Role of 5-hydroxytryptamine(1B) receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats

Mesolimbic dopamine pathways play a critical role in the behavioural effect s of cocaine in rodents. Nonetheless, research has also demonstrated involv ement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effect s. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhanc e or antagonise) the discriminative stimulus effects of cocaine. Male Wista r rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i .p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discriminat ion paradigm. In substitution tests, the selective 5-HT receptor agonist 3- (1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2 .5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i .p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combina tion experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of coc aine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2. 5 mg/kg) which elicited lower than 40% drug-lever responding, caused full s ubstitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submax imal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pre treatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-p iperazinyl)phenyl]-2 ' -methyl-4 '-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1 ' - biphenyl-4-carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamin o)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg , s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantl y attenuated the enhancement of cocaine discrimination evoked by a combinat ion of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in t he cocaine-induced discriminative stimuli In rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors - that also see m to be a target for fluoxetine-mediated increase in 5-HT neurotransmission - can enhance the overall effects of cocaine.