Pharmacological Evidence for an Abstinence-InducedSwitch in 5-HT1B Receptor Modulation of CocaineSelf-Administration and Cocaine-Seeking Behavior

摘要

Studies examining serotonin-1B (5-HT1B) receptor manipulations on cocaine self-administration and cocaine-seeking behavior initially seemed discrepant. However, we recently suggested based on viral-mediated 5-HT1B-receptor gene transfer that the discrepancies are likely due to differences in the length of abstinence from cocaine prior to testing. To further validate our findings pharmacologically, we examined the effects of the selective 5-HT1B receptor agonist CP 94,253 (5.6 mg/kg, s.c.) on cocaine self-administration during maintenance and after a period of protracted abstinence with or without daily extinction training. We also examined agonist effects on cocaine-seeking behavior at different time points during abstinence. During maintenance, CP 94,253 shifted the cocaine self-administration dose–effect function on an FR5 schedule of reinforcement to the left, whereas following 21 days of abstinence CP 94,253 downshifted the function and also decreased responding on a progressive ratio schedule of reinforcement regardless of extinction history. CP 94,253also attenuated cue-elicited and cocaine-primed drug-seeking behaviorfollowing 5 days, but not 1 day, of forced abstinence. The attenuatingeffects of CP 94,253 on the descending limb of the cocaine dose–effectfunction were blocked by the selective 5-HT1B receptorantagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating5-HT1B receptor mediation. The results support a switchin 5-HT1B receptor modulation of cocaine reinforcementfrom facilitatory during self-administration maintenance to inhibitoryduring protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medicationfor treating cocaine dependence.