A major barrier to successfully treating cocaine addiction is the high rate of drug relapse that occurs during periods of drug withdrawal. Cocaine relapse can be precipitated by exposure to drug-associated cues that induce cocaine craving and cocaine-seeking behavior. However, to date there are no FDA approved pharmacotherapies to treat cocaine addiction. Thus it is crucial that we understand the neurobiological mechanisms of cocaine-seeking behavior to be able to identify novel therapeutic targets to prevent this relapsing disorder. Drug-associated cues evoke burst firing of ventral tegmental area (VTA) dopamine (DA) neurons that results in phasic DA release in the nucleus accumbens (NAc). Work from our laboratory has revealed that phasic DA activity in the VTA to NAc circuit, and VTA cholinergic receptor regulation of such activity, is critical for cue-induced cocaine-seeking. However, the precise mechanisms that mediate phasic dopamine release and cue-induced drug-seeking behavior during cocaine withdrawal remain poorly understood. We have previously shown that Cav1.3 L-type Ca2+ channels (LTCCs) and their downstream Ca2+-activated pathways in VTA DA neurons are critical for sensitized psychomotor behavioral responses to cocaine following periods of prolonged withdrawal. Additionally our recent findings have revealed that Cav1.3 channels facilitate the transition of DA neurons from tonic to burst firing and act through cholinergic mechanisms, strongly suggesting that recruitment of Cav1.3 channels may underlie cue-induced cocaine-seeking behavior. Thus, the goal of this R21 application is to test the hypothesis that VTA Cav1.3 mechanisms underlie cue-induced cocaine-seeking behavior by regulating phasic DA release in the NAc. To achieve this goal, we will use an innovative and integrative experimental approach using pharmacology and viral vector-mediated genetic knockdown in the VTA in combination with behavioral testing and in vivo voltammetry in the NAc, to examine cue-induced cocaine seeking during withdrawal, using the preclinical self-administration rat model.
In specific aim 1, we will examine the role of VTA Cav1.3 channels in cue-induced cocaine-seeking during early and protracted withdrawal.
In specific aim 2, we will examine in vivo the role of VTA Cav1.3 channels in VTA-evoked- and acetylcholine receptor-mediated phasic DA release in the NAc during early and protracted withdrawal. The mechanistic insight gained from this study will provide new understanding of the neurobiology of drug relapse and will determine whether Cav1.3 channels may serve as a potential novel therapeutic target to prevent cocaine relapse.
Exposure to drug-related cues is a major precipitant of drug relapse and is a major barrier to successfully treating cocaine addiction. The goal of this project is to determine the role of Cav1.3 L-type Ca2+ channels (LTCCs) in mediating cue-induced cocaine relapse behavior. The findings from this study will provide a more complete understanding of the neurobiology of addiction and will determine whether Cav1.3 channels may serve as a potential novel therapeutic target to prevent cocaine relapse.
|Addy, Nii A; Nunes, Eric J; Hughley, Shannon M et al. (2018) The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway. Neuropsychopharmacology 43:2361-2372|
|Martínez-Rivera, A; Hao, J; Tropea, T F et al. (2017) Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. Mol Psychiatry 22:1735-1745|
|Small, Keri M; Nunes, Eric; Hughley, Shannon et al. (2016) Ventral tegmental area muscarinic receptors modulate depression and anxiety-related behaviors in rats. Neurosci Lett 616:80-5|