The 5-HT_2A Receptor (5-HT_2AR) Regulates Impulsive Action and Cocaine Cue Reactivity in Male Sprague-Dawley Rats

Abstract

Impulsivity and the attentional orienting response to cocaineassociated 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 2A R) 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 2A R 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.

Pimavanserin and Lorcaserin Attenuate Measures of Binge Eating in Male Sprague-Dawley Rats

“…Dunnett’s multiple comparisons test demonstrated that pimavanserin restricted binge intake at 0.3 mg/kg ( p < 0.001), 1.0 mg/kg ( p < 0.001), and 3.0 mg/kg ( p < 0.001) compared to vehicle administration (Figure 2B). This lack of dose-dependent responding is consistent with other studies that have demonstrated that 5-HT 2A R antagonists often exhibit flat or very narrow dose-response curves on behavioral analyses (Vanover et al, 2006; Nic Dhonnchadha et al, 2009; Anastasio et al, 2011; Sholler et al, 2018). Finally, a repeated measures one-way ANOVA demonstrated a main effect of pimavanserin on weight gain associated with HFF exposure in the combined analyses of Cohort 1 ( n = 16) and Cohort 3 ( n = 16) ( F 3,93 = 12.37; p < 0.001).…”

“…Pimavanserin and lorcaserin were injected 30 and 15 min prior to behavioral testing, respectively. Doses, routes of administration, and pretreatment times for single administration studies were chosen based on published (Neelakantan et al, 2017; Sholler et al, 2018) studies within our laboratory that suggested these dose ranges affect reward-related behaviors. Doses for the combined administration study were chosen based on the results of the single administration studies (i.e., the lowest dose of drug that decreased binge intake was used).…”

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits

“…In addition to 5-HT, several studies support a role of both 5-HT2A and 5-HT2C receptors in impulsive behavior. For example, 5-HT2A receptor expression in the mPFC was higher in high compared with low impulsive animals (170). Further, activation of 5-HT2A receptors induced behavioral impulsivity, while blockade of 5-HT2A receptors inhibited behavioral impulsivity (170, 171).…”

“…For example, 5-HT2A receptor expression in the mPFC was higher in high compared with low impulsive animals (170). Further, activation of 5-HT2A receptors induced behavioral impulsivity, while blockade of 5-HT2A receptors inhibited behavioral impulsivity (170, 171). Moreover, 5-HT2A receptor activation in the OFC induced decisional impulsivity (172).…”

Methylation Patterns of the HTR2A Associate With Relapse-Related Behaviors in Cocaine-Dependent Participants

“…There is mounting evidence that serotonin (5-HT) neurotransmission through the 5-HT 2A receptor (5-HT 2A R) controls neural mechanisms underlying relapse-related behavioral vulnerability to cocaine, including both impulsivity and cue reactivity (for reviews) (6,7). In preclinical models, selective 5-HT 2A R antagonists administered systemically consistently reduce impulsivity and cue-primed drug seeking (24)(25)(26)(27)(28)(29). In particular, pharmacological and genetic association studies implicate 5-HT 2A R regulation of impulsive choice (30)(31)(32)(33).…”