News and Publications

Neurobiology of Drug and Alcohol Dependence

F. Weiss, L.H. Parsons, G.F. Koob, D.L. Gessa,* R.A. Gonzales,** R.M. Richter,*** S.N. Katner, R. Martin-Fardon, O. Shahar, A.D. Smith, T.M. Kerr, D.L. Smith, K. Pedersen

* Università di Cagliari, Cagliari, Italy
** University of Texas, Austin, TX
*** Institute of Molecular Pharmacology, Berlin, Germany

Work in our laboratory is concerned with the neurobiological bases of motivation and reinforcement. Currently, this research focuses on neurochemical and neuroendocrine mechanisms in vulnerability to drug abuse and the development of drug dependence.

SUPPRESSION OF ETHANOL CONSUMPTION BY OPIATE ANTAGONISTS

The opiate antagonist naltrexone effectively decreases ethanol intake and the likelihood of relapse in human alcoholics. However, the mechanisms underlying these actions are not well understood. We examined the possibility that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine release in the nucleus accumbens; such stimulation is thought to play an important role in the reinforcing and addictive actions of ethanol.

Naltrexone significantly reduced ethanol self-administration by rats and attenuated ethanol-induced increases in dopamine release. Dose-effect analyses established that the latter effect was not merely a function of reduced ethanol intake; naltrexone attenuated the efficacy of ethanol in elevating extracellular levels of dopamine. These results suggest that suppression of ethanol intake by opiate antagonists may be the result of interference with dopamine-dependent aspects of ethanol reinforcement.

REINSTATEMENT OF ETHANOL-SEEKING BEHAVIOR BY ALCOHOL-ASSOCIATED ENVIRONMENTAL STIMULI

Environmental stimuli associated with the availability or the subjective effects of ethanol can induce alcohol craving and trigger episodes of relapse in human alcoholics. Despite the importance of these stimuli, controlled neurobiological studies on their role in relapse have been scarce, and appropriate animal models are still being developed. We examined the effects of discriminative stimuli associated with alcohol availability on ethanol-seeking behavior in rats after 3 weeks of forced abstinence in the animals. Presentation of these "ethanol cues" elicited and maintained behavior directed at obtaining ethanol, and this effect was selectively attenuated by the opiate antagonist naltrexone.

Thus, current procedures that dissociate the motivational from the consummatory aspects of ethanol reinforcement may be useful for investigating the neurobiological mechanisms that underlie ethanol-seeking behavior and relapse. Moreover, the reversal of relapse by naltrexone, an agent effective in preventing relapse in human alcoholics, confirms that these procedures have predictive validity as a model of relapse.

MODIFICATION OF COCAINE SELF-ADMINISTRATION

Agonist pharmacotherapeutic approaches such as methadone maintenance therapy have been among the most successful strategies in the treatment of opiate abuse. Until other treatments become available, agonist therapy may also be useful in the treatment of psychostimulant addiction. The novel phencyclidine derivative N-[1-(2-benzo(b)thiophenyl)cyclohxyl]piperidine (BTCP) has neurochemical properties similar to those of cocaine and may have agonist therapeutic potential. Our studies have tentatively confirmed this possibility.

We found that BTCP shares behavioral effects with cocaine and suppresses the self-administration of cocaine in rats. Moreover, although BTCP was readily self-administered by animals previously exposed to cocaine, the derivative did not support self-administration in drug-naive animals. These data suggest that BTCP can substitute for the psychoactive effects of cocaine in individuals with a history of cocaine use and that its potential for being addictive or habit forming in drug-naive subjects is limited.

EFFECT OF STRESS ON IMPAIRED MESOLIMBIC DOPAMINE FUNCTION DURING PSYCHOSTIMULANT WITHDRAWAL

Previously, we showed that enhanced release of the stress regulatory neuropeptide corticotropin-releasing factor within the central nucleus of the amygdala is an important factor in the stresslike and negative affective consequences of withdrawal from cocaine, ethanol, and cannabinoids. These data implicated activation of neurons containing the neuropeptide in the central nucleus of the amygdala as a common element in withdrawal from drugs of abuse and in vulnerability to relapse. Studies done during the past year indicate that in addition to causing disturbances in brain systems involving corticotropin-releasing factor, long-term exposure to psychostimulants can disrupt normal stress responses at other levels.

In rats, withdrawal after long-term exposure to amphetamine led to a long-lasting deficit in dopamine release within the limbic forebrain. More importantly, stimulation of dopamine release in response to restraint stress, a typical adaptive response to this stressor in normal animals, no longer occurred during amphetamine withdrawal. In fact, restraint stress significantly exacerbated the dopaminergic deficit induced by amphetamine withdrawal alone. These neurochemical alterations may reflect a disruption of mechanisms that regulate affective homeostasis, leading to an impairment in the ability to cope with stress or emotional challenges. Such defects may have important implications for emotional states such as depression or helplessness and in vulnerability to relapse.

PUBLICATIONS

de Fonseca, F.R., Carrera, M.R.A., Navarro, M., Koob, G.F., Weiss, F. Marijuana addiction. Science 277:751, 1997.

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

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

Parsons, L.H., Kerr, T.K., Weiss, F. A simple chromatographic HPLC method for the determination of dopamine and cocaine from a single in vivo brain microdialysis sample. J. Chromatogr., in press.

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., in press.

Weiss, F., Imperato, A., Casu, M.A., Mascia, M.S., Gessa, G.L. Opposite effects of stress on dopamine release in the limbic system of drug-naive and chronically amphetamine-treated rats. Eur. J. Pharmacol. 337:219, 1997.