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 motivated behavior and on how these systems change with the development of addiction, stress, and neurotoxic effects. Neuropharmacologic studies of addiction and stress are covered in the following report. Detailed results of neurochemical, neuromolecular, and neuroviral studies and of 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.H. Gold, A. Markou, L.H. Parsons, K.T. Britton,* M.B. Weinger,* M.A. Geyer,* M. Le Moal,** E. Riley,*** L. Stinus,** M. Cador,** L. Pulvirenti,**** F. Rodriguez De Fonseca,***** G. Schulteis,* S.C. Heinrichs,⁺ S.A. Ahmed, A.J. Roberts, D. Lin, J. Walker, A. Morse, E. Zorrilla, M. Vallee, A. Contarino, K.N. Gracy, V. David, C. Orsini, D. Macey, S. Watkins, G. Valdez, M.A. Arends, R. Lintz, M. Brennan, H. Moffitt, T. Guitierrez, I. Polis, R. Schroeder, M. Cole, V. Urena, D. Birkle

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

NEUROBIOLOGY OF ADDICTION

Studies on the neurobiology of addiction continue to focus on how the multiple neurochemical systems within the basal forebrain responsible for the acute reinforcing effects of drugs of abuse change with long-term drug administration. A primary interest in the past year was the development of animal models for the compulsive use of drugs associated with addiction and for the aversive motivational effects of drug withdrawal. Prolonged access to drugs produces changes in intake that may reflect changes in hedonic set point. In rats self-administering cocaine intravenously, access for 3 hours or less produced stable drug intake from day to day, and no escalation of intake occurred. However, in rats with 6 hours of access to cocaine each day, intake of cocaine escalated on a daily basis by 7--14 sessions.

When rats trained to self-administer alcohol orally were subjected to alcohol dependence by exposure to alcohol vapor for 2 weeks, intake of alcohol doubled during repeated testing during withdrawal. Animals subjected to long-term exposure to alcohol vapor also had enhanced alcohol self-administration even after detoxification, suggesting a potential model of protracted abstinence.

Animal models of aversive motivational effects of drug withdrawal were extended to nicotine and alcohol. Prolonged access to nicotine and the pairing of precipitated withdrawal with one compartment of a place-conditioning apparatus produced place aversion. Pairing of the "hangover" phase of short-term administration of alcohol (8--10 hours after administration of alcohol) with one compartment of a place-conditioning apparatus produced a similar place aversion.

Neuropharmacologic studies with these models of excessive drug intake indicated that neurotransmitter systems involved in the short-term reinforcing actions of drugs of abuse may become altered during dependence. With alcohol, agonists of the receptor for g-aminobutyric acid that do not alter ethanol intake in nondependent rats when injected into the central nucleus of the amygdala decrease alcohol intake when injected into alcohol-dependent animals.

In addition, in rats that self-administered alcohol, administration of a competitive antagonist of corticotropin-releasing factor (CRF) during acute withdrawal also decreased alcohol self-administration, suggesting that long-term use of alcohol increases the activity of this brain stress neurotransmitter system.

Doses of naloxone that induced place aversion in opiate-dependent rats produced a selective activation of brain activity as indicated by concentrations of c-fos in regions of the extended amygdala. In addition, naloxone precipitated a conditioned place aversion in rats after long-term exposure to nicotine or tetrahydrocannabinol, suggesting a role for opioid peptide systems in the development of motivational aspects of dependence. Altogether these results suggest further evidence of compromised function of neurotransmitter systems involved in the acute reinforcing effects of drugs of abuse and recruitment of brain stress systems. Future challenges will be to determine how these systems interact to produce the elevations in drug hedonic set point associated with protracted abstinence.

NEUROBIOLOGY OF STRESS: NEUROPEPTIDES

Work continues on the functional significance of neuropeptides of the CRF family, CRF and urocortin. For these studies, we used peptide antagonists and knockout mice that lack the CRF-1 receptor. Intracerebroventricular administration of CRF-related peptide fragments with little intrinsic activity at known CRF receptors improved cognitive performance, possibly by displacing the endogenous peptide from the CRF-binding protein. Consistent with this hypothesis, the performance-enhancing properties of CRF-related peptide fragments, but not their anxiogenic-like effects, in mice in the Morris water maze were related to the affinity of the fragments for the CRF-binding protein. In addition, CRF-1 knockout mice had deficits during retrieval of a spatial memory task. Altogether these results suggest that CRF systems may not only mediate behavioral responses to stressors by an action at limbic sites but also have a role in cognition at nonlimbic cortical sites.

PUBLICATIONS

Ahmed, S.H., Koob, G.F. Transition from moderate to excessive drug intake: A change in hedonic set point. Science 282:298, 1998.

Britton, K.T., Koob, G.F. Premenstrual steroids? Nature 392:869, 1998.

Eckardt, M.J., File, S.E., Gessa, G.L., Grant, K.A., Guerri, L., Hoffman, P.L., Kalant, H., Koob, G.F., Li, T.-K., Tabakoff, B. The effects of moderate alcohol consumption on the central nervous system. Alcohol. Clin. Exp. Res. 22:998, 1998.

Epping-Jordan, M.P., Markou, A., Koob, G.F. The dopamine D-1 receptor antagonist SCH 23390 injected into the dorsolateral bed nucleus of the stria terminalis decreased cocaine reinforcement in the rat. Brain Res. 784:105, 1998.

Epping-Jordan, M.P., Watkins, S.S., Koob, G.F., Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76, 1998.

Heinrichs, S.C., Klaasen, A., Koob, G.F., Schulteis, G., Ahmed, S., De Souza, E.B. Corticotropin-releasing factor receptor blockade enhances conditioned aversive properties of cocaine in rats. Psychopharmacology 136:247, 1998.

Heyser, C.J., Schulteis, G., Durbin, P., Koob, G.F. Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacology 18:125, 1998.

Kimes, A.S., Maldonado, R., Ambrosio, E., Koob, G.F., London, E.D. Cerebral glucose metabolism during opioid withdrawal following methylnaloxonium injection into the locus coeruleus. Brain Res. 814:1, 1998.

Koob, G.F., Carrera, R., Gold, L., Heyser, C., Maldonado-Irizarry, C., Markou, A., Parsons, L., Roberts, A., Schulteis, G., Stinus, L., Walker, J., Weissenborn, R., Weiss, F. Substance dependence as a compulsive behavior. J. Psychopharmacol. 12:39, 1998.

Koob, G.F., Roberts, A.J., Schulteis, G., Parsons, L.H., Heyser, C.J., Hyytia, P., Merlo-Pich, E., Weiss, F. Neurocircuitry targets in ethanol reward and dependence. Alcohol. Clin. Exp. Res. 22:3, 1998.

Koob, G.F., Sanna, P.P., Bloom, F.E. Neuroscience of addiction. Neuron 21:467, 1998.

Kosten, T.R., Markou, A., Koob, G.F. Depression and stimulant dependence: Neurobiology and pharmacotherapy. J. Nerv. Ment. Dis. 186:737, 1998.

Kreek, M.J., Koob, G.F. Drug dependence: Stress and dysregulation of brain reward pathways. Drug Alcohol Depend. 51:23, 1998.

Lee, R.S., Koob, G.F., Henriksen, S.J. Electrophysiological responses of nucleus accumbens neurons to novelty stimuli and exploratory behavior in the awake, unrestrained rat. Brain Res. 799:317, 1998.

Markou, A., Kosten, T.R., Koob, G.F. Neurobiological similarities in depression and drug dependence: A self-medication hypothesis. Neuropsychopharmacology 19:135, 1998.

Navarro, M., Chowen, J., Carrera, M.R.A., Del Arco, I., Villanua, M.A., Martin, Y., Roberts, A.J., Koob, G.F., Rodriguez de Fonseca, F., CB₁ cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport 9:3397, 1998.

Parsons, L.H., Weiss, F., Koob, G.F. Serotonin_1B receptor stimulation enhances cocaine reinforcement. J. Neurosci. 18:10078, 1998.

Pulvirenti, L., Balducci, C., Piercy, M., Koob, G.F. Characterization of the effects of the partial dopamine agonist terguride on cocaine self-administration in the rat. J. Pharmacol. Exp. Ther. 286:1231, 1998.

Raber, J., Sorg, O., Horn, T.F.W., Yu, N., Koob, G.F., Campbell, I.L., Bloom, F.E. Inflammatory cytokines: Putative regulators of neuronal and neuro-endocrine function. Brain Res. Brain Res. Rev. 26:320, 1998.

Roberts, A.J., McArthur, R.A., Hull, E.E., Post, C., Koob, G.F. Effects of amperozide, 8-OH-DPAT, and FG 5974 on operant responding for ethanol. Psychopharmacology 137:25, 1998.

Roberts, A.J., Smith, A.D., Weiss, F., Rivier, C., Koob, G.F. Estrous cycle effects on operant responding for ethanol in female rats. Alcohol. Clin. Exp. Res. 22:1564, 1998.

Schulteis, G., Stinus, L., Risbrough, V.B., Koob, G.F. Clonidine blocks acquisition but not expression of conditioned opiate withdrawal in rats. Neuropsychopharmacology 19:406, 1998.

Schulteis, G., Yackey, M., Risbrough, V., Koob, G.F. Anxiogenic-like effects of spontaneous and naloxone-precipitated opiate withdrawal in the elevated plus-maze. Pharmacol. Biochem. Behav. 60:727, 1998.

Smith, G.W., Aubry, J.-M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H., Chen, R., Marchuk, Y., Hauser, C., Bentley, C.A., Sawchenko, P.E., Koob, G.F., Vale, W., Lee, K.-F. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093, 1998.

Solbrig, M.V., Koob, G.F., Lipkin, W.I. Cocaine sensitivity in Borna disease virus infected rats. Pharmacol. Biochem. Behav. 59:1047, 1998.

Walker, J.R., Spina, M., Terenius, L., Koob, G.F. Nociceptin fails to affect heroin self-administration in the rat. Neuroreport 9:243, 1998.