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The Journal of Neuroscience, December 1, 1998, 18(23):10078-10089

Serotonin_1B Receptor Stimulation Enhances Cocaine Reinforcement

Loren H. Parsons, Friedbert Weiss, and George F. Koob

Department of Neuropharmacology, Division of Psychopharmacology, The Scripps Research Institute, La Jolla, California 92037

The effects of serotonin_1B [5-hydroxytryptamine_1B (5-HT_1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT_1B 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-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyridine (CP 93,129) (3 and 10 µg, 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-HT_1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT_1B 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-HT_1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935) (0.3-10 mg/kg) but was unaffected by the 5-HT_1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-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-HT_1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT_1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT_1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.

Key words: cocaine; self-administration; 5-HT_1B; 5-HT_1A; RU 24969; CP 94,253; CP 93,129; GR 127,935; 8-OH-DPAT; p-MPPI; progressive ratio

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182310078-12$05.00/0

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