Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

Abstract

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Dampened 5-HT 2C R agonist sensitivity is also associated with higher cue reactivity in outbred rats (Anastasio et al, 2014a,b). In outbred rats engineered with a genetic knockdown of the 5-HT 2C R in the mPFC, both impulsive action and cue reactivity were elevated over controls, suggesting that reduced 5-HT 2C R tone in the mPFC confers vulnerability to these interlocked behaviors (Anastasio et al, 2014b). These data suggest that therapeutic strategies to enhance 5-HT 2C R function may be useful to maximize suppression of impulsivity and cue reactivity which may enhancement control over relapse in cocaine use disorder.…”

“…Importantly, the 5-HT 2C R agonist Ro 60-0175 and M100907 both attenuated cocaine-induced premature responding on the 5-CSRT task, showing similar functional effects on a measure of impulsivity (Fletcher et al, 2011). A recent study used the 1-CSRT task to identify high and low impulsive phenotypes in rats (Anastasio et al, 2014b). Lower cortical 5-HT 2C R membrane protein levels and an increased frequency of edited 5-HT 2C R mRNA variants linked to reduced 5-HT 2C R signaling capacity distinguished high impulsive rats from low impulsive rats.…”

Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

“…32–36 Localized infusion of DOI into the mPFC enhances 37 while intra-mPFC M100907 38 suppresses premature responding assessed in the 5-CSRT task. The density of 5-HT 2A R 9 as well as 5-HT 2C R 6 protein expression in the mPFC predicts premature responses in the 1-CSRT task in outbred rats. High impulsive rats exhibit a greater 5-HT 2A R-mediated head-twitch response and are more sensitive to the suppressive effects of the selective 5-HT 2A R antagonist M100907 9 while virally-mediated 5-HT 2C R knockdown in the mPFC generates elevated premature responses in the 1-CSRT task.…”

Adolescent impulsivity as a sex- and subtype-dependent predictor of impulsivity, alcohol drinking, and dopamine D2 receptor expression in adult rats

“…Studies that used the 5-choice serial reaction time or similar tasks include a signaled timeout in every session (Lovic et al 2011;Burton & Fletcher 2012;Feja & Koch 2014;Anastasio et al 2014). Thus, the design and relative novelty of our task, especially the impulsive action assessment, should be considered when interpreting and comparing the current results to others.…”