SEROTONIN(1B) RECEPTOR STIMULATION ENHANCES COCAINE REINFORCEMENT

The effects of serotonin(1B) [5-hydroxytryptamine(1B) (5-HT1B)] recept or activation on cocaine reinforcement were investigated using intrave nous cocaine self-administration by rats. The 5-HT1B receptor agonists methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), rahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and ,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyridine (CP 93,129) (3 and 10 mu g, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the f ixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addi tion, each of these 5-HT1B agonists lowered the threshold dose of coca ine that supported self-administration. These results are consistent w ith a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterat ions similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl [1,2,4]oxadiazol-3-yl) -biphenyl-4-carboxylic methodoxy-3(4-methyl-piperazin-1-yl)-phenyl]-am ide (GR 127,935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A recep tor antagonist henyl)-1-piperazinyl]ethyl]-N-2-pyridinylbenzamide (p-M PPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effe cts alone. Together, these findings indicate that 5-HT1B receptor stim ulation facilitates the reinforcing properties of cocaine. These resul ts are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of dru g abuse research.