Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-administration in Rhesus Monkeys.
From: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. leonard@rmy.emory.edu
The Journal of pharmacology and experimental therapeutics
- Publish Date: Feb 2007
- ISSN: 0022-3565
- Volume: 320
- Issue: 2
- Pages: 757-65
- Medium: Print
- Language: English
- Citation (JAMA): Howell Leonard L, Carroll F Ivy, Votaw John R, et al. Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-administration in Rhesus Monkeys.. J. Pharmacol. Exp. Ther. Feb 2007;320:757-65
Abstract
Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3beta-(4-chlorophenyl)tropane-2beta-[3-(4’-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED(50)) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED(50) dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED(50) dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.
Mesh Headings (Keywords): Animals, Cocaine, Dopamine Plasma Membrane Transport Proteins, Dose-Response Relationship, Drug, Female, Fluoxetine, Macaca mulatta, Male, Self Administration, Serotonin Uptake Inhibitors, Tropanes
Check for Full Text / PubMed Unique Identifier (PMID): 17105829
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