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 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. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: Addiction; Cocaine; Cue reactivity; Dependence; Impulsivity; Serotonin.

Figure 1. Serotonin serves as a key nexus for vulnerability to relapse

The 5-HT neurotransmitter system regulates higher order neural circuits that ultimately control expression of the impulsivity and cue reactivity phenotypes that contribute to relapse to drug-seeking. Alterations in the level of 5-HT efflux and associated disruptions in 5-HT receptor homeostasis shifts the balance of 5-HT:DA:glutamate neurotransmission that govern impulsivity, sensitivity to reward and cues, and control over drug seeking. A global deficiency of 5-HT, such as that observed during withdrawal from cocaine administration, is associated with loss of restraint over arousing stimuli, such that measures of impulsive action, cocaine reward and cocaine-primed cocaine-seeking are elevated. These factors, coupled with elevated stress, anxiety and withdrawal discomfort set the stage for enhanced vulnerability to relapse. As such, medications that act to restore 5-HT rheostatic control may be effective in promoting abstinence. This may best be accomplished by targeting specific 5-HT receptors of which the 5-HT_2AR and 5-HT_2CR, which consistently exert oppositional influence upon impulsivity and cue reactivity, have emerged as key targets mediating the intersection of these interlocked phenotypes.

Figure 2. The PFC 5-HT_2AR and 5-HT_2CR is an important site of action for the intersection of impulsivity and cue reactivity

A schematic overview of the overlapping and reciprocal interactions between 5-HT, DA and glutamate neurotransmission is illustrated within the limbic-corticostriatal circuit. Serotonin neurons (blue) from the dorsal raphe nucleus (DRN) innervate the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC); DA neurons (red) from the VTA project to the DRN, NAc and PFC; pyramidal glutamate neurons (green) from the PFC innervate the DRN, VTA and NAc; GABA medium spiny projection neurons (gray) from the NAc project to the VTA and other primary output systems (e.g., thalamus). The microcircuitry within each brain region is comprised of the respective 5-HT, DA, or glutamate projection neurons and GABA interneurons. Within the PFC 5-HT_2AR (chevron) and 5-HT_2CR (diamond) are each localized to GABA interneurons and pyramidal glutamate projection neurons, and thus, are perfectly situated to tightly control the PFC microcircuitry. We theorize that disruption of the oppositional 5-HT_2AR:5-HT_2CR balance within the PFC shifts the 5-HT, DA and/or glutamate homeostatic framework within the limbic-corticostriatal circuitry and sets the stage for enhanced impulsivity and sensitivity to cues in cocaine dependence.