Pharmacological evidence for an abstinence-induced switch in 5-HT 1B receptor modulation of cocaine self-administration and cocaine-seeking behavior

Nathan S. Pentkowski, Bryan G. Harder, Samuel J. Brunwasser, Ryan M. Bastle, Natalie A. Peartree, Krishna Yanamandra, Matt D. Adams, Taleen Der-Ghazarian, Janet Neisewander

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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-HT 1B-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 94,253 also attenuated cue-elicited and cocaine-primed drug-seeking behavior following 5 days, but not 1 day, of forced abstinence. The attenuating effects of CP 94,253 on the descending limb of the cocaine dose-effect function were blocked by the selective 5-HT1B receptor antagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating 5-HT1B receptor mediation. The results support a switch in 5-HT 1B receptor modulation of cocaine reinforcement from facilitatory during self-administration maintenance to inhibitory during protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medication for treating cocaine dependence.

Original languageEnglish (US)
Pages (from-to)168-176
Number of pages9
JournalACS chemical neuroscience
Volume5
Issue number3
DOIs
StatePublished - Mar 19 2014

Keywords

  • Addiction
  • reinforcement
  • reinstatement
  • relapse
  • reward
  • serotonin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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    Pentkowski, N. S., Harder, B. G., Brunwasser, S. J., Bastle, R. M., Peartree, N. A., Yanamandra, K., Adams, M. D., Der-Ghazarian, T., & Neisewander, J. (2014). Pharmacological evidence for an abstinence-induced switch in 5-HT 1B receptor modulation of cocaine self-administration and cocaine-seeking behavior. ACS chemical neuroscience, 5(3), 168-176. https://doi.org/10.1021/cn400155t