Brain dopamine receptors play an important role in behavior and mediate the effects of certain abused drugs including cocaine and combinations of selected H1 antagonists and opioids (e.g., T's and Blues). Recently, two subtypes of dopamine receptors (D1 and D2) have been identified in vitro, suggesting that the role of dopamine in different behaviors and in the effects of abused drugs may involve selective effects at one type of receptor or interactions between the two types of receptors. Information regarding the role of the subtypes of dopamine receptors is of fundamental importance to our understanding of brain mechanisms in behavior. Yet, little is known regarding the interplay of D1 and D2 receptors in ongoing behavior or in the effects of abused drugs, and research in primate species is limited. In the present period, we have initiated studies of the behavioral effects of dopaminergic drugs in monkeys to specifically address these issues. Our preliminary findings already indicate that the behavioral effects of dopamine agonists differing in potency or selectivity can be markedly dissimilar. We propose to continue our investigations by systematically establishing the behavioral effects of direct agonists differing in selectivity for D1 and D2 receptors and of indirect nonselective dopamine agonists. Extension of our ongoing studies involving schedule-controlled performance, drug self-administration, drug discrimination, and unconditioned behavior to determine the effects of dopaminergic drugs differing in potency or efficacy will establish the characteristic behavioral actions of selective D1 or D2 agonists. The effects of D1 and D2 agonists after treatment with selective antagonists will allow us to evaluate the pharmacological specificity and quantitative nature of these actions. We also will study the effects of combinations of D1 and D2 agonists to evaluate the functional consequences of combined D1 and D2 receptor stimulation. Finally, we will evaluate the modification of the effects of dopaminergic drugs by the mixed-action opioid buprenorphine. The abuse of combinations of dopaminergic and opioid drugs (e.g., T's and Blues, black crack) is well-established. The results of our studies will provide important information for determining mechanisms that mediate such abuse-related effects as well as the potential therapeutic effects of buprenorphine in treatment of cocaine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003774-09
Application #
3208405
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1985-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Desai, Rajeev I; Bergman, Jack (2010) Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J Pharmacol Exp Ther 335:807-16
Bergman, Jack (2008) Medications for stimulant abuse: agonist-based strategies and preclinical evaluation of the mixed-action D-sub-2 partial agonist aripiprazole (Abilify). Exp Clin Psychopharmacol 16:475-83
Desai, Rajeev I; Neumeyer, John L; Paronis, Carol A et al. (2007) Behavioral effects of the R-(+)- and S-(-)-enantiomers of the dopamine D(1)-like partial receptor agonist SKF 83959 in monkeys. Eur J Pharmacol 558:98-106
Desai, Rajeev I; Neumeyer, John L; Bergman, Jack et al. (2007) Pharmacological characterization of the effects of dopamine D(1) agonists on eye blinking in rats. Behav Pharmacol 18:745-54
Bergman, Jack; Paronis, Carol A (2006) Measuring the reinforcing strength of abused drugs. Mol Interv 6:273-83
Gasior, Maciej; Bergman, Jack; Kallman, Mary Jeanne et al. (2005) Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys. Neuropsychopharmacology 30:758-64
Jutkiewicz, Emily M; Bergman, Jack (2004) Effects of dopamine D1 ligands on eye blinking in monkeys: efficacy, antagonism, and D1/D2 interactions. J Pharmacol Exp Ther 311:1008-15
Gasior, Maciej; Paronis, Carol A; Bergman, Jack (2004) Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys. J Pharmacol Exp Ther 308:249-59
Czoty, Paul W; Ramanathan, Chinnasamy R; Mutschler, Nicole H et al. (2004) Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors. J Pharmacol Exp Ther 311:720-7
Czoty, Paul W; Makriyannis, Alexandros; Bergman, Jack (2004) Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys. Psychopharmacology (Berl) 175:170-8

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