The convergence of the impulsivity trait with the dynamic state of cue reactivity is a synergy that contributes to greater vulnerability to relapse. A shared theme in the Translational Addiction Sciences Center (TASC) is that disrupted homeostasis in serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2cR neurotransmission in the prefrontal-striatal-thalamic circuit drives impulsivity and cue reactivity and that medications that normalize the 5-HT2AR:5-HT2CR imbalance will be especially efficacious to prevent relapse. This hypothesis is compellingly argued by clinical (Project 1) and preclinical (Project 2) observations, and our innovative strategy is to directly test the hypothesis that a 5-HT2AR:5-HT2CR imbalance in corticostriatal function drives impulsivity and cue reactivity employing validated behavioral models, intracranial microinjections, measures of receptor and cellular activation, receptor immunohistochemistry and genetic manipulations. The research proposed in four specific aims will discover the nature of 5-HT2AR:5-HT2CR imbalance and the integrity of the neurochemical circuit underlying these two phenotypes, site the control of 5-HT2AR and 5-HT2cR to a specific cortical subregion, and demonstrate effective pharmacological strategies to suppress impulsivity and cue reactivity based upon new chemical entities (Project 3). Lastly, our exciting discovery that 5-HT2AR and 5- HT2cR assemble into a heteromer in cells and brain provides an exploratory opportunity with Core B and Project 3 to identify the biological contribution of 5-HT2A+2CR heteromers to neuronal and behavioral function. This project is significant in that we will identify how unique signaling attributes for these two receptors and their balance contribute to the dynamic events underlying persistence of maladaptive behaviors associated with cocaine dependence. Completion of the proposed aims will link 5-HT2AR and 5-HT2cR homeostasis to two key phenotypes that precipitate relapse, and uncover pharmacological strategies to normalize system function and minimize vulnerability to relapse.
The outlined strategy will elucidate the key components of serotonergic neurobiology that drive relapse with the ultimate goal of optimizing novel serotonergic medications that maintain abstinence. These experiments will lend support to the prospects that these compounds may be useful to reduce phenotypic vulnerability to relapse, and set the stage for the use of such compounds therapeutically in humans.