Drug addiction arising from abuse of cocaine and other psychomotor stimulants continues to be a critical public health concern. Currently, effective pharmacotherapies are not available to combat the addictive power of cocaine. Consequently, medication strategies and candidate medications that reduce cocaine's reinforcing strength need to be identified. The proposed research is designed to address these problems with innovative self-administration procedures in which dose-effect functions for the relative reinforcing strength of cocaine can be rapidly determined. Self-administration procedures in nonhuman primates have been integral to previous studies of abuse liability and drug dependence; however, procedures that are suitably modified to identify medications that alter reinforcing strength, particularly in chronic studies and under varying behavioral conditions, have not yet been advanced. In our novel procedure, rhesus monkeys learn to distribute their behavior throughout the session on the basis of the relative reinforcing strengths of an i.v. solution that is available for self-injection and an alternative reinforcer (food). This procedure is especially designed to divorce the reinforcing strength of drugs from their other behavioral effects. In proposed studies, the distribution of behavior will be determined under varying conditions of response cost and response suppression to establish the full range of cocaine's relative reinforcing strength. Next, the acute and chronic effects of drugs that represent different agonist-based medication strategies will be fully evaluated. Strategies will be based upon indirect and direct monoaminergic mechanisms that may be associated with the reinforcing or other subjective effects of stimulant drugs. It is expected that some strategies may more effectively combat the reinforcing strength of cocaine when it is low whereas other strategies may be useful over a wider range of conditions. The effects of selected drugs in combination also will be evaluated to explore the possibility that mechanistic synergism may expand the effectiveness or increase the potency of medications. Finally, the effects of candidate medications on cocaine's overt behavioral effects (visual scanning/checking) also will be evaluated during chronic exposure. These effects may be related to behavioral toxicity, and will provide important information with which to evaluate the therapeutic advantage of different agonist-based medication strategies. Overall, our proposed studies in monkeys will provide significant advances for evaluating the reinforcing strength of cocaine and for assessing the effectiveness with which different agonist-based medications may combat the addictive power of stimulant drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA010566-07
Application #
6543053
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hubner, Carol B
Project Start
1996-09-30
Project End
2007-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$395,000
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Paronis, Carol A; Bergman, Jack (2011) Buprenorphine and opioid antagonism, tolerance, and naltrexone-precipitated withdrawal. J Pharmacol Exp Ther 336:488-95
Desai, Rajeev I; Bergman, Jack (2010) Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J Pharmacol Exp Ther 335:807-16
Desai, Rajeev I; Paronis, Carol A; Martin, Jared et al. (2010) Monoaminergic psychomotor stimulants: discriminative stimulus effects and dopamine efflux. J Pharmacol Exp Ther 333:834-43
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
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

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