Effects of serotonin 5-HT1B receptor ligands on the cocaine- and food-maintained self-administration in rats.

In order to substantiate the concept that cocaine behavioral effects may be influenced by serotonin (5-HT)1B receptors, male Wistar rats were trained to self-administer cocaine intravenously (0.5 mg/kg/injection), and were systemically pretreated with the selective 5-HT1B receptor antagonist N-[3-[3-(dimethylamine)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641), or with the agonist 5-propoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) before test session during the maintenance phase. The effects of the 5-HT1B receptor ligands on a control reinforcer (food)-induced self-administration and on basal locomotor activity were also assessed. SB 216641 (2.5-7.5 mg/kg) was inactive in altering the cocaine (0.5 mg/kg/injection)-maintained responding and at the highest dose (7.5 mg/kg) it did not alter the self-administration of a cocaine dose on the descending limb of the cocaine (0.125-0.5 mg/kg/injection) dose-effect function. On the other hand, CP 94253 (2.5-7.5 mg/kg) attenuated the cocaine (0.5 mg/kg/injection)-maintained responding with a significant inhibitory effect seen at 7.5 mg/kg, while its doses of 2.5-5 mg/kg potently reduced the self-administration of cocaine (0.125-0.25 mg/kg/injection), in a manner similar to the effect produced by increasing the unit dose of cocaine. The inhibitory effects of CP 94253 (5 mg/kg) on the cocaine (0.125 or 0.25 mg/kg/injection) self-administration were blocked by SB 216641 (7.5 mg/kg). Food reinforcing potential was not altered when either SB 216641 or CP 94253 was given in a dose range between 2.5-7.5 mg/kg. Moreover, none of the 5-HT1B receptor ligands altered horizontal locomotor activity while CP 9253 significantly reduced vertical activity. Our present findings extend previous observations that tonic activation of 5-HT1B receptors is not required for cocaine reinforcement while pharmacological stimulation of 5-HT1B receptors enhances such a property of the psychostimulant. Furthermore, we demonstrated that 5-HT1B receptor agonist-induced enhancement of cocaine reward was independent of an alteration in natural reinforcement.