Project Summary/Abstract Cocaine addiction is a major public health issue in the United States, and there are currently no effective treatments targeted towards preventing relapse. Deep brain stimulation (DBS) has been successful clinically at reducing symptoms of several neurological and psychiatric disorders and has been proposed as a potential therapy for the suppression of drug craving and relapse. Previous preclinical research has identified that conventional DBS in the nucleus accumbens (NAc) shell can be effective at preventing reinstatement of cocaine seeking, an animal model of relapse. This grant will exploit recent methodological advances in order to examine the cellular and physiological mechanisms underlying the efficacy of NAc DBS with greater specificity. We will examine the effects of DBS-like stimulation induced by light activation of channelrhodopsin (ChR2) expressed in specific neuronal subtypes of the NAc shell. Neuronal specificity will be achieved through viral expression in transgenic rat lines that express Cre recombinase selectively in D1 dopamine receptor (D1DR)- or D2DR-expressing medium spiny neurons (MSNs). Aim 1 will examine the electrophysiological effects of optogenetic DBS-like (opto-DBS) activation of D1DR- or D2DR-MSNs in male and female rats. Whole cell patch clamp experiments will assess the synaptic mechanisms that are engaged by opto-DBS, and determine if there are cell subtype-specific effects. Aim 2 will consist of parallel behavioral experiments to examine the effects of opto-DBS on cocaine-primed reinstatement. Optic fibers will be implanted in the NAc shell, and D1DR- or D2DR-MSNs will be activated optogenetically, at DBS-like frequencies following a priming dose of cocaine to assess the effects of this manipulation on cocaine-seeking behavior. Previous findings and preliminary data support the overarching hypothesis that DBS of the NAc shell blocks cocaine-primed reinstatement by inducing synaptic depotentiation specifically in D2DR-MSNs. Future directions will examine the effects of selective optogenetic inhibition of D1DR- or D2DR-MSN signaling in precise downstream regions. Optic fibers will be implanted in either the ventral pallidum (VP) or ventral tegmental area (VTA) and halorhodopsin-expressing D1DR- or D2DR- axon terminals will be activated during cocaine-primed reinstatement. This will determine whether DBS of NAc shell MSNs can be equated to overall suppression of neural activity. Overall, identification of the specific mechanisms by which DBS influences cocaine seeking will provide critical insights for future cell- and pathway-specific therapeutics for cocaine addiction.