News and Publications

Division of Psychopharmacology

George F. Koob, Ph.D., Director

Research in the Division of Psychopharmacology continues to focus on the brain mechanisms involved in emotional behavior and how these systems change with drug dependence, stress, and mental disease. The results will provide the key to explaining the vulnerability associated with acquisition and relapse of such chronic disorders. Neuropharmacologic advances in drug dependence and stress are covered in the following report. Neurochemical studies, neuromolecular and neuroviral studies, and studies on the neuropharmacology of reward systems are covered in the reports of F. Weiss, L. Gold, L. Parsons, and A. Markou.

Neurobiology of Stress, Dependence, and Disease

G.F. Koob, F. Weiss, L. Gold, A. Markou, L. Parsons, K.T. Britton,* M.B. Weinger,* M. Geyer,* M. Le Moal,** E. Riley,*** L. Stinus,** M. Cador,** L. Pulvirenti,**** F. De Fonseca,***** G. Schulteis,* S. Heinrichs,⁺ C. Heyser, S. Ahmed, A. Roberts, D. Lin, J. Walker, A. Morse, E. Zorrilla, M. Vallee, N. Gracy, E. Izzo, B. Baldo, D. Macey, S. Watkins, M. Arends, R. Lintz, B. Nadeau, R. Schroeder, M. Beschen

* University of California, San Diego, CA
** San Diego State University, San Diego, CA
*** INSERM U. 259 and Universite Bordeaux II, Bordeaux, France
**** Universita di Roma "TorVergata," Rome, Italy
***** Universidad Complutense de Madrid, Madrid, Spain
⁺ Neurocrine Biosciences, Inc., San Diego, CA

NEUROBIOLOGY OF DRUG DEPENDENCE

Studies on the neurobiology of drug dependence continue to focus on (1) multiple neurochemical systems within the basal forebrain that are important substrates for the acute reinforcing actions of drugs of abuse and (2) how these transmitter systems change with long-term drug administration. We hypothesized that drug addiction is the result of a continuing cycle of spiraling distress fueled by psychosocial, genetic, and behavioral factors. The addiction cycle was conceptualized as containing 3 stages: preoccupation-anticipation, binge-intoxication, and withdrawal-negative affect.

Different neurotransmitter systems most likely are affected at different stages of the cycle. For example, dopamine, opioid peptides, and neuromodulators such as neuroactive steroids appear to be activated during the preoccupation-anticipation and binge-intoxication stages but decreased in function during the withdrawal-negative affect stage. In contrast, stress neurotransmitters such as corticotropin-releasing factor (CRF) appear to be recruited during the withdrawal-negative affect stage. This hypothesized cycle of spiraling distress not only integrates findings from diverse disciplines to provide an understanding of the neurobiology of drug addiction but also provides a heuristic framework for future studies.

With this framework, our advances in the neurobiology of addiction this past year can be summarized by several highlights. Rats trained to self-administer cocaine intravenously and then subjected to extinction procedures in which the cocaine is no longer available showed strong reinstatement of responding when subjected to a mild stressor. This stress effect was specific, because it did not reinstate responding for food. In a burying task, animals with a history of cocaine administration also showed a stresslike effect that was reversed by administration of a CRF competitive antagonist. This finding suggests that the stresslike effects of cocaine exposure may be mediated by activation of CRF systems in the brain.

In our studies on alcohol, we found that the neuroactive steroid allopregananolone had anxiolytic-like actions when administered to rats. Pharmacologic studies provided evidence that these effects were mediated by activation of GABAergic systems in the brain. Even more intriguing, female rats in which the estrus cycle was entrained showed significantly greater ethanol intake during diestrus when circulating levels of progesterone and its metabolite allopregnanolone are low. This result suggests that circulating levels of allopregnanolone may set the tone for the reinforcing actions of alcohol in females.

In our studies on opiates, we made significant advances in developing animal models of addiction. Motivational signs of withdrawal were precipitated in rats after a single exposure to morphine, and this effect was potentiated with a second morphine treatment. Also, rats had stresslike effects during spontaneous and precipitated opiate withdrawal in an elevated plus maze test of emotionality. The ₂-adrenergic agonist clonidine blocked the conditioned withdrawal observed with opiates if it was administered before conditioning but not if it was given before expression of the conditioned response. These results suggest that opiate dependence begins with the first administration of the drug, has effects similar to those of other drugs of abuse in activating stresslike responses during withdrawal, and may be resistant to treatment once established.

NEUROBIOLOGY OF STRESS: NEUROPEPTIDES

Previously, we established that the stress neurotransmitters CRF and urocortin can suppress appetite and that urocortin is 10--100 times more potent than CRF. These results have been confirmed with an animal model of free feeding in which eating behavior is charted during a 23-hour period each day by measuring responding for individual pellets of food and small amounts of water. In this model, both urocortin and CRF suppressed food intake in a dose-dependent manner, but urocortin was significantly more potent than CRF.

Work has also continued on the behavioral response of knockout mice that lack the receptor for CRF-1. Previous studies indicated that these animals have little or no corticosterone response to stress and a blunted behavioral response to stressors. Lack of the receptor had an antistresslike effect on rats in the elevated plus maze test of emotionality, and this effect was not blocked by prior long-term administration of corticosterone. These results suggest that the CRF-1 knockout effect is mediated by CRF-1 receptors independent of the pituitary adrenal axis.

PUBLICATIONS

Ahmed, S.H., Koob, G.F. Cocaine- but not food-seeking behavior is reinstated by stress after extinction. Psychopharmacology 132:289, 1997.

Britton, K.T., Southerland, S., Van Uden, E., Kirby, D., Rivier, J., Koob, G. Anxiolytic activity of NPY receptor agonists in the conflict test. Psychopharmacology 132:6, 1997.

Brot, M.D., Akwa, Y., Purdy, R.H., Koob, G.F., Britton, K.T. The anxiolytic-like effects of the neurosteroid allopregnanolone: Interactions with GABA_A receptors. Eur. J. Pharmacol. 325:1, 1997.

Brot, M.D., Rall, G.F., Oldstone, M.B.A., Koob, G.F., Gold, L.H. Deficits in discriminated learning remain despite clearance of long-term persistent viral infection in mice. J. Neurovirol. 3:265, 1997.

Caine, S.B., Koob, G.F., Parsons, L.H., Everitt, B.J., Schwartz, J.-C., Sokoloff, P. D₃ receptor test in vitro predicts decreased cocaine self-administration in rats. Neuroreport 8:2373, 1997.

Deroche, V., Caine, S.B., Heyser, C.J., Polis, I., Koob, G.F., Gold, L.H. Differences in the liability to self-administer intravenous cocaine between C57BL6 x SJL and BALB/cByJ mice. Pharmacol. Biochem. Behav. 57:429, 1997.

Heyser, C.J., McDonald, J.S., Beauchamp, V., Koob, G.F., Gold, L.H. The effects of cocaine on operant responding for food in several strains of mice. Psychopharmacology 132:202, 1997.

Heyser, C.J., Schulteis, G., Koob, G.F. Increased ethanol self-administration after a period of imposed ethanol deprivation in rats trained in a limited access paradigm. Alcohol. Clin. Exp. Res. 21:784, 1997.

Koob, G.F., Caine, S.B., Parsons, L., Markou, A., Weiss, F. Opponent process model and psychostimulant addiction. Pharmacol. Biochem. Behav. 57:513, 1997.

Koob, G.F., Le Moal, M. Drug abuse: Hedonic homeostatic dysregulation. Science 278:52, 1997.

Koob, G.F., Nestler, E.J. The neurobiology of drug addiction. J. Neuropsychiatry Clin. Neurosci. 9:482, 1997.

Koob, G.F., Nestler, E.J. The neurobiology of drug addiction. In: Salloway, S., Malloy, P., Cummings, J.L. (Eds.). The Neuropsychiatry of Limbic and Subcortical Disorders. American Psychiatric Press, Washington, DC, 1997, p. 179.

Koob, G.F., Stinus, L. Neurobiologie et neurochemie des pharmacodependances: Effets conditionnes. In: Padieu, R., et al. (Eds.). Dependance et Conduites de Consommation. Les Editions INSERM, Paris, 1997, p. 145.

Roberts, A.J., Koob, G.F. The neurobiology of addiction: An overview. Alcohol Health Res. World 21:101, 1997.

Rodriguez de Fonseca, F., Carrera, M.R.A., Navarro, M., Koob, G.F., Weiss, F. Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050, 1997.

Schulteis, G., Gold, L.H., Koob, G.F. Preclinical behavioral models for addressing unmet needs in opiate addiction. Semin. Neurosci. 9:94, 1997.

Walker, J.R., Koob, G.F. Orphan anxiety [Commentary]. Proc. Natl. Acad. Sci. U.S.A. 94:14217, 1997.