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NEUROPHARMACOLOGY

Serotonin_1B Receptors in the Ventral Tegmental Area Modulate Cocaine-Induced Increases in Nucleus Accumbens Dopamine Levels

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California

Previous work has demonstrated that peripheral serotonin_1B (5-HT_1B) receptor agonist administration facilitates the behavioral and neurochemical effects of cocaine. This study used dual probe microdialysis to investigate whether activation of serotonin_1B (5-HT_1B) receptors in the ventral tegmental area (VTA) alters the ability of peripherally administered cocaine to elevate dopamine (DA) levels in the ipsilateral nucleus accumbens (NAcc) of drug-naive Wistar rats. Intra-VTA administration of the selective 5-HT_1B agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b]pyridin-5-one dihydrochloride (CP 93,129) by reverse dialysis produced a dose-dependent (30 and 100 µM) potentiation of cocaine-induced (10 mg/kg i.p.) increases in NAcc DA efflux and concurrent cocaine-induced decreases in VTA GABA efflux. There was no effect of either local CP 93,129 or peripheral cocaine on VTA glutamate efflux. Intra-VTA administration of the 5-HT_1A/7 receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT; 100 µM) did not alter cocaine-induced alterations in NAcc DA or VTA GABA, suggesting that the effects of CP 93,129 were not mediated through 5-HT_1A receptors. Moreover, the effects of intra-VTA CP 93,129 (100 µM) on both cocaine-induced increases in NAcc DA levels and cocaine-induced decreases in VTA GABA levels were reversed by coadministration of the selective 5-HT_1B receptor antagonist 3-[3-(dimethylamine)propyl]-4-hydroxy-N-[4-(4-pyridinyl] phenyl] benzamide dihydrochloride (GR 55562; 300 µM). In the absence of cocaine, intra-VTA CP 93,139 produced an increase in NAcc DA and decrease in VTA GABA levels. However, intra-VTA GR 55562 alone had no effect on any of our neurochemical measures. These findings indicate that activation of VTA 5-HT_1B receptors potentiates cocaine-induced increases in NAcc DA levels by enhancing the ability of cocaine to decrease VTA GABA efflux.

Address correspondence to: Dr. Loren H. Parsons, The Scripps Research Institute, Department of Neuropharmacology, CVN-7, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: lparsons{at}scripps.edu