The 5-HT2A Receptor (5-HT2AR) Regulates Impulsive Action and Cocaine Cue Reactivity in Male Sprague-Dawley Rats

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-HT_2A receptor (5-HT_2AR) 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-HT_2AR 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.

Fig. 1.

M100907 and pimavanserin suppress target premature responses in the 1-CSRT task. The effects of M100907 (0.001, 0.01, and 0.1 mg/kg; n = 11) or pimavanserin (0.3, 1, 3 mg/kg; n = 9) were each evaluated under an ITI5 schedule in the 1-CSRT task. (A) M100907 significantly decreased target premature responses at 0.1 mg/kg (*P < 0.05 vs. VEH). (B) Pimavanserin significantly decreased target premature responses at 0.3, 1, and 3 mg/kg (*P < 0.05 vs. VEH).

Fig. 2.

Pimavanserin suppresses cue reactivity on FA day 30, but not FA day 1, from cocaine self-administration. (A) Total presses (mean ± S.E.M.) on the active (white circles) or inactive lever (black circles; left y-axis), and total number of cocaine infusions (mean ± S.E.M.) obtained (gray circles; right y-axis) are presented for the acquisition and maintenance phase of cocaine self-administration. (B) Previously active and inactive lever presses (mean ± S.E.M.) are presented for the cue reactivity test session in VEH-treated rats on FA day 1 and FA day 30 from cocaine self-administration. Cue reactivity is significantly elevated on FA day 30 vs. FA day 1 from cocaine self-administration (*P < 0.05; n = 11 or 14/group). The effects of pimavanserin (0.3, 1, 3, 10 mg/kg) on previously active and inactive lever presses (mean ± S.E.M.) on (C) FA day 1 (n = 12–15/group) or (D) FA day 30 (n = 11–12/group) from the last cocaine self-administration session are presented. Pimavanserin suppressed previously active, but not inactive, lever presses on FA day 30 from cocaine self-administration (*P < 0.05 vs. VEH).

Fig. 3.

Baseline levels of impulsive action predict the efficacy of pimavanserin to suppress cocaine cue reactivity on FA day 30 from cocaine self-administration. Target premature responses under an ITI5 schedule in the 1-CSRT task (mean ± S.E.M.) are presented on the x-axis, and previously active lever presses (mean ± S.E.M.) on the cue reactivity test session are presented on the y-axis. The relationship between target premature responses and previously active lever presses after pretreatment with VEH or pimavanserin (PIM; 0.3, 1, 3, 10 mg/kg) is represented by a linear regression line for each pretreatment condition. (A) Target premature responses predicted the number of previously active lever presses exhibited on FA day 1 and on FA day 30 in VEH-treated rats (F_(1,22) = 5.081, P < 0.05). (B) No relationship was found between target premature responses and the number of previously active lever presses exhibited on FA day 1 after pretreatment with vehicle or pimavanserin (F_(4,62) = 0.405; n.s.). (C) Target premature responses predicted the number of previously active lever presses exhibited on FA day 30 after pretreatment with vehicle or pimavanserin (F_(4,52) = 4.04, P = 0.05).