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Addicted to stress. (Articles).

Stressed out? You're likely not in as much danger as an addict, who must contend with the possibility of relapse in addition to the source of tension. Recent studies conducted with laboratory animals have begun to illuminate the neurochemical systems and neuroanatomical pathways linking stress to relapse to drug seeking.

Drug addiction is characterized by a recurrent pattern of drug taking, withdrawal, and relapse to drug taking. Episodes of relapse that occur after prolonged periods of abstinence, when drug in the body can no longer influence desire for more drug, remain the most difficult challenge for treatment (1, 2).

Exposure to stress has long been thought to trigger relapse in humans (3, 4) and was recently shown for the first time in an experimental setting to induce craving for cocaine in abstaining addicts (5). By and large, however, studies on the relationship between stress and relapse in humans are correlational in nature, making it difficult to draw a causal link between the two factors.

We have been using an animal model of relapse to drug seeking to study the relationship between stress and relapse (6). In this model, which was originally developed to study the effects of acute, 'priming' injections of drug on relapse, rats are allowed to self-administer a drug intravenously by depressing a lever during daily sessions. Subsequently, extinction conditions, in which lever presses are no longer reinforced with drug, are introduced and kept in place until animals reach persistently low rates of responding. Animals are then tested for relapse following exposure to stress in the form of brief intermittent electric footshocks. Significantly higher rates of lever-pressing after rather than before footshock is considered evidence of relapse to drug seeking. Using this model, we and others have found that footshock serves as a powerful stimulus for inducing relapse to heroin, cocaine, alcohol, and nicotine seeking after many extinction sessions and prolonged drug-free periods [see 6 for a review].

The central focus of our work on stress-induced relapse to drug seeking has been on characterizing the brain systems and circuitry involved. Two neurochemical systems that we have determined to play a critical role are corticotropin-releasing factor (CRF) and noradrenaline (NE). Our work suggests that an interaction between these systems within two functionally and anatomically related limbic brain structures, the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA), may mediate the effects of stress on relapse to drug seeking.

CRF and Stress-Induced Relapse

GRF release from the hypothalamus initiates a cascade of events including release of adrenocorticotropin hormone from the pituitary and, in turn, release of glucorticoids from the adrenal cortex (release of glucocorticoids from the adrenal is considered a hallmark feature of the endocrine stress response). GRF secretion from the hypothalamus also mediates the rise in corticosterone (the primary glucocorticoid in the rat) induced by cocaine (7), and may mediate the rise in corticosterone induced by other psychostimulant drugs. In addition to this hormonal function, GRF acts directly in the brain, in the manner of a classic neurotransmitter, to mediate a number of stress and drug-related effects.

We recently discovered that, following extended periods of abstinence, CRE in the brain plays a critical role in stress-induced relapse to drug seeking in rats. Furthermore, we have determined that its role in this effect is as a neurotransmitter.

In experiments carried out in heroin- (8), cocaine- (9), and alcohol-trained rats (10), blockade of brain CRF receptors, via injections of GRF-receptor antagonists into the cerebral ventricles, markedly suppressed the ability of footshock stress to provoke relapse to drug seeking. On the other hand, stimulation of CRF receptors, via injections of the peptide itself into the ventricles, induced relapse, at least partially mimicking the effects of footshock. These effects of CRF occurred independent of the pituitary and adrenal because manipulations of the adrenal gland (pharmacological or surgical adrenalectomy), which prevented a stress-induced rise in corticosterone from occurring, did not affect footshock-induced relapse; that is, footshock was capable of inducing relapse in the absence of stress-induced release of glucocorticoids from the adrenal gland.

NE and Stress-Induced Relapse

Activation of NE systems within the brain is another hallmark feature of the stress response. Stress-induced release of brain NE contributes to sympathetic activation, including increases in heart rate and blood pressure, and regulates the endocrine stress response by stimulating the release of CRF in the hypothalamus.

We have discovered that, like CRF, NE plays an important role in mediating the effects of stress on relapse to drug seeking. In experiments carried out in heroin-(11) and cocaine-trained rats (12) and rats trained with a heroin-cocaine mixture (13), we found that pharmacological inhibition of NE cell firing and release (by systemic injections of alpha-2 adrenergic receptor agonists at doses that suppress NE cell firing through auto-inhibition), strongly attenuated footshock-induced relapse. These effects were determined to be centrally mediated because injections of the NE compounds in the cerebral ventricles were as effective as systemic injections in interfering in the effects of footshock on relapse.

The NE system is comprised of a dorsal projection originating in the locus coeruleus and a ventral projection originating in the lateral tegmental nuclei of the pons and medulla. In an attempt to determine which NE projection is involved in the effects of stress on relapse, two experiments were conducted in heroin-trained rats; one involved interference in transmission of the dorsal pathway, via local injections of alpha-2 adrenergic receptor agonists in the locus coeruleus, and the other involved a selective lesion (6-hydroxydopamine) of the ventral NE pathway (11). Manipulations of the dorsal pathway were without effect; however, lesions of the ventral pathway significantly attenuated footshock-induced relapse to heroin seeking. Taken together, these results provide support for the idea that the ventral pathway, but not the dorsal pathway, provides a functionally important source of NE in mediating the effects of footshock on relapse.

Localizing the Effects of CRF and NE: Role of the BNST and CEA in Stress-Induced Relapse

We have hypothesized that an interaction between CRF and NE systems within the BNST and/or CeA mediates stress-induced relapse. Both structures have been implicated in stress-related responses, including fear and anxiety, and there is mounting evidence that they are involved in addictive behaviours [see 14 for review]. Furthermore, there are anatomical data to support the feasibility of the hypothesis. Of particular significance, NE terminals have been found to lie in close proximity to CRF-containing cell bodies in the CeA and to synapse directly with the dendrites of CRF-containing cell bodies in the BNST (15). Interestingly, the ventral NE pathway, which, unlike the dorsal pathway, was found to play an important role in stress-induced relapse to heroin seeking, provides the major source of NE in the BNST and amygdala (16). Figure 1 depicts some of the known circuitry of the BNST and CeA, and possible mechanisms of NE-CRF interactions, that we believe may be involved in the effects of footshock on relapse.

In a set of experiments carried out in cocaine-trained animals (17), we found that pharmacological blockade of CRF receptors in the amygdala did not interfere in footshock-induced relapse and that stimulation of CRF receptors in the amygdala, by local injections of the peptide, did not induce relapse. Manipulations of CRF receptors in the BNST, on the other hand, produced dramatic results; pharmacological blockade of CRF receptors here completely blocked the ability of footshock stress to provoke relapse to cocaine seeking and stimulation of CRF receptors, by local injections of the peptide, induced relapse in the absence of footshock. Consistent with the effects of CRF receptor manipulations in the BNST, it was recently shown that blockade of NE receptors in the BNST also interferes in stress-induced relapse (18), a result that indirectly supports the idea that an interaction between NE and CRF systems in the BNST may mediate the effects of stress on relapse.

Pharmacological stimulation or blockade of CRF receptors in the BNST could mimic or block, respectively, the effects of CRF released either from cells intrinsic to this structure, or from CRF cells projecting from the CeA (see Figure 1). To determine whether the CRF projection originating in the CeA plays a role, we functionally disconnected the CRF-containing pathway projecting between the CeA and BNST using an asymmetric lesion procedure [see 19]. It was found that the functional lesion, relative to control manipulations, significantly reduced footshock-induced relapse, suggesting a role for this CRF-containing pathway in the effects of stress on relapse to cocaine seeking.

We do not yet known on which efferent neurons of the BNST CRF, and possibly NE (see Fig. 1, 'b'), act to initiate the behaviours involved in relapse. There are, however, several possible candidates. It is known, for example, that the BNST provides input to a variety of hypothalamic and brain-stem sites (see 'd') implicated in general approach behaviours, such as maternal behaviour, sex, and feeding [see 6 and 14 for a discussion]. We have argued previously that footshock may facilitate relapse to drug seeking by activating pathways, such as these, that are compatible with general approach behaviours; that is, footshock might induce relapse by activating a generalized motivational system compatible with drug seeking [see 6 for a discussion].

Conclusions

CRF and NE systems within the BNST and CeA are integral components of what is sure to be a complex circuitry and constellation of neurochemical events mediating stress-induced relapse to drug seeking. Although the neurobiology of footshock-induced relapse is not yet fully characterized, it is anticipated that work aimed at revealing the systems and circuitry involved will facilitate a better understanding of the relationship between stress and relapse in the human population.

Acknowledgements

The author wishes to acknowledge Jane Stewart (Concordia University, Montreal, QC) and Yavin shaham (National Institute of Drug Abuse, Baltimore, MD) who initiated the seminal studies on stress and relapse from which much of the subsequent work cited in this article emerged.

References

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(2.) Stitzer, M.L. and Cox, W.M. 'Introduction to special section. Relapse to substance abuse', Exp. Clin. Psychopharm., 4:3-4, 1996.

(3.) Kreek, M.J., Koob, G.F. 'Drug dependence: stress and dysregulation of brain reward systems', Drug Alcoh. Dep., 51:23-47, 1998.

(4.) Shiffman, S., wills, T.A. coping and substance Abuse, Academic Press, Orlando, 1985.

(5.) Sinha, R., catapano, D., and O'Malley, S. 'Stress-induced craving and stress response in cocaine dependent individuals', Psychopharm., 142:343-437, 1999.

(6.) Shaham, Y., Erb, S., Stewart, J. 'Stress-induced relapse to heroin and cocaine seeking rats: A review', Br. Res. Rev., 33:13-33, 2000.

(7.) Sarnyai, Z., Shaham, Y., and Heinrichs, S. C. 'The role of corticotropin-releasing factor in drug addiction', Pharmacol. Rev., 53:209-243, 2001.

(8.) Shaham, Y., Funk, D., Erb, S., Brown, T., walker, C.-D. and Stewart, i. 'Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats', J. Neurosci., 17:2605-2614, 1997.

(9.) Erb, S., Shaham. Y., Stewart, J. 'The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats', J Neurosci., 14: 5529-5536, 1998.

(10.) Le, A.D., Harding, S., Juzytsch, W. and Shaham, Y. 'The role of corticotropin-releasing factor in stress-induced relapse to alcohol seeking', Psychopharm., 150: 317-24, 2000.

(11.) Shaham, Y., Highfield, D., Delfs, J., Leung, S., and Stewart, J., "Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons', Eur. J. Neurosci., 12:292-302, 2001.

(12.) Erb, S., Hitchcott, P.K., Rajabi, H., Mueller, D., Shaham, Y. and Stewart, J. a2-Adrenergic agonists block stress-induced reinstatement of cocaine seeking', Neuropsychopharm., 23: 138-150, 2000.

(13.) Highfield, D., Yap, J., Grimm, J., Shalev, U. and Shaham, Y. 'Repeated lofexidine treatment attenuates stress-induced, but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedhall) seeking in rats', Neuropsychopharm., 25:320-331, 2001.

(14.) Erb, S., Shaham, Y., and Stewart, J. 'Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminails and amygdala'. Stress, 4: 289-303, 2001.

(15.) Phelix, C.F. and Paull, WK. 'Demonstration of distinct corticotropin releasing factor-containing neuron populations in the bed nucleus of the stria terminalis. A light and electron microscopic immunocytochemical study in the rat', Histochem., 94: 345-364, 1990.

(16.) Moore, R. and Bloom, F. 'central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems', Ann. Rev. Neurosci., 2:113-168, 1979.

(17.) Erb, 5. and Stewart, J. 'A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on strss-induced reinstatement of cocaine seeking', J. Neurosci., RC35:1-6, 1999.

(18.) Leri, F., Flores, J., and Stewart, J. 'Beta-1 and beta-2 noradrenergic antagonists injected in the bed nucleus of the stria terminalis (bnst) block stress-induced relapse to cocaine seeking in rats', Abstract presented at the Septieme Journee Scientifique du RSMQ & des Neurosciences, Quebec city, 2001.

(19.) Erb, S., Salmaso, N., Rodaros, D., and Stewart, J. 'A role for the GRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats', Psychopharm., 158: 360-365, 2001.

Suzanne Erb is an assistant professor of psychology in the division of life sciences at the University of Toronto at Scarborough. She was a recipient in 2001 of a University Faculty Award from the Natural Sciences and Engineering Research Council of Canada.
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Title Annotation:Drug addiction
Author:Erb, Suzanne
Publication:Canadian Chemical News
Article Type:Brief Article
Geographic Code:1CANA
Date:Mar 1, 2002
Words:2242
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