Drug AddictionDrug Addiction

History: Opiate EffectsHistory: Opiate Effects Characteristics of drug addiction:Characteristics of drug addiction:

Tolerance: decreased drug effect w/ repeated useTolerance: decreased drug effect w/ repeated use

Dependence: withdrawal syndromeDependence: withdrawal syndrome

Initial hypothesis:Initial hypothesis:

Tolerance = down-regulation of opiate receptorsTolerance = down-regulation of opiate receptors

Dependence = up-regulation of opiate receptorsDependence = up-regulation of opiate receptors

Does addiction entail physical Does addiction entail physical dependence?dependence?

Opiate addiction leads to physical Opiate addiction leads to physical withdrawal symptoms.withdrawal symptoms.

BUT: Cocaine and amphetamine do not.BUT: Cocaine and amphetamine do not.

All abused drugs increase DA in nucleus All abused drugs increase DA in nucleus accumbens (Nacc).accumbens (Nacc).

Separate (opioid?) mechanism for physical Separate (opioid?) mechanism for physical dependencedependence

Role of DopamineRole of Dopamine All abused drugs increase dopamine All abused drugs increase dopamine

release in nucleus accumbens (NAcc), release in nucleus accumbens (NAcc), terminus of mesolimbic dopamine tract.terminus of mesolimbic dopamine tract. Either directly or indirectly (by disinhibition: Either directly or indirectly (by disinhibition:

inhibiting an inhibitor)inhibiting an inhibitor)

Mesolimbic dopamine systemMesolimbic dopamine system

Role of DopamineRole of Dopamine Dopamine neurons in flies and worms Dopamine neurons in flies and worms

regulate responses to food and drugs.regulate responses to food and drugs.

Abnormalities in humans may Abnormalities in humans may compulsive gambling, eating, sex, compulsive gambling, eating, sex, depression.depression.

Decreased “liking” (tolerance) Decreased “liking” (tolerance) Increased “wanting” (craving)Increased “wanting” (craving)

Role of DopamineRole of Dopamine How do you measure “liking” in a rat???How do you measure “liking” in a rat???

An analysis of facial expressions in the An analysis of facial expressions in the rat. H. Davis, S. Simmons, 1979rat. H. Davis, S. Simmons, 1979

Role of DopamineRole of Dopamine Hyper-dopaminergic mice (bred to have fewer Hyper-dopaminergic mice (bred to have fewer

dopamine transporters dopamine transporters increased dopamine in increased dopamine in synapse) showed fewer “liking” responses to synapse) showed fewer “liking” responses to sucrose (fig. below).sucrose (fig. below).

However, they ate more food, drank more water, However, they ate more food, drank more water, ran faster for food in a runway, & gained more ran faster for food in a runway, & gained more weight than wild-type. weight than wild-type. i.e., they showed more “wanting.” i.e., they showed more “wanting.”

Hyper-dopaminergic mice show Hyper-dopaminergic mice show fewer “liking” responses to sucrose.fewer “liking” responses to sucrose.

Role of DopamineRole of Dopamine It’s not clear why some circuits show It’s not clear why some circuits show

tolerance and others show sensitization. tolerance and others show sensitization. However, different regions of the NAcc are However, different regions of the NAcc are important for “liking” (NAcc shell) vs important for “liking” (NAcc shell) vs “wanting” (NAcc core). “wanting” (NAcc core). Therefore, tolerance may occur in the shell Therefore, tolerance may occur in the shell

region, and craving may result from changes region, and craving may result from changes in the core.in the core.

Also, different types of receptors may be Also, different types of receptors may be important.important.

How do drugs affect dopamine?How do drugs affect dopamine? Amphetamine makes dopamine vesicles in axon Amphetamine makes dopamine vesicles in axon

terminals “leaky” & reverses the transporters terminals “leaky” & reverses the transporters flood of dopamine in synapses.flood of dopamine in synapses.

Cocaine blocks the transporters Cocaine blocks the transporters dopamine dopamine can’t be removed from synapse after release can’t be removed from synapse after release more dopamine in synapses (similar to hyper-more dopamine in synapses (similar to hyper-dopaminergic mice above)dopaminergic mice above)

Role of DopamineRole of Dopamine What does Ritalin do?What does Ritalin do?

Role of DopamineRole of Dopamine Is Ritalin addictive?Is Ritalin addictive?

Role of DopamineRole of Dopamine What does nicotine do?What does nicotine do?

Role of DopamineRole of Dopamine Nicotinic receptors on dopamine terminals Nicotinic receptors on dopamine terminals

in NAcc increase dopamine release.in NAcc increase dopamine release.

Nicotinic receptors on dopamine cell Nicotinic receptors on dopamine cell bodies in ventral tegmental area (VTA) of bodies in ventral tegmental area (VTA) of midbrain increase firing.midbrain increase firing.

Therefore, nicotine increases dopamine Therefore, nicotine increases dopamine

activity in NAcc in 2 ways.activity in NAcc in 2 ways.

Role of DopamineRole of Dopamine What do opiates do?What do opiates do?

Role of DopamineRole of Dopamine Inhibit inhibitory GABA neurons in VTA Inhibit inhibitory GABA neurons in VTA

disinhibits dopamine neurons disinhibits dopamine neurons increases increases dopamine in Nacc.dopamine in Nacc.

Benzodiazepine anti-anxiety drugs also Benzodiazepine anti-anxiety drugs also inhibit VTA GABA neurons and increase inhibit VTA GABA neurons and increase dopamine in NAcc.dopamine in NAcc.

More permanent effectsMore permanent effects Cocaine Cocaine increased dendritic spine increased dendritic spine

density on NAcc neurons & increased cell density on NAcc neurons & increased cell body size in VTA.body size in VTA.

Therefore, temporary biochemical Therefore, temporary biochemical changes can changes can permanent morphology permanent morphology changeschanges

Role of EnvironmentRole of Environment Home cage vs. novel cage administration Home cage vs. novel cage administration

Sensitization = increased motor activity in Sensitization = increased motor activity in response to previously ineffective doseresponse to previously ineffective dose Often used as measure of “wanting” or craving.Often used as measure of “wanting” or craving.

Intravenous catheter: no cues to onset of drugIntravenous catheter: no cues to onset of drug Low doses Low doses sensitization only in novel cage sensitization only in novel cage High doses High doses sensitization in both cages sensitization in both cages

Role of EnvironmentRole of Environment Therefore, stress response to novel Therefore, stress response to novel

environment may contribute to addiction.environment may contribute to addiction.

Effects of StressEffects of Stress Cocaine can Cocaine can anxiety via corticotropin anxiety via corticotropin

releasing hormone (CRH) release.releasing hormone (CRH) release. (CRH activates ACTH from anterior pituitary; also (CRH activates ACTH from anterior pituitary; also

is used as a transmitter in the brain is used as a transmitter in the brain stress) stress) May seem odd that CRH could mediate the May seem odd that CRH could mediate the

reward, as well as anxiety.reward, as well as anxiety. But, self-administration is a CONTROLLABLE But, self-administration is a CONTROLLABLE

stressor, which often has better effects than stressor, which often has better effects than no stress at all.no stress at all.

Analogous to thrill-seekingAnalogous to thrill-seeking

15.17 Autonomic Activation during a Stress Situation (Part 1)

Effects of StressEffects of Stress Uncontrollable shock Uncontrollable shock increased increased

sensitivity to low doses of cocainesensitivity to low doses of cocaine Inverted U curve for cocaine: low doses Inverted U curve for cocaine: low doses

reinforcing; high doses reinforcing; high doses anxiety anxiety All self-administered doses increased All self-administered doses increased

corticosterone above a certain level.corticosterone above a certain level. Further increase above that level Further increase above that level no further no further

effect.effect.

Effects of StressEffects of Stress Inject corticosterone (no shock): mimicked Inject corticosterone (no shock): mimicked

effects of uncontrollable stress effects of uncontrollable stress increased self-administration of low doses increased self-administration of low doses of cocaine.of cocaine.

Adrenalectomy abolished acquisition of Adrenalectomy abolished acquisition of self-administration of cocaine, but not of self-administration of cocaine, but not of food. (Therefore, they could still learn the food. (Therefore, they could still learn the response.)response.)

Effects of StressEffects of Stress Humans: ketoconazole, a glucocorticoid Humans: ketoconazole, a glucocorticoid

(GC) synthesis antagonist, decreased (GC) synthesis antagonist, decreased anxiety, depression, and craving.anxiety, depression, and craving.

3 of 5 continued to use cocaine and still 3 of 5 continued to use cocaine and still got high; 2 remained drug-freegot high; 2 remained drug-free

Therefore, GCs do not affect “liking” of Therefore, GCs do not affect “liking” of drug, but do decrease “wanting” (craving).drug, but do decrease “wanting” (craving).

Estrogen & Sex DifferencesEstrogen & Sex Differences Estrogen (E) rapidly increases DA release Estrogen (E) rapidly increases DA release

in NAcc in NAcc Test ovariectomized (OVX) females, OVX Test ovariectomized (OVX) females, OVX

+ E, CAST males, intact males + E, CAST males, intact males Unilateral lesion of dopamine neurons Unilateral lesion of dopamine neurons

circling in response to increased dopaminecircling in response to increased dopamine E or oil 30’ before cocaine for 4 daE or oil 30’ before cocaine for 4 da

Nothing for 3 da; continue pattern for 3 wks.Nothing for 3 da; continue pattern for 3 wks. Test for circling.Test for circling.

No group differences on Day 1No group differences on Day 1

OVX+EOVX+E greater sensitization to greater sensitization to 20 mg/kg cocaine20 mg/kg cocaine

OVX+EOVX+E greater sensitization to greater sensitization to 5 mg/kg cocaine5 mg/kg cocaine

Challenge R to 10 mg/kg cocaine, Challenge R to 10 mg/kg cocaine, w/o E (10 da after last doses)w/o E (10 da after last doses)

E & Sex Differences SummaryE & Sex Differences Summary No group difference on first dayNo group difference on first day OVX+E sensitized more to each dose of OVX+E sensitized more to each dose of

cocaine.cocaine. Even 10 da later, after no more E or Even 10 da later, after no more E or

cocaine, OVX females previously treated cocaine, OVX females previously treated with E+cocaine showed greater remaining with E+cocaine showed greater remaining sensitization to cocaine.sensitization to cocaine.

May explain why women are more easily May explain why women are more easily addicted to various substances. addicted to various substances.

Summary and Common ThreadsSummary and Common Threads 2 main elements of drug addiction: 2 main elements of drug addiction:

tolerance to the rewarding effects (“liking”) tolerance to the rewarding effects (“liking”) & sensitization to motivational effects & sensitization to motivational effects (“wanting”).(“wanting”). Tolerance may result from down-regulation of Tolerance may result from down-regulation of

synapses in NAcc shellsynapses in NAcc shell Cells that are over-stimulated try to normalize their Cells that are over-stimulated try to normalize their

activity.activity. Craving may result from sensitization of Craving may result from sensitization of

synapses in NAcc core.synapses in NAcc core.

Summary and Common ThreadsSummary and Common Threads ““Stress” hormones and novel Stress” hormones and novel

environmental cues contribute to craving.environmental cues contribute to craving. Stress or exposure to drug-related cues can Stress or exposure to drug-related cues can

relapse in people that had been “on the relapse in people that had been “on the wagon” (abstinent) for a long time.wagon” (abstinent) for a long time.

Estrogen contributes to women’s greater Estrogen contributes to women’s greater susceptibility to addiction.susceptibility to addiction.

Similar mechanisms underlie compulsive Similar mechanisms underlie compulsive gambling, eating, sex.gambling, eating, sex.