- Email: [email protected]
The impact of stress on addiction
W2 Peptides and stress withdrawal phase has yet to be elucidated. Maybe, alterations in the endogenous opioid systems during this phase have influences on the next stage, relapse. The fourth phase of the addiction course, the relapse phase, is quite important from a theoretical as well as from a therapeutic viewpoint of addiction. The major problem of treating addicts is not discontinuation of drug taking, but the relapse in their former addiction habit sooner or later after discontinuation of drug taking. In experimental animals, it has been shown that after extinction of selfadministration behavior, priming with the drug of abuse, the presence of drug-associated cues or experimental stress reinstates responding on the lever associated with formerly taken drug. This indicates that conditioned drug effects but also other events like stressful experiences, are important for reinitiating drug self-administration. An important issue in relapse is craving. Craving - the intense desire to use the drug - is already present during the maintenance phase but also long after discontinuation of drug taking. Whether the craving during maintenance and after discontinuation is mediated by the same brain mechanisms is not known but likely. Craving and relapse are opioid-mediated suggested by the facts that blockade of opioid receptors with naltrexone reduced cocaineseeking behavior in rats and abstinence-induced increase in ethanol intake in monkeys [5, unpublished observations]. Moreover, an attenuating effect of low doses of the opioid antagonist naltrexone on expression of conditioned place preference - a paradigm that may measure aspects of drug craving - with addictive drugs has been found [5]. In conclusion, endogenous opioids seem to be involved in addictive behavior. Although their significance is not yet established, there are indications for a modulatory role of endogenous opioids in the ventral tegmental area in drug reinforcement, which may be pertinent for the individual susceptibility with respect to development of (psychic) dependence. On the other hand, endogenous opioids in limbic areas may play a role in the dynamics of drug taking behavior during the maintenance phase of drug dependence and in certain motivational effects induced by repeated drug (self-) administration, which may be involved in craving and relapse. The ability to manipulate the genetic make-up of organisms by specific targeting of selected genes has provided a novel means of investigating the neurobiological mechanisms underlying drug addiction. The analysis of responses of mutant mice to drugs of abuse clarified the essential role of e.g. p-opioid receptor in opiate, ethanol and cannabinoid reward and addiction [3]. Presently, p-opioid receptor knockout mice are tested for cocaine self-administration. Moreover, the availability of numerous mutant mice will allow to investigate the role of other neurotransmitter systems in the course of
S5
(opiate) addiction (e.g. camrabinoid or dopamine receptor knockouts). Finally, although a heritable basis for the vulnerability of drug addiction has been established, the specific genes involved have not been identified yet. In this respect, individual genetic differences that lead to functional differences in the endogenous opioid system may be of interest for the (future) research into addiction processes. For example, the human p-opioid receptor gene has been a primary focus of the majority of studies of a potential association of the endogenous opioid system genes with drugs of abuse [4]. Of particular interest for the future is more focus on the relation between genotype and phenotype in addiction. References VI Gerrits, M.A.F.M., Wiegant, VM., Van Ree, J.M., 1999. Endogenous opioids implicated in the dynamics of experimental drug addiction: an in vivo autoradiographic analysis. Neuroscience 89, 1219-1227. PI Gerrits, M.A.F.M., Petromilli, P., Westenberg, H.G.M., Di Chiara, G., Van Ree, J.M., 2002. Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats. Brain Research 924, 141-150. C., 2002. Exploring [31Kieffer, B.L., Gaveriaux-Ruff, the opioid system by gene knockout. Progress in Neurobiology 66, 286-306. [41LaForge, K.S., Yuferov, V!, Kreek, M.J., 2000. Opioid receptor and peptide gene polymorphisms: potential implications for addictions. European Journal of Pharmacology 4 10, 249-268. [51Van Ree, J.M., Gerrits, M.A.F.M., Vanderschuren, L.J.M.J., 1999. Opioids, reward and addiction: an encounter of biology, psychology and medicine. Pharmacological Reviews 51, 341-395.
W.2.02
The impact of stress on addiction
N. Goeders. Louisiana State University Health Sciences Center; Department of Pharmacology & Therapeutics, Shreveport, LA, USA Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamopituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous selEadministration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to
S6
W3 Brain circuit and craving
consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases, and this presentation will explore our results for each phase. Uncontrollable electric footshock stress shifts the ascending limb of the acquisition doseresponse curve upwards and to the left, demonstrating an increased sensitivity to cocaine. Corticosterone appears to be critical since bilateral adrenalectomy prevents the acquisition of cocaine self-administration over a wide range of doses. In addition, self-administration does not occur in intact rats unless corticosterone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can also be augmented by increasing circulating levels of corticosterone with exogenous injections of the hormone, but similar treatments do not affect responding maintained by higher doses. Since corticosterone secretion ultimately results from the actions of corticotropin-releasing hormone (CRH), our results indirectly suggest a role for CRH in the acquisition of cocaine self-administration. In a similar vein, ongoing, low-dose cocaine self- administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. The corticosterone synthesis inhibitors ketoconazole and metyrapone each reduce low-dose cocaine self-administration, as do the benzodiazepines chlordiazepoxide, alprazolam and oxazepam. These effects can be overcome by increasing the unit dose of cocaine. Apparently, when higher cocaine doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach a hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine doseresponse curve can be attenuated by drugs that block central CRH receptors, which further demonstrates the role for CRH in cocaine reward. Finally, corticosterone and CRH are also critical for the stress- and cueinduced reinstatement of extinguished cocaine-seeking behavior, which illustrates the involvement of CRH and the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress, CRH secretion and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction. References [l] Goeders, N.E., 2002. The HPA Axis and Cocaine Reinforcement. Ps_ychoneuroendocrinology 27, 1333.
[2] Goeders, N.E., 2002. Stress and Cocaine Addiction (Perspectives in Pharmacology). 1 Pharmacol Exp Ther: 301(3), 785-789.
W.3 Brain circuit and craving W.3.01
Sensitization
and addiction
T.E. Robinson. Department of Psychology, University of Michigan, 525 E. University, Ann Arbol; MI 48109, USA The repeated administration of many potentially addictive drugs produces a host of long-lasting neuroadaptations in brain systems that mediate their rewarding and psychomotor activating effects and these neuroadaptations are thought to contribute to the long-term sequelae associated with drug use and abuse, including tolerance, sensitization, dependence and addiction. This talk will review evidence that one form of very persistent drug experience-dependent plasticity, behavioral sensitization, is accompanied not only by biochemical changes in a number of brain regions, but also structural adaptations in brain circuits that mediate drug reward and cognitive function. For example, repeated treatment with amphetamine, cocaine, or morphine alters the structure of dendrites on medium spiny neurons in the nucleus accumbens and pyramidal cells in the prefrontal cortex, changes that are still evident months after the discontinuation of drug treatment. Psychostimulants increase dendritic branching, the density of dendritic spines and, in the accumbens, the number of branched spines (i.e., spines with multiple heads). The effects of morphine vary depending on the mode of drug administration (whether it is experimenter-administered or self-administered). In most brain areas morphine decreases spine density, but in the orbital frontal cortex it increases spine density. In addition, evidence that these effects of drugs interact with similar effects produced by other life experiences will be discussed. Specifically, prior exposure to amphetamine or cocaine appears to limit the ability of later experience in a complex environment to promote structural plasticity. The ability of drugs to produce sensitization is not, however, a simple function of their pharmacological actions. Through associative learning stimuli and actions associated with drugs may activate sensitized neural substrates. Even the expression or induction of sensitization can be powerfully modulated by the circumstances surrounding drug administration. Studies illustrating the ability of environmental context to modulate the development of psychomotor sensitization produced by amphetamine or cocaine will be presented, as will evidence
S5
(opiate) addiction (e.g. camrabinoid or dopamine receptor knockouts). Finally, although a heritable basis for the vulnerability of drug addiction has been established, the specific genes involved have not been identified yet. In this respect, individual genetic differences that lead to functional differences in the endogenous opioid system may be of interest for the (future) research into addiction processes. For example, the human p-opioid receptor gene has been a primary focus of the majority of studies of a potential association of the endogenous opioid system genes with drugs of abuse [4]. Of particular interest for the future is more focus on the relation between genotype and phenotype in addiction. References VI Gerrits, M.A.F.M., Wiegant, VM., Van Ree, J.M., 1999. Endogenous opioids implicated in the dynamics of experimental drug addiction: an in vivo autoradiographic analysis. Neuroscience 89, 1219-1227. PI Gerrits, M.A.F.M., Petromilli, P., Westenberg, H.G.M., Di Chiara, G., Van Ree, J.M., 2002. Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats. Brain Research 924, 141-150. C., 2002. Exploring [31Kieffer, B.L., Gaveriaux-Ruff, the opioid system by gene knockout. Progress in Neurobiology 66, 286-306. [41LaForge, K.S., Yuferov, V!, Kreek, M.J., 2000. Opioid receptor and peptide gene polymorphisms: potential implications for addictions. European Journal of Pharmacology 4 10, 249-268. [51Van Ree, J.M., Gerrits, M.A.F.M., Vanderschuren, L.J.M.J., 1999. Opioids, reward and addiction: an encounter of biology, psychology and medicine. Pharmacological Reviews 51, 341-395.
W.2.02
The impact of stress on addiction
N. Goeders. Louisiana State University Health Sciences Center; Department of Pharmacology & Therapeutics, Shreveport, LA, USA Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamopituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous selEadministration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to
S6
W3 Brain circuit and craving
consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases, and this presentation will explore our results for each phase. Uncontrollable electric footshock stress shifts the ascending limb of the acquisition doseresponse curve upwards and to the left, demonstrating an increased sensitivity to cocaine. Corticosterone appears to be critical since bilateral adrenalectomy prevents the acquisition of cocaine self-administration over a wide range of doses. In addition, self-administration does not occur in intact rats unless corticosterone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can also be augmented by increasing circulating levels of corticosterone with exogenous injections of the hormone, but similar treatments do not affect responding maintained by higher doses. Since corticosterone secretion ultimately results from the actions of corticotropin-releasing hormone (CRH), our results indirectly suggest a role for CRH in the acquisition of cocaine self-administration. In a similar vein, ongoing, low-dose cocaine self- administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. The corticosterone synthesis inhibitors ketoconazole and metyrapone each reduce low-dose cocaine self-administration, as do the benzodiazepines chlordiazepoxide, alprazolam and oxazepam. These effects can be overcome by increasing the unit dose of cocaine. Apparently, when higher cocaine doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach a hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine doseresponse curve can be attenuated by drugs that block central CRH receptors, which further demonstrates the role for CRH in cocaine reward. Finally, corticosterone and CRH are also critical for the stress- and cueinduced reinstatement of extinguished cocaine-seeking behavior, which illustrates the involvement of CRH and the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress, CRH secretion and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction. References [l] Goeders, N.E., 2002. The HPA Axis and Cocaine Reinforcement. Ps_ychoneuroendocrinology 27, 1333.
[2] Goeders, N.E., 2002. Stress and Cocaine Addiction (Perspectives in Pharmacology). 1 Pharmacol Exp Ther: 301(3), 785-789.
W.3 Brain circuit and craving W.3.01
Sensitization
and addiction
T.E. Robinson. Department of Psychology, University of Michigan, 525 E. University, Ann Arbol; MI 48109, USA The repeated administration of many potentially addictive drugs produces a host of long-lasting neuroadaptations in brain systems that mediate their rewarding and psychomotor activating effects and these neuroadaptations are thought to contribute to the long-term sequelae associated with drug use and abuse, including tolerance, sensitization, dependence and addiction. This talk will review evidence that one form of very persistent drug experience-dependent plasticity, behavioral sensitization, is accompanied not only by biochemical changes in a number of brain regions, but also structural adaptations in brain circuits that mediate drug reward and cognitive function. For example, repeated treatment with amphetamine, cocaine, or morphine alters the structure of dendrites on medium spiny neurons in the nucleus accumbens and pyramidal cells in the prefrontal cortex, changes that are still evident months after the discontinuation of drug treatment. Psychostimulants increase dendritic branching, the density of dendritic spines and, in the accumbens, the number of branched spines (i.e., spines with multiple heads). The effects of morphine vary depending on the mode of drug administration (whether it is experimenter-administered or self-administered). In most brain areas morphine decreases spine density, but in the orbital frontal cortex it increases spine density. In addition, evidence that these effects of drugs interact with similar effects produced by other life experiences will be discussed. Specifically, prior exposure to amphetamine or cocaine appears to limit the ability of later experience in a complex environment to promote structural plasticity. The ability of drugs to produce sensitization is not, however, a simple function of their pharmacological actions. Through associative learning stimuli and actions associated with drugs may activate sensitized neural substrates. Even the expression or induction of sensitization can be powerfully modulated by the circumstances surrounding drug administration. Studies illustrating the ability of environmental context to modulate the development of psychomotor sensitization produced by amphetamine or cocaine will be presented, as will evidence