Effects of 5-HT1B receptor ligands microinjected into the ventral tegmental area on cocaine discrimination in rats.

Some recent data indicate a significant interaction between serotonin (5-hydroxytryptamine; 5-HT) and dopamine in mesolimbic brain structures (e.g. the ventral tegmental area) which modulate the behavioral effects of cocaine in rats. The present study investigated the role of 5-HT(1B) receptors in the ventral tegmental area in the discriminative stimulus effects of cocaine in rats. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, intraperitoneally (i.p.)) from saline (i.p.) in a two-choice, water-reinforced fixed-ratio 20 procedure. After reaching the cocaine-saline discrimination criterion, the rats were stereotaxically implanted with bilateral cannulae in the ventral tegmental area and were then microinjected with selective 5-HT(1B) receptor ligands. In substitution studies, microinjections of the 5-HT(1B) receptor antagonist, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride (GR 55562; 0.1-1 microg/side), did not evoke cocaine-lever responding, whereas the 5-HT(1B) receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP 93129; 0.3-1 microg/side), induced partial substitution for cocaine. Intra-tegmental microinjections with the 5-HT(1B) receptor antagonist, GR 55562 (0.1-1 microg/side), before cocaine (5 mg/kg), which alone produced 98% cocaine-lever responses, decreased in a dose-dependent manner the discriminative stimulus effects of the psychostimulant. On the other hand, combination tests using a fixed dose of CP 93129 (0.3 or 1 microg/side), given into the ventral tegmental area prior to low systemic doses of cocaine (1.25-2.5 mg/kg), increased cocaine discrimination. These results seem to indicate that tegmental 5-HT(1B) receptors are necessary to express the discriminative stimulus effects of cocaine.