Activation of the hypothalamicpituitaryadrenal axis by addictivedrugs: different pathways, commonoutcomeAntonio Armario

Institute of Neurosciences and Animal Physiology Unit (Department of Cellular Biology, Physiology and Immunology),Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain

Addictive drugs (opiates, ethanol, cannabinoids (CBs),nicotine, cocaine, amphetamines) induce activation ofthe hypothalamicpituitaryadrenal (HPA) axis, with thesubsequent release of adrenocorticotropic hormone andglucocorticoids. The sequence of events leading to HPAactivation appears to start within the brain, suggestingthat activation is not secondary to peripheral homeo-static alterations. The precise neurochemical mechan-isms and brain pathways involved are markedlydependent on the particular drug, although it is assumedthat information eventually converges into the hypo-thalamic paraventricular nucleus (PVN). Whereas somedrugs may act on the hypothalamus or directly withinPVN neurons (i.e. ethanol), others exert their primaryaction outside the PVN (i.e. CBs, nicotine, cocaine).Corticotropin-releasing hormone (CRH) has a critical rolein most cases, but the changes in c-fos and CRH geneexpression in the PVN also reveal differences amongdrugs. More studies are needed to understand howaddictive drugs act on this important neuroendocrinesystem and their functional consequences.

IntroductionThe hypothalamicpituitaryadrenal (HPA) axis is a com-plex neuroendocrine system involved in an importantnumber of central and peripheral physiological functions,most of them related to appropriate adaptation to stressfulsituations. The HPA axis is also altered in an importantnumber of pathophysiological and psychopathological pro-cesses, including drug addiction [1,2]. The main features ofthe organization of the HPA axis and brain areas control-ling it are well-known [3,4]. In brief, theHPA axis ismainlygoverned by the paraventricular nucleus (PVN) of thehypothalamus, particularly the medial dorsal parvocellu-lar region (mpdPVN). In this region, there is rich popu-lation of parvocellular neurons expressing a wide range ofneuropeptides. The most important neuropeptides for theregulation of the HPA axis are the corticotrophin-releasingfactor or hormone (CRF or CRH) and vasopressin (arginin-vasopressin (AVP) in most mammals, including rats andhumans). AVP is formed in a percentage of CRHergicneurons and the number of CRH+ neurons also expressing

Review

Glossary of terms

ACTH: adrenocorticotropic hormone, the hormone synthesized in the anterior

pituitary gland that controls glucocorticoid secretion in the adrenal gland.

A1/C1: refers to a cluster of neurons using noradrenaline (A1) or adrenaline

(C1) as neurotransmitters, which are within the anatomically defined

ventrollateral medulla.

A2/C2: refers to a cluster of neurons using noradrenaline (A2) or adrenaline

(C2) as neurotransmitters, which are within the anatomically defined nucleus

tractus solitarius.

AP: anterior pituitary (hypophysis), part of the hypophysis where an important

number of hormones (including ACTH) are formed.

AVP: arginin-vasopressin, a neuropeptide formed in the supraoptic and

paraventricular nuclei of the hypothalamus that participates in the control of

ACTH in the anterior pituitary.

BBB: bloodbrain barrier, the barrier that limits entry into the brain of

peripheral hydrophilic molecules.

BLA: basolateral amygdala

CB: cannabinoids, the exogenous and endogenous (eCBs) substances that

interact with cannabinoid receptors.

CB1, CB2: the two well-characterized types of receptors for cannabinoids.

CRH (or CRF): corticotropin-releasing hormone, the most important hypotha-

lamic stimulatory factors for the control of ACTH.

DARPP-32: dopamine- and cAMP-dependent phosphoprotein of 32 kDa; it is a

protein activated by dopamine and other neurotransmitters which inhibits

phosphatases.

DOR: d (delta) opioid receptors

eEOPs: endogenous opioids, the endogenous peptides that interact with opioid

receptors.

GR: glucocorticoid (type II) receptors, a type of genomic receptors for

glucocorticoid hormones.

HPA: hypothalamicpituitaryadrenal axis; refers to the neuroendocrine

system that controls glucocorticoid secretion by the adrenal gland.

IEGs: immediate early genes, genes that are expressed immediately in

response to stimuli and are markers of neuronal activation.

KOR: k (kappa) opioid receptors

MDMA: 3,4-methylenedioximetamphetamine.

ME: median eminence, part of the hypophysis where the capillaries of the

pituitary portal blood are located.

MOR: m (mu) opioid receptors

MR: mineralocorticoid (type I) receptors, a type of genomic receptor for

glucocorticoid hormones.

NGFI-B: a transcription factor rapidly induced by the neurotrophin nerve

growth factor, which is considered to be an immediate early gene.

NMDA: n-methyl-D-aspartate, defines a subtype of the ionotropic glutamate

receptor.

PDYN: pro-dynorphin; refers to the gene and precursor molecule of some

endogenous opioids, mainly dynorphin.

PENK: pro-enkephalin; refers to the gene and the precursor molecule of the

endogenous opioids enkephalins.

POMC: pro-opiomelanocortin; refers to the gene and the precursor molecule of

ACTH and b-endorphin.

PPB: pituitary-portal blood, a special circulatory system that collects sub-

stances released by hypothalamic axons and directs them to the anterior

pituitary.

PVN: paraventricular nucleus of the hypothalamus, the key nucleus in the

control of the HPA axis. The PVN has several subregions, including the medial

parvocellular dorsal (mpdPVN), whose neurons send axons to the externalCorresponding author: Armario, A. (antonio.armario@uab.es).318 0165-6147/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.04.005 Trends in Pharmacological Sciences 31 (2010) 318325

for CRH (and sometimes for AVP) can be detected in thempdPVN 24 h after initial exposure to stress. However,more sensitive tools such as intronic probes (which detectnuclear primary transcripts (hnRNA)), are needed to ana-lyze the situation after brief exposures or low intensitystressors [5,6]. Exposure to stress can result in increasedgene expression of pro-opiomelanocortin (POMC), the pre-cursor of ACTH that also gives rise to endogenous opioids(eOPs) such as b-endorphin in the AP.

In addition to the different time-course of ACTH andcorticosterone secretion, evaluation of the effects of stress(or drugs) based only on glucocorticoids can lead to mis-leading interpretations. Adrenocortical secretion saturateswith intermediate levels of plasma ACTH, so plasma levelsof corticosterone may not reflect actual ACTH release ifonly a single time-point is evaluated [4]. In addition, thereis evidence for an actual dissociation after exposure toprolonged stress (usually >6 h) when almost normal levelsof ACTH can be observed with high levels of corticosterone[7]. We do not have a direct explanation for this phenom-enon, but we know that sympathetic neural innervation ofthe adrenal gland can modulate adrenal sensitivity tocirculating ACTH [8] and this may explain (at least inpart) some cases of partial dissociation between the twohormones. Finally, locally generated signals as well asother circulating factors can contribute, under certainconditions, to the release of glucocorticoids, although inall cases the presence of a minimum amount of ACTHappears to be critical. Glucocorticoids released duringstress have a wide impact on peripheral tissues and the

type-II or glucocorticoid receptors (GR). In addition, thereis evidence for fast non-genomic effects of glucocorticoidthrough putative transmembrane receptors. One criticalaction of glucocorticoids is the negative feedback they exertat multiple levels within the brain and the AP.

Within the context of stress theories, it is unclear why somany drugs can activate the HPA axis [4]. Although theeffects of some drugs may be secondary to homeostaticalterations, it is more likely that they are related to thepharmacological activation of brain pathways involved inthe response to stressors. A general scheme of the placewhere addictive drugs and other stimuli can initiate theevents leading to the activation of the HPA axis can be seenin Figure 1. Controversial results are more frequentlyencountered in in vitro studies that evaluate the directeffects of addictive drugs on the hypothalamus, AP oradrenal cortex than in in vivo studies. This is probablydue to important problems inherent to in vitro prep-arations.

Due to space limitations, the present review will focuson how acute exposure to addictive drugs activates theHPA axis. I shall exclude the interesting topics of long-term exposure to drugs in early life and the consequences ofchronic exposure to drugs (including tolerance and with-drawal) in adults. There is evidence that all addictivedrugs can activate the HPA axis in humans with theexception of opiates, which have a predominant inhibitoryrole in humans [11]. Putative mechanisms have beenstudied in laboratory animals, so specific references tohuman studies will not bemade. Tables 1 and 2 summarizeAVP is increased after chronic activation of the HPA axis[4]. AVP, acting through V1b receptors, exerts a weakstimulation of corticotropes but markedly potentiatesthe effects of CRH. In addition to CRH and AVP, otherhypothalamic factors can regulate the HPA axis. Axons ofparvocellular mpdPVN neurons terminate around thecapillaries of the pituitary portal blood (PPB) of themedianeminence (ME) where they release CRH, AVP and otherneuropeptides. These reach the anterior pituitary (AP) toactivate adrenocorticotropic hormone (ACTH) release bycorticotrope cells. CRH acts in the AP through type-1receptors (CRH-R1). ACTH then activates the synthesisand secretion of glucocorticoids (cortisol in humans andmost mammals; corticosterone in rodents) in the zonafasciculata of the adrenal cortex throughmelanocortin type2 receptors. Maximum release of ACTH is usually observed510 min after the start of exposure to stressors, whereasmaximum corticosterone levels are achieved after only 2030 min.

Stimuli that activate the release of HPA hormones notonly induce the release of CRH, AVP and other putativesecretagogues into the PPB, but also increase transcriptionof those genes in the mpdPVN. When the stressors are ofsufficient magnitude and exposure to them is relativelylong (30 min to several hours), increased levels of mRNA

median eminence, and the magnocellular (mPVN), whose neurons send axonsto the neurohypophysis.

SA: self-administration; refers to the procedure that allow animals to self-

administer the drug using operant learning.

THC: delta9-tetrahydrocannabinol, the major psychotropic component of

cannabis.

Reviewbrain [9,10], acting through two types of genomic receptors:type-I or mineralocorticoid receptors (MR) receptors and

Figure 1. Putative pathways whereby drugs can activate different components of

the HPA axis. Drugs can act at the following sites: 1) peripherally, by inducing

homeostatic alterations or other peripheral changes (i.e. release of other

substances) that can then activate receptors located in neurons of the

autonomous nervous system. These neurons in turn could inform the brain

through synapses in the nucleus tractus solitarius (NTS) or adjacent regions; 23)

on brain areas (NTS, VLM) that send direct inputs to the PVN; 4) on

circumventricular areas that are outside the BBB (i.e, organum vasculosum

lamina terminals or subfornical organ (SFO); 5) on receptors located in specific

brain regions, proximal (i.e. other hypothalamic nuclei) or more distal (i.e. limbic

areas) to the PVN, thus activating circuits that finally would convey into the PVN; 6)

directly on PVN neurons or even on CRH neurons; 7) on the ME, directly controlling

the release of hypothalamic factors from axon terminals; 8) on the AP, modulating

the response of corticotropes to hypothalamic regulatory factors; 9) on the zona

fasciculata of the adrenal cortex or on the brain areas controlling the sympathetic

innervation of the adrenal, in both cases modulating the response to ACTH.

Trends in Pharmacological Sciences Vol.31 No.7319

f ad

c

C

Y

Y

Y

sive

nvo

dial

erethe main results that I elaborate on and which may assistthe reader in following the discussion. Among the drugs tobe reviewed, some of them are classically considered asdepressants (opiates, ethanol, CBs), whereas the othersare psychostimulants (nicotine, cocaine, amphetamines

Table 1. Summary of the knowledge about the acute effects o

Drug Inside

BBB

PVN

lesions

IEGs

PVN

Opiates Yesa Yes

Ethanol Yes Yes Yes

Cannabinoids Yes Yes

Nicotine Yes Yes

Cocaine Yes Yes No

Amphetamine Yes

a: Yes indicates positive evidence and No negative evidence; ? indicates no conclu

Table 2. Brain areas and neurotransmitters/neuromodulators i

Drug Primary site(s) of action

Opiates Hypothalamus

Ethanol HypothalamusPVN?

Cannabinoids Basolateral amygdala, Me

Nicotine Nucleus tractus solitarius

Cocaine Ventral striatum

Amphetamine and derivatives

? indicates a possible, but not conclusive, site of action; empty squares indicate that th

Reviewand their derivatives).

Opiates and eOPsThere are three families of eOPs, each one coded by a singlegene: proopiomelanocortin (POMC), proenkephalin(PENK) and prodynorphin (PDYN). Each protein precur-sor can give rise to different peptides, somewith affinity fordifferent opioid receptors. b-endorphin (derived fromPOMC) has preferential affinity for m receptors (MOR),leu and met-enkephalin (derived mainly from PENK) havepreferential affinity for d receptors (DOR) and dynorphins(derived from PDYN) has preferential affinity for kreceptors (KOR). Opiate drugs (i.e. morphine, heroin,methadone) are predominantly agonists of MOR, whereasnaloxone is a well-characterized opioid receptor antagonistwith affinity for all types of receptors, but particularly forMOR. Naltrexone has similar properties as naloxone, but alonger-lasting action. Most of the data on the role of opiatesand eOPs on neuroendocrine regulation were obtained inthe 1960s and 1980s, and the interest subsequentlydeclined, although very recently some of these effects havebeen reviewed [11]. Whereas in rodents eOPs may exertstimulatory and inhibitory roles in the control of the HPAaxis, they have a predominantly inhibitory role in humans,with consequent activation of the HPA axis after admin-istration of naloxone/naltrexone [11]. Exposure to opiatescan therefore have clearly different consequences on theHPA axis and physiological functions affected by the HPAaxis in humans as compared with rodents.

320Early reports demonstrated that morphine can activateadrenocortical secretion through a mechanism dependentupon the hypothalamus and the AP [12]. Although somedirect effects at the adrenal level have been reported [12],the main effects are exerted above the AP. Methadone also

dictive drugs on the HPA axis

-fos in PVN

RF neurons

PVN CRF gene

expression

Role

of CRF

Role

of AVP

es ? Yes

Yes Yes Yes

Yes

es

Yes Yes No

es Yes

evidence; empty squares indicate that no studies have been done.

lved in the effects of addictive drugs on the HPA axis

Neurotransmitters/neuromodulators involved

amygdala Noradrenaline, Serotonin

Noradrenaline/adrenalineGlutamate (NMDA)Nitric oxideCRHDopamineNoradrenaline/adrenalineAcetylcholine (muscarinic)Glutamate (NMDA)Endogenous opioidsCRHSerotonin

are no studies or positive evidence for any site or neurotransmitter/neuromodulator.

Trends in Pharmacological Sciences Vol.31 No.7activates the HPA axis in rats dose-dependently, the effectbeing blocked by naloxone [13]. In rats, activation of theHPA axis was observed with agonists of the three types ofopioid receptors when given peripherally and centrally[1416]. The critical role of MOR in the effects of morphineis supported by the lack of effect of the drug on corticos-terone levels in MOR knockout mice [17]. An independenteffect of each type of receptor on HPA activation is sup-ported by the lack of cross-tolerance after repeated admin-istration [16].

A direct hypothalamic effect of opioids is supported bythe fact that morphine and enkephalins can increase invitro hypothalamic CRH secretion, an effect blocked bynaloxone [18]. Prior administration of an antiserumagainst rat CRH completely blocked HPA activationcaused by the KOR agonist MR-2034, whereas it onlypartially reduced the response to morphine [19]. Thespecific contribution of CRH to the activation induced byDOR is not known. Despite the involvement of CRH,neither acute nor chronic peripheral morphine adminis-tration altered CRH mRNA levels in the mpdPVN,although enhanced expression was found after naloxone-precipitated withdrawal [20]. Consistent with these find-ings, six repeated administrations of morphine every twohours did not increase CRH gene expression in the PVN, orPOMC gene expression in the AP [21]. There is evidencethat agonists of MOR and KOR (morphine and U-50,488H,respectively) induce c-fos expression in the PVN [22], soopiates can promote expression of the immediate early

gene (IEG) c-fos without affecting expression of the CRHgene. However, results with intronic probes are needed toconfirm the lack of effect of opiates in CRHgene expression.Interestingly, intracerebroventricular (i.c.v.) adminis-tration of b-endorphin in rats not only increased plasmaACTH, but also c-fos and CRH gene expression in the PVN[23]. This could be because the effect of b-endorphin wassufficient to be detected with CRHmRNA levels or becausethe peptide and some of its in vivo-generated fragmentsalso activated DOR [24].

Although weak MOR receptor expression and strongerKOR expression is observed in the PVN [25], there is nodirect evidence for the presence of some types of opioidreceptor specifically in CRH neurons. Similarly, in vivostudies on the local PVN action of opioids have not beenreported. It is therefore possible that the primary effects ofopioids are exerted outside the PVN and perhaps in part atthe level of the ME, where the presence of MOR has beenclearly identified [25].

Naloxone at relatively high doses activates the HPAaxis [12,26], suggesting a dual role of eOPs in regulation oftheHPA axis. The effects of naloxone are intriguing in that:(i) naloxone methylbromide, an analog that cannot crossthe bloodbrain barrier (BBB), can enhance ACTHsecretion [27]; (ii) its effect was maintained after totalhypothalamic deafferentation and blocked by the syntheticglucocorticoid dexamethasone [28]; and (iii) it was blockedby prior CRH antiserum [19], although the drug did notstimulate in vitro CRH release [18]. Considering thepossible mechanisms outlined in Figure 1, the drug mayact directly on hypothalamic nuclei located outside theBBB that have direct or indirect connections to the PVN.

EthanolPeripheral ethanol administration activates the HPA axisin laboratory animals and humans. Most of our knowledgeabout how it acts is based on the great contribution of theRivier research team, who reviewed the topic in 1996 [29].Ethanol self-administration (SA) modestly increasesplasma ACTH [30]. Although some effect at the level ofthe AP or the adrenal gland has been described [29], amajor contribution of these actions to plasma levels of HPAhormones is unlikely. In fact, recent evidence with i.c.v.administration demonstrates that ethanol mainly acts inthe brain to activate theHPA axis [31]. Interestingly, whileinducing similar levels of ACTH, the intraperitoneal (i.p.)administration preferentially activates mpdPVN c-fos andCRH gene expression as compared to oral (p.o.) adminis-tration [32]. Whereas there is evidence that some of thebehavioral effects of ethanol are due to the generation ofacetaldehyde from ethanol by catalase rather than toethanol [33], the results regarding the HPA axis are con-troversial [34,35].

An important number of studies have delineated themain effects of ethanol, demonstrating [29]: (i) a reductionof the response after PVN lesions; (ii) an enhanced expres-sion of IEGs c-fos and NGFI-B; (iii) an increase in PVNCRH gene expression, which was observed with intronicprobes; and (iii) amodest contribution of AVP. In support of

Reviewa contribution of both peptides, the HPA response toethanol is completely blocked by i.v. administration of aCRH antiserum [36], basically disappears in mice null forthe CRH-R1 [37], and is reduced in V1b knockoutmice [38].An AVP antiserum reduced the ACTH response to ethanolnot only in control, but also in PVN-lesioned rats [39], so acontribution of AVP neurons outside the PVN is likely.Unfortunately, the origin of AVP neurons that participatein ethanol-induced activation of the HPA axis is unclear. Inany case, CRH appears to be the main mediator of ethanol,which acts on the hypothalamus, perhaps directly on CRHneurons [40]. The i.c.v. administration increased the PVNCRH primary transcript, in accordance with previous datausing peripheral administration. In addition, i.p. and i.c.v.administration increased plasma ACTH and AP POMCgene expression, and these effects were completely blockedby simultaneous administration of CRH and AVP antisera[31].

CBsD9-tetrahydrocannabinol (THC) is the major psychotropiccomponent ofCannabis sativa and themost studied CB. CBdrugs interact with CB1 and CB2 receptors, the formerbeing the most expressed CB receptor in the brain.Endogenous cannabinoids (eCBs) such as anandamide(N-arachidonoyl-ethanolamine) and 2-arachidonoyl-gly-cerol have affinity for CB1 and CB2 receptors. From the1970s, evidence has accumulated about a stimulatory effectof THC and other CB1 agonists on the HPA axis in severalspecies [41]. CBs exert their effects on the HPA axis actingmainly in the brain as demonstrated by i.c.v. adminis-tration of THC and anandamide [42,43]. The effect ofTHC is not observed in hypothalamic-deafferented rats[44], so the primary effect should be outside the hypothala-mus, although the PVN and the CRHappear to be involved.

Exogenous CBs and eCBs increase c-fos expression andCRH mRNA levels in the PVN [41]. Nevertheless, directevidence for a role of CRH (i.e. using peripheral adminis-tration of CRH antisera or CRH antagonists) is lacking.The finding that THC-induced release of HPA hormones islikely to be initiated in extra-hypothalamic regions raisessome questions about the role of CB receptors in the PVN.Double in-situ procedures have shown that CB1 receptorsare expressed in >50% of CRH neurons of the PVN [45]. Ifsuch CB1 receptors were demonstrated to be localized inthe terminals of CRH neurons, they could exert an inhibi-tory presynaptic role on ME CRH release after exposure tostress or other stimuli (see below), but a stimulatory role atthis level is unlikely.

Consistent with a stimulatory role of CBs on HPAactivity, administration of AM404 (eCB reuptake inhibi-tor) and URB597 (inhibitor of the eCB degrading enzymefatty acid amide hydrolase), increased plasma corticoster-one in mice [46] and the effects were blocked by the CB1antagonist AM251. This is important because under cer-tain conditions, eCBs would not activate the HPA axisthrough CB1. Thus, administration of anandamide wasfound to induce release of HPA hormones and c-fos expres-sion in the PVN; neither of the two effects was blocked bythe CB1 antagonist SR 141716 [47]. In addition, activationof the HPA by anandamide is observed in CB1/ mice

Trends in Pharmacological Sciences Vol.31 No.7[48]. The precise receptors involved in the effects of exogen-ously administered anandamide on the HPA axis are not

321

known, but it is important to be certain that brain levels ofanandamide are within the physiological range to demon-strate a putative biological significance.

Another intriguing aspect of CBs and the HPA axis isthat CB1 antagonists can also activate the HPA axis dose-dependently. This has been reported with SR141716 afterperipheral and i.c.v. administration in rats and mice[43,4951]. These data suggest a tonic inhibitory role ofeCBs on HPA activity that is compatible with the fact thatSR141716 potentiated corticosterone response to restraintand restraint-induced c-fos expression in the PVN,whereas the opposite was found after potentiation of eCBs[50]. The stimulatory effect of CB1 antagonists on the HPAaxis was not observed in CB1/ mice [50,51], supportingthe hypothesis of mediation by CB1 receptors.

The data detailed above strongly indicate that CB1exerts a dual effect on the regulation of the HPA axis.CB1/ mice showed higher CRH mRNA levels in thePVN than wild-type mice [45], so it is possible that theinhibitory effects of CB1 receptors predominate overstimulatory effects or that inhibition has a tonic componentand stimulation a phasic one. The inhibitory effects of CB1on HPA activation are compatible with the electrophysio-logical evidence that eCBs may participate in fast negativeglucocorticoid feedback in the PVN through presynapticprotein G-dependent modulation of glutamate release onexcitatory synapses on CRH neurons [52]. However,additional evidence for a functional role of eCBs on nega-tive glucocorticoid feedback is lacking.

Recent studies shed light on the extra-PVN locationswhere eCBs could act to initiate activation of the HPA axis.Local administration of both the CB1 agonistWIN55,212-2and the CB1 antagonist AM251 in the basolateral amyg-dala (BLA) increased plasma corticosterone in rats [53].These results indicate that the BLA may be one of thestructures where a double function of CB1 on HPA regu-lation is operating. The authors also observed thatexposure to stress after WIN did not further increasecorticosterone levels above those observed with WIN andthey interpret these data as evidence for a role of CB1receptors to inhibit stress-induced HPA activation. This issupported by another report in which activation of CB1 inthe BLA with local administration of a dose of the agonistHU-210 that per se had no effect markedly reduced thecorticosterone response to restraint stress [54]. No effectwas observed in the central amygdala whereas, in themedial amygdala, HU210 enhanced the response torestraint. The different results obtained with HU210 ver-sus WIN injected within the BLA under non-stress con-ditions cannot be explained, although interaction of thesedrugs with receptors other than CB1 may be considered.Nevertheless, we may tentatively conclude that eCBs mayhave a dual role within the BLA to control the restingactivity of theHPA axis, whereas eCBswithin the BLA andthe medial amygdala may have important (but opposite)roles in stress-induced HPA activation. All these data arecompatible with an important extra-PVN role of eCBs tocontrol the HPA axis. Corticosterone response to the CB1agonist HU-210 was not blocked by i.c.v. administration of

Reviewthe CRH antagonist d-Phe CRH1241 [55], suggesting noextra-pituitary actions of CRH. Recent evidence suggests a

322partial role of noradrenergic and serotoninergic trans-mission [56].

NicotineAfter early reports of increases in plasma glucocorticoidsafter nicotine administration in dogs and rats, Cam et al.[57] demonstrated a dose-dependent response that wascompletely abolished in hypophysectomized rats, makingan ACTH-independent effect at the level of the adrenalcortex unlikely. Nicotine levels achieved during SA pro-cedures are sufficient to modestly increase HPA hormones[58,59]. The central action of nicotine and the critical role ofthe PVN have been demonstrated with i.c.v. adminis-tration of nicotine receptor antibodies and bilateral PVNlesions that blocked the HPA response [60]. Low doses ofnicotine preferentially induce c-fos expression in thempdPVN, whereas higher doses also activate the magno-cellular region (mPVN) [61], andmost of mpdPVN neuronsactivated are CRH+ [62,63]. However, there is no report onthe acute effects of the drug on PVN CRH gene expression,and no direct evidence for a critical role of CRH at the AP.

Sharp and colleagues made the most important contri-butions to the characterization of the brain mechanismsinvolved in nicotine-induced activation of the HPA axis[64]. They conclusively confirmed (using agonists andantagonists that can or cannot cross the BBB) that themain action of nicotine is within the brain, with noadditional effect at the level of the AP [65]. The drugwas less effective when given around the PVN than inthe fourth ventricle [66], ruling out a major direct actionwithin the PVN. The PVN is innervated by noradrenergicand adrenergic neurons from the nucleus tractus solitarius(corresponding to A2/C2 areas) and the ventrollateralmedulla (corresponding to A1/C1) and, to a lesser extent,by locus coeruleus (LC). The authors demonstrated that alow peripheral dose of nicotine activated (in terms of c-fos)the mpdPVN and the A2/C2 region, whereas higher dosesadditionally activated A1/C1, LC and mPVN [61]. Accord-ingly, after local injection of nicotine and the nicotinicantagonist mecamylamine, they concluded that the mainlocus of action was the A2/C2 region [67]. Although only aminority of neurons activated in these regions was tyro-sine-hydroxylase+ [68], there is evidence that nicotine-induced release of noradrenaline in the PVN, actingthrough a1 and a2 but not b-adrenoceptors, is involvedin HPA activation [69,70]. Nicotine-induced activation ofA2/C2 neurons appears to be exerted through bungaro-toxin-insensitive nicotinic receptors [71] and requires thelocal action of glutamate through NMDA receptors andnitric oxide [72]. Administration via i.c.v. means of a CRH-R1 antagonist (CP-154,526) has demonstrated a role ofcentral CRH through CRH-R1 in nicotine-induced releaseof noradrenaline in the PVN and HPA activation [73],although the precise sites of action remain unknown.

Cocaine and amphetamine-like drugsThe main action of cocaine is to inhibit the reuptake ofmonoamines (dopamine, noradrenaline, serotonin). Acuteadministration of cocaine has been repeatedly found to

Trends in Pharmacological Sciences Vol.31 No.7dose-dependently activate the HPA axis [74,75]. Achievinga supra-threshold level of cocaine rather than the total

amount of drug entering the circulation in a period of timeappears to be critical because cocaine administration withosmotic minipumps did not result in HPA activation [76].Cocaine levels achieved after drug SA also increased corti-costerone [77,78], although whether the increase is higherafter contingent than non-contingent administration iscontroversial [79,80]. A central action of cocaine is sup-ported by the increase in HPA hormones observed afteri.c.v. administration [81,82].

CRH appears to be critical because HPA response to thedrug is blocked by peripheral administration of CRH butnot AVP antiserum [83]. Surprisingly, cocaine-inducedrelease of HPA hormones is not paralleled by enhancedc-fos expression in the PVN [76], although cocaineincreased CRH gene expression and lesions of the PVNmarkedly reduced the ACTH response to the drug [83]. Itwas suggested that cocaine may directly act at the PVNbecause the drug dose-dependently increased CRH releasefrom hypothalamic explants [84]. However, in pentobarbi-tal-anesthetized rats, local in vivo administration ofcocaine just posterior to the PVN requires doses muchhigher than i.c.v. administration to increase plasma corti-costerone, suggesting a main locus of action outside thePVN [82].

HPA activation is found after local administration ofcocaine into the ventral striatum (that includes the nucleusaccumbens) [85]. However, there is no evidence for directprojections from the ventral striatum to the PVN and theprecise pathways are not known. Interestingly, CRH mayalso act within the brain to stimulate the HPA axis becausethe response was blocked by i.c.v. administration of a CRHantiserum and a CRH antagonist [86]. Dopamine appearsto be involved in cocaine-induced activation of the HPAaxis because peripheral administration of D1 and D2 re-ceptor antagonists partially blocked the corticosteroneresponse [75,8789] and reduced PVN CRH gene expres-sion caused by an acute cocaine binge [89]. A role fordopamine is also supported by the reduced response inDARPP-32-deficient mice to chronic administration ofcocaine [90] and blockade of the corticosterone responseto ventral striatum cocaine administration by haloperidol[85]. In addition to dopamine, other monoamines are likelyto be involved. Peripheral and i.c.v. administration ofdopamine, adrenergic (a and b), muscarinic and opioidreceptor antagonists has been found to reduce cocaine-induced activation of the HPA axis [75,87] and glutamateNMDA receptors also have a role [91,92]. Therefore, sev-eral different neurotransmitters participate in the acti-vation of the HPA axis caused by cocaine, suggesting amultifactorial regulation or a complex circuit whoseprimary place of activation is outside the hypothalamusand PVN.

Methamphetamine (methylamphetamine), d-Amphet-amine, and 3,4-methylenedioximetamphetamine (MDMA,Ecstasy) exert complex biochemical effects on monoaminesynapses. They interfere with monoamine plasma andvesicular transporters, thus favoring the release of thethree monoamines from presynaptic terminals, indepen-dently of whether the synapses are active [93]. Amphet-

Reviewamine has been found to dose-dependently increaseplasma corticosterone in rats [94,95], withmaximum levelsat 30-min post-injection. In our hands, HPA activation wasclearly observed at 90-min post-injection [96]. The mech-anisms involved in amphetamine-induced HPA activationhave been poorly characterized. HPA activation appears toinvolve CRH release because the response was blocked by aCRH antiserum [95]. However, we recently observed, usingdouble-labelling of c-fos and CRH, that amphetamine acti-vates a lower percentage of CRH neurons in the PVN thana severe stressor such as immobilization despite a similarnumber of activated neurons with both stimuli [97]. Thissuggests that other hypothalamic factors in addition toCRH may be involved in amphetamine-induced HPA acti-vation. Positive (but limited) evidence exists concerningmethamphetamine-induced activation of the HPA axis inexperimental animals [98]. At doses between 5 mg/kg and20 mg/kg, MDMA dose-dependently increased plasmacorticosterone in rats when given i.p., with a maximumat 1 h after administration [99]. It is of interest thatserotonin rather than catecholamines appears to beinvolved in the action of amphetamine, methamphetamineand MDMA on the HPA axis [94,99,100].

ConclusionsThe data reviewed strongly suggest that all addictive drugsactivate the HPA axis acting mainly within the brain. Theprecise mechanisms and brain areas other than the PVNinvolved appear to greatly differ among the various drugs,and important information about events taking place atthe level of the PVN is lacking (see Table 1). Nevertheless,it is clear that classical classification of addictive drugs asstimulants or depressants does not contribute to explaintheir effects on theHPA axis, the particular mechanisms ofaction, or the development of tolerance after repeated drugadministration (not discussed here). Knowledge about howaddictive drugs activate the HPA axis is important for abetter understanding of the physiological and behavioralconsequences of acute and chronic exposure to drugs, andthe critical interaction between addictive drugs and stress.

AcknowledgementsThis work was supported by grants SAF2008-01175 (MEC), PlanNacional sobre drogas, RD06/0001/0015 (Instituto de Salud Carlos III,Redes tematicas de Investigacion Cooperativa en Salud) and SGR2009-16. Thanks are given to David Rotllant, Xavier Belda and Raul Delgado-Morales for their help with preparation of the manuscript.

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Activation of the hypothalamic-pituitary-adrenal axis by addictive drugs: different pathways, common outcomeIntroductionOpiates and eOPsEthanolCBsNicotineCocaine and amphetamine-like drugsConclusionsAcknowledgementsReferences