rajendran P, Spear LP (2005) Factorsinfluencing elevated ethanol consumption in adolescent relativeto adult rats. Alcohol Clin Exp Res 29:1796–1808

Earleywine M (1993a) Hangover moderates the association betweenpersonality and drinking problems. Addict Behav 18:291–297

Earleywine M (1993b) Personality risk for alcoholism covaries withhangover symptoms. Addict Behav 18:415–420

Egerton A, Bret t RR, Prat t JA (2005) Acute del ta9-tetrahydrocannabinol-induced deficits in reversal learning: neuralcorrelates of affective inflexibility. Neuropsychopharmacology30:1895–1905

Egerton A, Allison C, Brett RR, Pratt JA (2006) Cannabinoids andprefrontal cortical function: insights from preclinical studies.Neurosci Biobehav Rev 30:680–695

Ehrlich ME, Sommer J, Canas E, Unterwald EM (2002) Periadoles-cent mice show enhanced DeltaFosB upregulation in response tococaine and amphetamine. J Neurosci 22:9155–9159

Elliott BM, Faraday MM, Phillips JM, Grunberg NE (2004) Effects ofnicotine on elevated plus maze and locomotor activity in maleand female adolescent and adult rats. Pharmacol Biochem Behav77:21–28

Ernst M, Nelson EE, Jazbec S, McClure EB, Monk CS, Leibenluft E,Blair J, Pine DS (2005) Amygdala and nucleus accumbens inresponses to receipt and omission of gains in adults andadolescents. Neuroimage 25:1279–1291

Ernst M, Pine DS, Hardin M (2006) Triadic model of theneurobiology of motivated behavior in adolescence. PsycholMed 36:299–312

Eshel N, Nelson EE, Blair RJ, Pine DS, Ernst M (2007) Neuralsubstrates of choice selection in adults and adolescents: devel-opment of the ventrolateral prefrontal and anterior cingulatecortices. Neuropsychologia 45:1270–1279

Evenden JL (1999) Varieties of impulsivity. Psychopharmacology(Berl) 146:348–361

Evenden J, Ko T (2005) The psychopharmacology of impulsivebehaviour in rats VIII: effects of amphetamine, methylphenidate,and other drugs on responding maintained by a fixed consecutivenumber avoidance schedule. Psychopharmacology (Berl)180:294–305

Faraday MM, Elliott BM, Phillips JM, Grunberg NE (2003)Adolescent and adult male rats differ in sensitivity to nicotine’sactivity effects. Pharmacol Biochem Behav 74:917–931

Fitzgerald LW, Nestler EJ (1995) Molecular and cellular adaptations insignal transduction pathways following ethanol exposure. ClinNeurosci 3:165–173

Franken IH, Hendriks VM (2000) Early-onset of illicit substance useis associated with greater axis-II comorbidity, not with axis-Icomorbidity. Drug Alcohol Depend 59:305–308

Frantz KJ, O’Dell LE, Parsons LH (2007) Behavioral and neuro-chemical responses to cocaine in periadolescent and adult rats.Neuropsychopharmacology 32:625–637

Fullgrabe MW, Vengeliene V, Spanagel R (2007) Influence of age atdrinking onset on the alcohol deprivation effect and stress-induced drinking in female rats. Pharmacol Biochem Behav86:320–326


Gaiardi M, Bartoletti M, Bacchi A, Gubellini C, Costa M, Babbini M(1991) Role of repeated exposure to morphine in determining itsaffective properties: place and taste conditioning studies in rats.Psychopharmacology (Berl) 103:183–186

Gelbard HA, Teicher MH, Faedda G, Baldessarini RJ (1989) Postnataldevelopment of dopamine D1 and D2 receptor sites in ratstriatum. Brain Res Dev Brain Res 49:123–130

George O, Mandyam CD, Wee S, Koob GF (2008) Extended access tococaine self-administration produces long-lasting prefrontalcortex-dependent working memory impairments. Neuropsycho-pharmacology 33:2474–2482

Goldstein RZ, Volkow ND (2002) Drug addiction and its underlyingneurobiological basis: neuroimaging evidence for the involve-ment of the frontal cortex. Am J Psychiatry 159:1642–1652

Gossop M, Griffiths P, Powis B, Strang J (1992) Severity ofdependence and route of administration of heroin, cocaine andamphetamines. Br J Addict 87:1527–1536

Grueter BA, Gosnell HB, Olsen CM, Schramm-Sapyta NL, NekrasovaT, Landreth GE, Winder DG (2006) Extracellular-signal regulat-ed kinase 1-dependent metabotropic glutamate receptor 5-induced long-term depression in the bed nucleus of the striaterminalis is disrupted by cocaine administration. J Neurosci26:3210–3219

Grueter BA, McElligott ZA, Winder DG (2007) Group I mGluRs andlong-term depression: potential roles in addiction? Mol Neurobiol36:232–244

Haertzen CA, Kocher TR, Miyasato K (1983) Reinforcements fromthe first drug experience can predict later drug habits and/oraddiction: results with coffee, cigarettes, alcohol, barbiturates,minor and major tranquilizers, stimulants, marijuana, hallucino-gens, heroin, opiates and cocaine. Drug Alcohol Depend 11:147–165

Helms CM, Reeves JM, Mitchell SH (2006) Impact of strain and D-amphetamine on impulsivity (delay discounting) in inbred mice.Psychopharmacology (Berl) 188:144–151

Hill SY, Shen S, Lowers L, Locke J (2000) Factors predicting theonset of adolescent drinking in families at high risk fordeveloping alcoholism. Biol Psychiatry 48:265–275

Hodos W (1961) Progressive ratio as a measure of reward strength.Science 134:943–944

Hoffmann JP, Su SS (1998) Parental substance use disorder, mediatingvariables and adolescent drug use: a non-recursive model.Addiction 93:1351–1364

Hyman SE, Malenka RC (2001) Addiction and the brain: theneurobiology of compulsion and its persistence. Nat Rev Neuro-sci 2:695–703

Infurna RN, Spear LP (1979) Developmental changes inamphetamine-induced taste aversions. Pharmacol BiochemBehav 11:31–35

Izumi Y, Zorumski CF (1995) Developmental changes in long-termpotentiation in CA1 of rat hippocampal slices. Synapse 20:19–23

Jerome A, Sanberg PR (1987) The effects of nicotine on locomotorbehavior in non-tolerant rats: a multivariate assessment. Psycho-pharmacology (Berl) 93:397–400

Kalivas PW, O’Brien C (2008) Drug addiction as a pathology ofstaged neuroplasticity. Neuropsychopharmacology 33:166–180

Kalivas PW, Stewart J (1991) Dopamine transmission in the initiationand expression of drug- and stress-induced sensitization of motoractivity. Brain Res Brain Res Rev 16:223–244

Kalivas PW, Volkow ND (2005) The neural basis of addiction: apathology of motivation and choice. Am J Psychiatry 162:1403–1413

Kalivas PW, Widerlov E, Stanley D, Breese G, Prange AJ Jr (1983)Enkephalin action on the mesolimbic system: a dopamine-dependent and a dopamine-independent increase in locomotoractivity. J Pharmacol Exp Ther 227:229–237

Kantak KM, Goodrich CM, Uribe V (2007) Influence of sex, estrouscycle, and drug-onset age on cocaine self-administration in rats(Rattus norvegicus). Exp Clin Psychopharmacol 15:37–47

Kerstetter KA, Kantak KM (2007) Differential effects of self-administered cocaine in adolescent and adult rats on stimulus-reward learning. Psychopharmacology (Berl) 194:403–411

Kirkwood A, Lee HK, Bear MF (1995) Co-regulation of long-termpotentiation and experience-dependent synaptic plasticity invisual cortex by age and experience. Nature 375:328–331

Knackstedt LA, Kalivas PW (2007) Extended access to cocaineself-administration enhances drug-primed reinstatement butnot behavioral sensitization. J Pharmacol Exp Ther 322:1103–1109

Kolta MG, Scalzo FM, Ali SF, Holson RR (1990) Ontogeny of theenhanced behavioral response to amphetamine in amphetamine-pretreated rats. Psychopharmacology (Berl) 100:377–382

Koob GF (1996) Drug addiction: the yin and yang of hedonichomeostasis. Neuron 16:893–896

Koob GF (2009) Neurobiological substrates for the dark side ofcompulsivity in addiction. Neuropharmacology 56(Suppl 1):18–31

Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostaticdysregulation. Science 278:52–58

Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward,and allostasis. Neuropsychopharmacology 24:97–129

Kosofsky BE, Genova LM, Hyman SE (1995) Postnatal age definesspecificity of immediate early gene induction by cocaine indeveloping rat brain. J Comp Neurol 351:27–40

Kota D, Martin BR, Robinson SE, Damaj MI (2007) Nicotinedependence and reward differ between adolescent and adult malemice. J Pharmacol Exp Ther 322:399–407

Kreek MJ, Nielsen DA, Butelman ER, LaForge KS (2005) Geneticinfluences on impulsivity, risk taking, stress responsivity andvulnerability to drug abuse and addiction. Nat Neurosci 8:1450–1457

Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, TruongHT, Russo SJ, Laplant Q, Sasaki TS, Whistler KN, Neve RL,Self DW, Nestler EJ (2005) Chromatin remodeling is a keymechanism underlying cocaine-induced plasticity in striatum.Neuron 48:303–314

Land C, Spear NE (2004) Ethanol impairs memory of a simplediscrimination in adolescent rats at doses that leave adult memoryunaffected. Neurobiol Learn Mem 81:75–81

Lanier LP, Isaacson RL (1977) Early developmental changes in thelocomotor response to amphetamine and their relation tohippocampal function. Brain Res 126:567–575

Laviola G, Wood RD, Kuhn C, Francis R, Spear LP (1995) Cocainesensitization in periadolescent and adult rats. J Pharmacol ExpTher 275:345–357

Laviola G, Adriani W, Terranova ML, Gerra G (1999) Psychobiolog-ical risk factors for vulnerability to psychostimulants in humanadolescents and animal models. Neurosci Biobehav Rev 23:993–1010

Laviola G, Pascucci T, Pieretti S (2001) Striatal dopamine sensitiza-tion to D-amphetamine in periadolescent but not in adult rats.Pharmacol Biochem Behav 68:115–124

Le Houezec J, Halliday R, Benowitz NL, Callaway E, Naylor H,Herzig K (1994) A low dose of subcutaneous nicotine improvesinformation processing in non-smokers. Psychopharmacology(Berl) 114:628–634

Lee EH, Ma YL (1995) Amphetamine enhances memory retention andfacilitates norepinephrine release from the hippocampus in rats.Brain Res Bull 37:411–416

Lenroot RK, Giedd JN (2006) Brain development in children andadolescents: insights from anatomical magnetic resonance imag-ing. Neurosci Biobehav Rev 30:718–729


Leslie FM, Loughlin SE, Wang R, Perez L, Lotfipour S, Belluzzia JD(2004) Adolescent development of forebrain stimulant respon-siveness: insights from animal studies. Ann N Y Acad Sci1021:148–159

Levin ED (1992) Nicotinic systems and cognitive function. Psycho-pharmacology (Berl) 108:417–431

Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement incognitive function in animals. Psychopharmacology (Berl)138:217–230

Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS(2003) Adolescent-onset nicotine self-administration modeled infemale rats. Psychopharmacology (Berl) 169:141–149

Levin ED, Lawrence SS, Petro A, Horton K, Rezvani AH, Seidler FJ,Slotkin TA (2007) Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differentialnicotinic receptor correlates. Neurotoxicol Teratol 29:458–465

Lewinsohn PM, Rohde P, Brown RA (1999) Level of current and pastadolescent cigarette smoking as predictors of future substance usedisorders in young adulthood. Addiction 94:913–921

Liao D, Malinow R (1996) Deficiency in induction but not expressionof LTP in hippocampal slices from young rats. Learn Mem3:138–149

Little PJ, Kuhn CM, Wilson WA, Swartzwelder HS (1996) Differen-tial effects of ethanol in adolescent and adult rats. Alcohol ClinExp Res 20:1346–1351

Lopez M, Simpson D, White N, Randall C (2003) Age- and sex-related differences in alcohol and nicotine effects in C57BL/6Jmice. Addict Biol 8:419–427

Lu W, Wolf ME (1999) Repeated amphetamine administration altersAMPA receptor subunit expression in rat nucleus accumbens andmedial prefrontal cortex. Synapse 32:119–131

Lu W, Chen H, Xue CJ, Wolf ME (1997) Repeated amphetamineadministration alters the expression of mRNA for AMPAreceptor subunits in rat nucleus accumbens and prefrontal cortex.Synapse 26:269–280

Lu W, Monteggia LM, Wolf ME (1999) Withdrawal from repeatedamphetamine administration reduces NMDAR1 expression in therat substantia nigra, nucleus accumbens and medial prefrontalcortex. Eur J Neurosci 11:3167–3177

Lynskey MT, Heath AC, Bucholz KK, Slutske WS, Madden PA,Nelson EC, Statham DJ, Martin NG (2003) Escalation of druguse in early-onset cannabis users vs co-twin controls. Jama289:427–433

Majchrowicz E (1975) Induction of physical dependence upon ethanoland the associated behavioral changes in rats. Psychopharmaco-logia 43:245–254

Maldonado AM, Kirstein CL (2005) Cocaine-induced locomotoractivity is increased by prior handling in adolescent but not adultfemale rats. Physiol Behav 86:568–572

Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, SergeJP (2008) Stressor- and corticotropin releasing factor-inducedreinstatement and active stress-related behavioral responsesare augmented following long-access cocaine self-administration by rats. Psychopharmacology (Berl) 195:591–603

Markwiese BJ, Acheson SK, Levin ED, Wilson WA, SwartzwelderHS (1998) Differential effects of ethanol on memory inadolescent and adult rats. Alcohol Clin Exp Res 22:416–421

Martinez JL Jr, Jensen RA, Messing RB, Vasquez BJ, Soumireu-Mourat B, Geddes D, Liang KC, McGaugh JL (1980) Centraland peripheral actions of amphetamine on memory storage. BrainRes 182:157–166

McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediatesreversal learning and not attentional set shifting in the rat. BehavBrain Res 146:97–103

McCarthy LE, Mannelli P, Niculescu M, Gingrich K, Unterwald EM,Ehrlich ME (2004) The distribution of cocaine in mice differs byage and strain. Neurotoxicol Teratol 26:839–848

McDonald CG, Eppolito AK, Brielmaier JM, Smith LN, BergstromHC, Lawhead MR, Smith RF (2007) Evidence for elevatednicotine-induced structural plasticity in nucleus accumbens ofadolescent rats. Brain Res 1151:211–218

McDougall SA, Duke MA, Bolanos CA, Crawford CA (1994)Ontogeny of behavioral sensitization in the rat: effects of directand indirect dopamine agonists. Psychopharmacology (Berl)116:483–490

McGue M, Iacono WG, Legrand LN, Elkins I (2001a) Origins andconsequences of age at first drink. II. Familial risk andheritability. Alcohol Clin Exp Res 25:1166–1173

McGue M, Iacono WG, Legrand LN, Malone S, Elkins I (2001b)Origins and consequences of age at first drink. I. Associationswith substance-use disorders, disinhibitory behavior and psycho-pathology, and P3 amplitude. Alcohol Clin Exp Res 25:1156–1165

Meng SZ, Ozawa Y, Itoh M, Takashima S (1999) Developmental andage-related changes of dopamine transporter, and dopamine D1and D2 receptors in human basal ganglia. Brain Res 843:136–144

Meyer JM, Neale MC (1992) The relationship between age at firstdrug use and teenage drug use liability. Behavior Genetics22:197–213

Moghaddam B, Homayoun H (2008) Divergent plasticity of prefrontalcortex networks. Neuropsychopharmacology 33:42–55

Montague DM, Lawler CP, Mailman RB, Gilmore JH (1999)Developmental regulation of the dopamine D1 receptor in humancaudate and putamen. Neuropsychopharmacology 21:641–649

Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL,Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA(2006) Effect of rate of administration on subjective andphysiological effects of intravenous cocaine in humans. DrugAlcohol Depend 82:19–24

Nestler EJ (1994) Molecular neurobiology of drug addiction. Neuro-psychopharmacology 11:77–87

Nestler EJ, Berhow MT, Brodkin ES (1996) Molecular mechanisms ofdrug addiction: adaptations in signal transduction pathways. MolPsychiatry 1:190–199

Obernier JA, White AM, Swartzwelder HS, Crews FT (2002)Cognitive deficits and CNS damage after a 4-day binge ethanolexposure in rats. Pharmacol Biochem Behav 72:521–532

O’Dell LE (2009) A psychobiological framework of the substrates thatmediate nicotine use during adolescence. Neuropharmacology 56(Suppl 1):263–278

O’Dell LE, Bruijnzeel AW, Smith RT, Parsons LH, Merves ML,Goldberger BA, Richardson HN, Koob GF, Markou A (2006)Diminished nicotine withdrawal in adolescent rats: implicationsfor vulnerability to addiction. Psychopharmacology (Berl)186:612–619

O’Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE,Markou A, Zorrilla EP, Koob GF (2007a) Extended access tonicotine self-administration leads to dependence: circadianmeasures, withdrawal measures, and extinction behavior in rats.J Pharmacol Exp Ther 320:180–193

O’Dell LE, Torres OV, Natividad LA, Tejeda HA (2007b) Adolescentnicotine exposure produces less affective measures of withdrawalrelative to adult nicotine exposure in male rats. NeurotoxicolTeratol 29:17–22

O’Shea M, Singh ME, McGregor IS, Mallet PE (2004) Chroniccannabinoid exposure produces lasting memory impairment andincreased anxiety in adolescent but not adult rats. J Psychophar-macol 18:502–508


Paine TA, Dringenberg HC, Olmstead MC (2003) Effects of chroniccocaine on impulsivity: relation to cortical serotonin mecha-nisms. Behav Brain Res 147:135–147

Palacios JM, Camps M, Cortes R, Probst A (1988) Mappingdopamine receptors in the human brain. J Neural Transm Suppl27:227–235

Partridge JG, Tang KC, Lovinger DM (2000) Regional and postnatalheterogeneity of activity-dependent long-term changes in synap-tic efficacy in the dorsal striatum. J Neurophysiol 84:1422–1429

Parylak SL, Caster JM, Walker QD, Kuhn CM (2008) Gonadalsteroids mediate the opposite changes in cocaine-inducedlocomotion across adolescence in male and female rats. Pharma-col Biochem Behav 89:314–323

Pattij T, Wiskerke J, Schoffelmeer AN (2008) Cannabinoid modula-tion of executive functions. Eur J Pharmacol 585:458–463

Patton GC, McMorris BJ, Toumbourou JW, Hemphill SA, Donath S,Catalano RF (2004) Puberty and the onset of substance use andabuse. Pediatrics 114:e300–e306

Perry JL, Anderson MM, Nelson SE, Carroll ME (2007) Acquisitionof i.v. cocaine self-administration in adolescent and adult malerats selectively bred for high and low saccharin intake. PhysiolBehav 91:126–133

Pert A, Sivit C (1977) Neuroanatomical focus for morphine andenkephalin-induced hypermotility. Nature 265:645–647

Philpot RM, Badanich KA, Kirstein CL (2003) Place conditioning:age-related changes in the rewarding and aversive effects ofalcohol. Alcohol Clin Exp Res 27:593–599

Popke EJ, Allen SR, Paule MG (2000) Effects of acute ethanol onindices of cognitive-behavioral performance in rats. Alcohol20:187–192

Prat G, Adan A, Perez-Pamies M, Sanchez-Turet M (2008) Neuro-cognitive effects of alcohol hangover. Addict Behav 33:15–23

Prescott CA, Kendler KS (1999) Age at first drink and risk foralcoholism: a noncausal association. Alcohol Clin Exp Res23:101–107

Provost SC, Woodward R (1991) Effects of nicotine gum on repeatedadministration of the Stroop test. Psychopharmacology (Berl)104:536–540

Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC,Gunasekaran N, Thompson MR, Dawson B, Mallet PE, KashemMA, Matsuda-Matsumoto H, Iwazaki T, McGregor IS (2008)Adolescent rats find repeated Delta(9)-THC less aversive thanadult rats but display greater residual cognitive deficits andchanges in hippocampal protein expression following exposure.Neuropsychopharmacology 33:1113–1126

Rajendran P, Spear LP (2004) The effects of ethanol on spatial andnonspatial memory in adolescent and adult rats studied using anappetitive paradigm. Ann N Y Acad Sci 1021:441–444

Rasmussen K, Beitner-Johnson DB, Krystal JH, Aghajanian GK, NestlerEJ (1990) Opiate withdrawal and the rat locus coeruleus: behavioral,electrophysiological, and biochemical correlates. J Neurosci10:2308–2317

Rethy CR, Smith CB, Villarreal JE (1971) Effects of narcoticanalgesics upon the locomotor activity and brain catecholaminecontent of the mouse. J Pharmacol Exp Ther 176:472–479

Rezvani AH, Levin ED (2004) Adolescent and adult rats responddifferently to nicotine and alcohol: motor activity and bodytemperature. Int J Dev Neurosci 22:349–354

Ristuccia RC, Spear LP (2005) Sensitivity and tolerance to autonomiceffects of ethanol in adolescent and adult rats during repeatedvapor inhalation sessions. Alcohol Clin Exp Res 29:1809–1820

Roberts DC, Loh EA, Vickers G (1989) Self-administration of cocaineon a progressive ratio schedule in rats: dose–response relation-ship and effect of haloperidol pretreatment. Psychopharmacology(Berl) 97:535–538

Robins LN, Przybeck TR (1985) Age of onset of drug use as a factorin drug and other disorders. NIDA Res Monogr 56:178–192

Robinson TE, Berridge KC (1993) The neural basis of drug craving:an incentive-sensitization theory of addiction. Brain Res BrainRes Rev 18:247–291

Robinson TE, Berridge KC (2000) The psychology and neurobiology ofaddiction: an incentive-sensitization view. Addiction 95(Suppl 2):S91–S117

Robinson TE, Berridge KC (2001) Incentive-sensitization andaddiction. Addiction 96:103–114

Robinson TE, Berridge KC (2008) Review. The incentive sensitizationtheory of addiction: some current issues. Philos Trans R SocLond B Biol Sci 363:3137–3146

Robinson TE, Kolb B (2004) Structural plasticity associated withexposure to drugs of abuse. Neuropharmacology 47(Suppl 1):33–46

Roesch MR, Takahashi Y, Gugsa N, Bissonette GB, Schoenbaum G(2007) Previous cocaine exposure makes rats hypersensitive toboth delay and reward magnitude. J Neurosci 27:245–250

Russell JM, Newman SC, Bland RC (1994) Epidemiology ofpsychiatric disorders in Edmonton. Drug abuse and dependence.Acta Psychiatr Scand Suppl 376:54–62

SAMHSA (2008) National survey on drug use and health. SAMHSA,Rockville

Santucci AC, Capodilupo S, Bernstein J, Gomez-Ramirez M,Milefsky R, Mitchell H (2004) Cocaine in adolescent ratsproduces residual memory impairments that are reversible withtime. Neurotoxicol Teratol 26:651–661

Schepis TS, Adinoff B, Rao U (2008) Neurobiological processes inadolescent addictive disorders. Am J Addict 17:6–23

Schneider M, Koch M (2003) Chronic pubertal, but not adult chroniccannabinoid treatment impairs sensorimotor gating, recognitionmemory, and the performance in a progressive ratio task in adultrats. Neuropsychopharmacology 28:1760–1769

Schochet TL, Kelley AE, Landry CF (2004) Differential behavioraleffects of nicotine exposure in adolescent and adult rats.Psychopharmacology (Berl) 175:265–273

Schramm NL, Egli RE, Winder DG (2002) LTP in the mouse nucleusaccumbens is developmentally regulated. Synapse 45:213–219

Schramm-Sapyta NL, Pratt AR, Winder DG (2004) Effects ofperiadolescent versus adult cocaine exposure on cocaine condi-tioned place preference and motor sensitization in mice.Psychopharmacology (Berl) 173:41–48

Schramm-Sapyta NL, Olsen CM, Winder DG (2005) Cocaine self-administration reduces excitatory responses in the mouse nucleusaccumbens shell. Neuropsychopharmacology 31:1444–1451

Schramm-Sapyta NL, Morris RW, Kuhn CM (2006) Adolescent ratsare protected from the conditioned aversive properties of cocaineand lithium chloride. Pharmacol Biochem Behav 84:344–352

Schramm-Sapyta NL, Cha YM, Chaudhry S, Wilson WA, SwartzwelderHS, Kuhn CM (2007) Differential anxiogenic, aversive, andlocomotor effects of THC in adolescent and adult rats. Psychophar-macology (Berl) 191:867–877

Schwandt ML, Barr CS, Suomi SJ, Higley JD (2007) Age-dependentvariation in behavior following acute ethanol administration inmale and female adolescent rhesus macaques (Macaca mulatta).Alcohol Clin Exp Res 31:228–237

Seeman P, Bzowej NH, Guan HC, Bergeron C, Becker LE, ReynoldsGP, Bird ED, Riederer P, Jellinger K, Watanabe S et al (1987)Human brain dopamine receptors in children and aging adults.Synapse 1:399–404

Segal DS, Kuczenski R (1992a) In vivo microdialysis reveals adiminished amphetamine-induced DA response corresponding tobehavioral sensitization produced by repeated amphetaminepretreatment. Brain Res 571:330–337


Segal DS, Kuczenski R (1992b) Repeated cocaine administrationinduces behavioral sensitization and corresponding decreasedextracellular dopamine responses in caudate and accumbens.Brain Res 577:351–355

Sellers EM, Busto U, Kaplan HL (1989) Pharmacokinetic andpharmacodynamic drug interactions: implications for abuseliability testing. NIDA Res Monogr 92:287–306

Shaffer HJ, Eber GB (2002) Temporal progression of cocainedependence symptoms in the US National Comorbidity Survey.Addiction 97:543–554

Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) Thereinstatement model of drug relapse: history, methodology andmajor findings. Psychopharmacology (Berl) 168:3–20

Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse toheroin and cocaine seeking: a review. Pharmacol Rev 54:1–42

Shram MJ, Funk D, Li Z, Le AD (2006) Periadolescent and adult ratsrespond differently in tests measuring the rewarding and aversiveeffects of nicotine. Psychopharmacology (Berl) 186:201–208

Shram MJ, Funk D, Li Z, Le AD (2007a) Acute nicotine enhances c-fos mRNA expression differentially in reward-related substratesof adolescent and adult rat brain. Neurosci Lett 418:286–291

Shram MJ, Funk D, Li Z, Le AD (2007b) Nicotine self-administration,extinction responding and reinstatement in adolescent and adultmale rats: evidence against a biological vulnerability to nicotineaddiction during adolescence. Neuropsychopharmacology 33:739–748

Shuster L, Webster GW, Yu G (1975a) Increased running response tomorphine in morphine-pretreated mice. J Pharmacol Exp Ther192:64–67

Shuster L, Webster GW, Yu G (1975b) Perinatal narcotic addiction inmice: sensitization to morphine stimulation. Addict Dis 2:277–292

Shuster L, Yu G, Bates A (1977) Sensitization to cocaine stimulationin mice. Psychopharmacology (Berl) 52:185–190

Shuster L, Hudson J, Anton M, Righi D (1982) Sensitization of miceto methylphenidate. Psychopharmacology (Berl) 77:31–36

Siegmund S, Vengeliene V, Singer MV, Spanagel R (2005) Influenceof age at drinking onset on long-term ethanol self-administrationwith deprivation and stress phases. Alcohol Clin Exp Res29:1139–1145

Sircar R, Sircar D (2005) Adolescent rats exposed to repeated ethanoltreatment show lingering behavioral impairments. Alcohol ClinExp Res 29:1402–1410

Slawecki CJ, Roth J, Gilder A (2006) Neurobehavioral profiles duringthe acute phase of ethanol withdrawal in adolescent and adultSprague-Dawley rats. Behav Brain Res 170:41–51

Slotkin TA (2002) Nicotine and the adolescent brain: insights from ananimal model. Neurotoxicol Teratol 24:369–384

Snyder KJ, Katovic NM, Spear LP (1998) Longevity of the expressionof behavioral sensitization to cocaine in preweanling rats.Pharmacol Biochem Behav 60:909–914

Soderstrom K, Qin W, Williams H, Taylor DA, McMillen BA(2007) Nicotine increases FosB expression within a subset ofreward- and memory-related brain regions during both peri-and post-adolescence. Psychopharmacology (Berl) 191:891–897

Soetens E, D’Hooge R, Hueting JE (1993) Amphetamine enhanceshuman-memory consolidation. Neurosci Lett 161:9–12

Soetens E, Casaer S, D’Hooge R, Hueting JE (1995) Effect ofamphetamine on long-term retention of verbal material. Psycho-pharmacology (Berl) 119:155–162

Spear LP (2000) The adolescent brain and age-related behavioralmanifestations. Neurosci Biobehav Rev 24:417–463

Spear LP, Brick J (1979) Cocaine-induced behavior in the developingrat. Behav Neural Biol 26:401–415

Spear LP, Horowitz GP, Lipovsky J (1982) Altered behavioralresponsivity to morphine during the periadolescent period inrats. Behav Brain Res 4:279–288

Stevenson RA, Besheer J, Hodge CW (2008) Comparison of ethanollocomotor sensitization in adolescent and adult DBA/2J mice.Psychopharmacology (Berl) 197:361–370

Stinus L, Koob GF, Ling N, Bloom FE, Le Moal M (1980) Locomotoractivation induced by infusion of endorphins into the ventraltegmental area: evidence for opiate–dopamine interactions. ProcNatl Acad Sci U S A 77:2323–2327

Swartzwelder HS, Richardson RC, Markwiese-Foerch B, Wilson WA,Little PJ (1998) Developmental differences in the acquisition oftolerance to ethanol. Alcohol 15:311–314

Tambour S, Brown LL, Crabbe JC (2008) Gender and age at drinkingonset affect voluntary alcohol consumption but neither thealcohol deprivation effect nor the response to stress in mice.Alcohol Clin Exp Res 32:2100–2106

Tarazi FI, Tomasini EC, Baldessarini RJ (1998a) Postnatal develop-ment of dopamine and serotonin transporters in rat caudate-putamen and nucleus accumbens septi. Neurosci Lett 254:21–24

Tarazi FI, Tomasini EC, Baldessarini RJ (1998b) Postnatal develop-ment of dopamine D4-like receptors in rat forebrain regions:comparison with D2-like receptors. Brain Res Dev Brain Res110:227–233

Tarazi FI, Tomasini EC, Baldessarini RJ (1999) Postnatal developmentof dopamine D1-like receptors in rat cortical and striatolimbicbrain regions: an autoradiographic study. Dev Neurosci 21:43–49

Tarter R, Vanyukov M, Giancola P, Dawes M, Blackson T, MezzichA, Clark DB (1999) Etiology of early age onset substance usedisorder: a maturational perspective. Dev Psychopathol 11:657–683

Teicher MH, Andersen SL, Hostetter JC Jr (1995) Evidence fordopamine receptor pruning between adolescence and adulthoodin striatum but not nucleus accumbens. Brain Res Dev Brain Res89:167–172

Teichner G, Horner MD, Harvey RT (2001) Neuropsychologicalpredictors of the attainment of treatment objectives in substanceabuse patients. Int J Neurosci 106:253–263

Terry AV Jr, Hernandez CM, Hohnadel EJ, Bouchard KP, BuccafuscoJJ (2005) Cotinine, a neuroactive metabolite of nicotine: potentialfor treating disorders of impaired cognition. CNS Drug Rev11:229–252

Thomas MJ, Beurrier C, Bonci A, Malenka RC (2001) Long-termdepression in the nucleus accumbens: a neural correlate ofbehavioral sensitization to cocaine. Nat Neurosci 4:1217–1223

Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioralsensitization and conditioned place preference induced bypsychostimulants in laboratory rodents. Neurosci Biobehav Rev27:163–178

Torrella TA, Badanich KA, Philpot RM, Kirstein CL, Wecker L(2004) Developmental differences in nicotine place conditioning.Ann N Y Acad Sci 1021:399–403

Torres OV, Tejeda HA, Natividad LA, O’Dell LE (2008) Enhancedvulnerability to the rewarding effects of nicotine during theadolescent period of development. Pharmacol Biochem Behav90:658–663

Truxell EM, Molina JC, Spear NE (2007) Ethanol intake in thejuvenile, adolescent, and adult rat: effects of age and priorexposure to ethanol. Alcohol Clin Exp Res 31:755–765

Ujike H, Tsuchida K, Akiyama K, Fujiwara Y, Kuroda S (1995)Ontogeny of behavioral sensitization to cocaine. PharmacolBiochem Behav 50:613–617

Vaidya JG, Grippo AJ, Johnson AK, Watson D (2004) A comparativedevelopmental study of impulsivity in rats and humans: the roleof reward sensitivity. Ann N Y Acad Sci 1021:395–398


Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compul-sive after prolonged cocaine self-administration. Science 305:1017–1019

Varlinskaya EI, Spear LP (2004a) Acute ethanol withdrawal (hang-over) and social behavior in adolescent and adult male andfemale Sprague-Dawley rats. Alcohol Clin Exp Res 28:40–50

Varlinskaya EI, Spear LP (2004b) Changes in sensitivity to ethanol-induced social facilitation and social inhibition from early to lateadolescence. Ann N Y Acad Sci 1021:459–461

Varlinskaya EI, Spear LP (2006) Ontogeny of acute tolerance toethanol-induced social inhibition in Sprague-Dawley rats. Alco-hol Clin Exp Res 30:1833–1844

Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP (2002) Nicotine-induced conditioned place preference in adolescent and adult rats.Physiol Behav 77:107–114

Vetter CS, Doremus-Fitzwater TL, Spear LP (2007) Time course ofelevated ethanol intake in adolescent relative to adult rats undercontinuous, voluntary-access conditions. Alcohol Clin Exp Res31:1159–1168

Vezina P, Leyton M (2009) Conditioned cues and the expression ofstimulant sensitization in animals and humans. Neuropharmacol-ogy 56(Suppl 1):160–168

Volkow ND, Fowler JS (2000) Addiction, a disease of compulsion anddrive: involvement of the orbitofrontal cortex. Cereb Cortex10:318–325

Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007)Dopamine in drug abuse and addiction: results of imaging studiesand treatment implications. Arch Neurol 64:1575–1579

Vorhees CV, Reed TM, Morford LL, Fukumura M, Wood SL, BrownCA, Skelton MR, McCrea AE, Rock SL, Williams MT (2005)Periadolescent rats (P41–50) exhibit increased susceptibility to D-methamphetamine-induced long-term spatial and sequentiallearning deficits compared to juvenile (P21–30 or P31–40) oradult rats (P51–60). Neurotoxicol Teratol 27:117–134

Walker QD, Kuhn CM (2008) Cocaine increases stimulated dopaminerelease more in periadolescent than adult rats. NeurotoxicolTeratol 30:412–418

Welzl H, D’Adamo P, Lipp HP (2001) Conditioned taste aversionas a learning and memory paradigm. Behav Brain Res 125:205–213

Wenger GR, Wright DW (1990) Behavioral effects of cocaine and itsinteraction with d-amphetamine and morphine in rats. PharmacolBiochem Behav 35:595–600

White AM, Swartzwelder HS (2005) Age-related effects of alcohol onmemory and memory-related brain function in adolescents andadults. Recent Dev Alcohol 17:161–176

White AM, Ghia AJ, Levin ED, Swartzwelder HS (2000) Bingepattern ethanol exposure in adolescent and adult rats: differentialimpact on subsequent responsiveness to ethanol. Alcohol ClinExp Res 24:1251–1256

Wilhelm CJ, Mitchell SH (2008) Rats bred for high alcohol drinkingare more sensitive to delayed and probabilistic outcomes. GenesBrain Behav 7:705–713

Wilhelm CJ, Reeves JM, Phillips TJ, Mitchell SH (2007) Mouse linesselected for alcohol consumption differ on certain measures ofimpulsivity. Alcohol Clin Exp Res 31:1839–1845

Wilmouth CE, Spear LP (2004) Adolescent and adult rats’ aversion toflavors previously paired with nicotine. Ann N Y Acad Sci1021:462–464

Wilmouth CE, Spear LP (2006) Withdrawal from chronic nicotine inadolescent and adult rats. Pharmacol Biochem Behav 85:648–657

Winder DG, Egli RE, Schramm NL, Matthews RT (2002) Synapticplasticity in drug reward circuitry. Curr Mol Med 2:667–676

Wise RA (1987) The role of reward pathways in the development ofdrug dependence. Pharmacol Ther 35:227–263

Wise RA, Yokel RA, DeWit H (1976) Both positive reinforcementand conditioned aversion from amphetamine and from apomor-phine in rats. Science 191:1273–1275

Yuferov V, Nielsen D, Butelman E, Kreek MJ (2005) Microarraystudies of psychostimulant-induced changes in gene expression.Addict Biol 10:101–118

Zakharova E, Leoni G, Kichko I, Izenwasser S (2008a) Differentialeffects of methamphetamine and cocaine on conditioned placepreference and locomotor activity in adult and adolescent malerats. Behav Brain Res 198:45–50

Zakharova E, Wade D, Izenwasser S (2008b) Sensitivity to cocaineconditioned reward depends on sex and age. Pharmacol BiochemBehav 92:131–134

Zhang Y, Picetti R, Butelman ER, Schlussman SD, Ho A, Kreek MJ(2008) Behavioral and neurochemical changes induced by oxy-codone differ between adolescent and adult mice. Neuropsycho-pharmacology 34:912–922

Zombeck JA, Gupta T, Rhodes JS (2009) Evaluation of a pharmaco-kinetic hypothesis for reduced locomotor stimulation frommethamphetamine and cocaine in adolescent versus adult maleC57BL/6J mice. Psychopharmacology (Berl) 201:589–599


are adolescents more vulnerable to drug addiction than ... · times (alcohol and cigarettes in late...

Documents