Serotonin1BReceptor Stimulation Enhances Cocaine Reinforcement

The effects of serotonin1B 5-hydroxytryptamine1B (5-HT1B) receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo3,2-bpyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo3, 2-bpyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with 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 alterations 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-methyl1,2, 4oxadiazol-3-yl)-biphenyl-4-carboxylic acid4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-2-[4-(methoxyphenyl)-1-piperazinylethyl]-N-2-pyridinyl- benzamide (p-MPPI; 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 effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.