Neuroscience Program, Alcohol & Drug Abuse Research Center

Behavioral Science Laboratory, McLean Hospital

S. Barak Caine, Ph.D.

This basic (preclinical) research program incorporates neuroscience, pharmacology, behavior and genetics to study the roles of distinct proteins and genes in the addictive effects of drugs, particularly psychomotor stimulants including cocaine. One major line of investigation is focused on evaluating the roles of monoamine transporters and receptor subtypes, particularly those expressed in dopaminergic systems, and assessing the potential of related compounds as candidate medications for cocaine abuse and dependence. Behavioral pharmacology procedures are used to evaluate pharmacological mechanisms underlying the psychomotor, discriminative stimulus and reinforcing effects of cocaine and related drugs. These studies are conducted in collaboration with Alex Makriyannis (University of Connecticut) and also the Cocaine Treatment Discovery Program at the National Institute on Drug Abuse. A second major line of investigation includes behavioral studies in mice that are genetically altered as a result of either targeted mutations ("reverse genetics") or random mutations identified as potentially important from high throughput screening ("forward genetics"). These studies are aimed at assessing the roles of candidate genes and also identifying novel genes that may be involved in the behavioral effects of cocaine related to its abuse. Collaborators for these studies include Ming Xu (University of Cincinatti), Marc Caron (Duke University) and Joe Takahashi (Northwestern University).

Recent results from some of these studies suggest an important role for the dopamine D2 receptor in the behavioral effects of cocaine and particularly in the self-administration of high cocaine doses. First, dopamine D2-like agonists produced cocaine-like subjective and reinforcing effects, whereas other dopamine agonists produced these effects under a much narrower range of conditions (Caine et al., 1999a, 2000a, b). Second, pretreatment with dopamine D2 receptor antagonists increased rates of self-administration of high cocaine-doses (Caine and Koob, 1994; Caine et al., submitted). Third, dopamine D2 receptor "knockout" mice spontaneously self-administered high cocaine-doses at increased rates relative to wild type mice (Caine et al., 2000c; Caine et al., submitted). These latter findings suggest a role for the D2 receptor in mechanisms that normally limit rates of high-dose cocaine self-administration. Parallel studies are underway with mutant mice that lack either the dopamine D1 receptor or the dopamine D3 receptor. Collectively, systematic studies along these lines will increase our understanding of the functions of dopaminergic systems in general and their roles in the abuse-related effects of cocaine in particular. In addition, identification of novel genes and molecular mechanisms involved in the abuse-related effects of cocaine may provide new targets for the development of novel treatment medications.

Key words: Cocaine, dopamine, D1, D2, D3, receptor, transporter, knockout, mice, self-administration, reinforcer, addiction.

Grant Support: NIDA: R29 DA12142, Cocaine self-administration in dopamine knockout mice (Caine); RO1 DA11949, Dopamine transporter ligands as cocaine medications (Makriyannis), N01 DA08806, Screening compounds for utility as cocaine pharmacotherapies using the rat self-administration test (Caine). The Zaffaroni Foundation: Consortium for mouse genetics of addiction - Analysis of drug self-administration behavior (Caine).

Program Site: Behavioral Science Laboratory, Alcohol and Drug Abuse Research Center (J. H. Mendelson, N. K. Mello, Co-Directors), McLean Hospital.

Program Director: S. Barak Caine, Ph.D., McLean Hospital, 115 Mill St., Belmont, MA 02478. e-mail: barak@ mclean.harvard.edu Tel. (617) 855-2258; Fax. (617) 855-3865.

Training Opportunities: Both pre- and post-doctoral training positions are available.

Caine SB. Cocaine Abuse: Hard knocks for the dopamine hypothesis? Nature Neuroscience 1:90-92, 1998.

Caine SB, Negus SS, Mello NK, Bergman, J. Effects of dopamine D1-like and D2-like agonists in rats that self-administer cocaine. Journal of Pharmacology and Experimental Therapeutics 1999a;291:353-360.

Caine SB, Negus SS, Mello NK. Method for training operant responding and evaluating cocaine self-administration behavior in mutant mice. Psychopharmacology 1999b;147:22-24.

Caine SB, Negus SS, Mello NK. Effects of dopamine D1-like and D2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions. Psychopharmacology 2000a;148:41-51.

Caine SB, Negus SS, Mello NK, Bergman J. Effects of dopamine D1-like and D2-like agonists in rats trained to discriminate cocaine from saline: Influence of Experimental History. Experimental and Clinical Psychopharmacology 2000b;8:404-414.