The 5-HT2A receptor (5-HT2AR) regulates impulsive action and cocaine cue reactivity in Male Sprague-Dawley rats

Dennis J. Sholler, Sonja J. Stutz, Robert G. Fox, Edward L. Boone, Qin Wang, Kenner C. Rice, F. Gerard Moeller, Noelle Anastasio, Kathryn Cunningham

Research output: Contribution to journalArticle

Abstract

Impulsivity and the attentional orienting response to cocaine-associated cues (cue reactivity) promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity (incubation) occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist M100907 suppresses impulsive action, or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration–approved selective 5-HT2AR antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action (premature responses) measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD.

LanguageEnglish (US)
Pages41-49
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume368
Issue number1
DOIs
StatePublished - Jan 1 2019

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Receptor, Serotonin, 5-HT2A
Cocaine
Cues
Sprague Dawley Rats
Self Administration
Serotonin 5-HT2 Receptor Antagonists
Recurrence
Reaction Time
Serotonin
Diagnostic Self Evaluation
Impulsive Behavior
United States Food and Drug Administration

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

The 5-HT2A receptor (5-HT2AR) regulates impulsive action and cocaine cue reactivity in Male Sprague-Dawley rats. / Sholler, Dennis J.; Stutz, Sonja J.; Fox, Robert G.; Boone, Edward L.; Wang, Qin; Rice, Kenner C.; Gerard Moeller, F.; Anastasio, Noelle; Cunningham, Kathryn.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 368, No. 1, 01.01.2019, p. 41-49.

Research output: Contribution to journalArticle

Sholler, Dennis J. ; Stutz, Sonja J. ; Fox, Robert G. ; Boone, Edward L. ; Wang, Qin ; Rice, Kenner C. ; Gerard Moeller, F. ; Anastasio, Noelle ; Cunningham, Kathryn. / The 5-HT2A receptor (5-HT2AR) regulates impulsive action and cocaine cue reactivity in Male Sprague-Dawley rats. In: Journal of Pharmacology and Experimental Therapeutics. 2019 ; Vol. 368, No. 1. pp. 41-49.
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