Abstract
The 5-HT indirect agonist, d-fenfluramine, attenuates cue reinstatement of extinguished cocaine-seeking behavior. To investigate the role of 5-HT receptor subtypes in this effect, we examined whether the attenuation is reversed by either a 5-HT1A, 5-HT2A/C, or 5-HT2C receptor antagonist. We also examined the effects of the antagonists alone on both cue and cocaine-primed reinstatement. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, i.v.) paired with light and tone cues underwent daily extinction sessions during which responding had no consequences. We then examined the effects of WAY 100635 (0–1.0 mg/kg, s.c.), ketanserin (0–10.0 mg/kg, i.p.), or SB 242,084 (0–1.0 mg/kg, i.p.) with and without d-fenfluramine (1.0 mg/kg, i.p.) pretreatment on cue reinstatement. Subsequently, we examined the effects of the antagonists on cocaine-primed (7.5 or 15.0 mg/kg, i.p.) reinstatement. The 5-HT1A antagonist, WAY 100635, failed to alter cue reinstatement, but attenuated cocaine reinstatement. Conversely, the 5-HT2A/C antagonist, ketanserin, attenuated cue reinstatement, but failed to alter cocaine reinstatement. The 5-HT2C-selective antagonist, SB 242,084, did not alter cue or cocaine reinstatement, but was the only drug that reversed the d-fenfluramine-induced attenuation of cue reinstatement. The findings suggest that stimulation of 5-HT1A receptors plays a critical role in cocaine-primed, but not cue, reinstatement. Furthermore, 5-HT2A and 5-HT2C receptors may play oppositional roles in cue reinstatement. The SB 242,084 reversal of the d-fenfluramine attenuation suggests that stimulation of 5-HT2C receptors inhibits cue reinstatement, whereas the ketanserin-induced attenuation of cue reinstatement suggests that decreased stimulation of 5-HT2A receptors inhibits this behavior.
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Acknowledgements
The authors thank Arturo Zavala, Adam Taylor, and Dr Brock Schroeder for their expert technical assistance, and Arturo Zavala and Andrea Alleweireldt for their comments on a previous version of this manuscript. This research was supported by a grant from NIDA, DA11064, and the Howard Hughes Medical Institute through the Undergraduate Biology Enrichment Program.
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Burmeister, J., Lungren, E., Kirschner, K. et al. Differential Roles of 5-HT Receptor Subtypes in Cue and Cocaine Reinstatement of Cocaine-Seeking Behavior in Rats. Neuropsychopharmacol 29, 660–668 (2004). https://doi.org/10.1038/sj.npp.1300346
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DOI: https://doi.org/10.1038/sj.npp.1300346
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