Neuromodulatory mechanisms mediating escalation of drug consumption

点击翻译按钮获取中文摘要

PROJECT SUMMARY Alterations in dopamine transmission are implicated in most contemporary theories of drug addiction. One of the leading theories ascribes dopamine transmission within the nucleus accumbens core (NAcc) responsible for the loss of control in regulating drug consumption, a hallmark of addiction. Consistent with this theory dopamine within the NAcc has been demonstrated to be involved in producing drug-satiety, and thus regulating drug-intake. Recent work in our lab has revealed that phasic dopamine signals, elicited by response- contingent drug associated cues, are attenuated in animals that have transitioned into excessive or escalated drug consumption. Administration of L-DOPA, or stimulated release of dopamine through the use of optogenetics within the NAcc, decreased the amount of cocaine consumed in animals that had escalated their daily drug intake. These causal data indicate that attenuated phasic dopamine signals promote escalated cocaine consumption. However, the mechanisms mediating the reduction of phasic dopamine signaling are unresolved. Antagonism of either the kappa opioid receptor (KOR) or the corticotrophin releasing hormone receptor-1 (CRHR1) alters escalated drug consumption. Given the necessity of dopamine attenuation in the development of escalated cocaine intake, and that antagonists of both KOR and CRHR1 affect this behavior, I hypothesize that activation of KOR and CRHR1 promote escalation of drug consumption by mediating the attenuation of phasic dopamine release. In order to test this hypothesis, I have developed two separate aims to investigate neuropeptide action on both the progression of escalated drug-intake and dopamine signaling within the nucleus accumbens core. Animals will receive local NAcc delivery of pharmacological agents to manipulate either KOR or CRHR1 receptors during extended self-administration behavioral assays. I will utilize chronically implanted fast-scan cyclic voltammetry carbon fiber microelectrodes to detect phasic changes in dopamine transmission to drug-associated cues following the administration of the KOR and CRHR1 targeted pharmacological agents. I will implement a double disassociation manipulation technique to examine if KOR inactivation and dopamine replacement techniques alter escalated drug consumption through converging or indepedent mechanisms. Furthermore, to better our understanding in the role CRHR1 in the NAcc has in producing escalated drug consumption I will use a cre-depedent, viral-mediated CRISPR/SaCas9 system to knock-out the CRHR1 gene in a pathway specific manner. Revealing these mechanisms will provide potential pharmacological targets for drug addiction therapy, and increase our knowledge and understanding in modulation of aberrant dopamine transmission, which is implicated in many psychiatric disorders.