Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction

Abstract

Cocaine abuse and addiction remain great challenges on the public health agendas in the U.S. and the world. Increasingly sophisticated perspectives on addiction to cocaine and other drugs of abuse have evolved with concerted research efforts over the last 30 years. Relapse remains a particularly powerful clinical problem as, even upon termination of drug use and initiation of abstinence, the recidivism rates can be very high. The cycling course of cocaine intake, abstinence and relapse is tied to a multitude of behavioral and cognitive processes including impulsivity (a predisposition toward rapid unplanned reactions to stimuli without regard to the negative consequences), and cocaine cue reactivity (responsivity to cocaine-associated stimuli) cited as two key phenotypes that contribute to relapse vulnerability even years into recovery. Preclinical studies suggest that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in key neural circuits may contribute to these interlocked phenotypes well as the altered neurobiological states evoked by cocaine that precipitate relapse events. As such, 5-HT is an important target in the quest to to understand the neurobiology of relapse-predictive phenotypes, to successfully treat this complex disorder and improve diagnostic and prognostic capabilities. This review emphasizes the role of 5-HT and its receptor proteins in key addiction phenotypes and the implications of current findings to the future of therapeutics in addiction.

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

“…Clinical trials have not yet identified DA-based medications that lack abuse liability yet exhibit efficacy to enhance abstinence, reduce craving, and prevent relapse. Investigations have now broadened the search to explore other neural systems that play equally important roles in addictive processes, and the results have generated interesting new prospects for pharmacotherapy (Kalivas and Volkow, 2011;Skolnick and Volkow, 2012;Cunningham and Anastasio, 2014;Howell and Negus, 2014). We propose that an opportunity exists to advance toward the goal of accessible, effective pharmacotherapies for cocaine addiction by targeting 5-HT neurotransmission that may result in beneficial downstream outcomes via DA function.…”

“…The influence of 5-HT begins during development at a time when the brain is particularly sensitive to early life events known to trigger plasticity of 5-HT systems (Mitchell et al, 1990;Smythe et al, 1994;Garoflos et al, 2005;Cunningham and Anastasio, 2014). Furthermore, serotonergic stimulation is one of the first steps in encoding of short-and long-term memory at the level of the synapse (Pittenger and Kandel, 1998;Kandel, 2005).…”

“…However, the 5-HT 2A R and 5-HT 2C R in particular have been implicated as likely candidates for mediating the influence of 5-HT in drug abuse Cunningham, 2006, 2008;Cunningham and Anastasio, 2014). The 5-HT 2A R and 5-HT 2C R are expressed throughout the brain with distinct but overlapping expression patterns (Pompeiano et al, 1994) and can functionally oppose each other in regulation of the DA system (Bubar and Cunningham, 2008;Cunningham and Anastasio, 2014). The regional distribution of 5-HT 2A R and 5-HT 2C R within the mesolimbic DA system is illustrated in Fig.…”

“…Numerous studies documented that pharmacological activation of the 5-HT 2C R mimics the effects of 5-HT indirect agonists in rodent models of cocaine use and relapse Cunningham, 2006, 2008;Cunningham and Anastasio, 2014). Studies in rodents have reliably found that 5-HT 2C R agonists attenuate, whereas antagonists enhance the behavioral effects of cocaine (Table 3).…”

“…The 5-HT 2A R has been linked to measures of impulsivity, a trait that is believed to contribute to both the predisposition to develop drug abuse and to drug relapse in humans (de Wit, 2009;Winstanley et al, 2010;Kirby et al, 2011;Cunningham and Anastasio, 2014). Cocaine-dependent subjects are more impulsive than nondrug using subjects (Moeller et al, 2001a,b), whereas greater impulsivity predicts reduced retention in outpatient treatment trials for cocaine use disorder (Moeller et al, 2001b(Moeller et al, , 2007Schmitz et al, Cocaine, 5-HT 2 Receptors, and Dopamine 2009).…”