Action of psychostimulant drugs on neuronal intrinsic excitability and drug-seeking behavior

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Drug addiction is a chronic psychiatric disorder that imposes a huge burden on the lives of addicted individuals, their families and society as a whole. Importantly, a significant proportion of addicts remain resistant to treatment. Diversifying pharmacotherapies that target mechanisms beyond canonical mechanisms of addiction involving dopamine (DA) and monoamine signaling could address this gap. Here we propose to study a novel and long-lasting neuroadaptation to chronic cocaine that is mediated by a non-canonical, DA-independent mechanism. Chronic cocaine induces a persistent decrease in the intrinsic excitability (firing rate) of nucleus accumbens shell (NAcSh) neurons. This adaptation is mediated by the sigma-1 protein (σ1; a.k.a. Sig-1R), a chaperone whose activity is regulated by synthetic and endogenous molecules in a clear agonist-antagonist manner. Cocaine is an agonist of σ1, and our accumulating evidence suggests that cocaine activation of σ1 enhances the formation of σ1-Kv1.2 protein complexes, their subsequent accumulation at the plasma membrane, thereby decreasing intrinsic excitability of NAcSh neurons. This mechanism is not unique to cocaine, and is induced by other psychostimulant drugs including methamphetamine, suggesting a common mechanism contributing to psychostimulant addiction. Our previous study showed that either pharmacological blockade or NAcSh-specific knockdown of σ1 prevents the development of enhanced Kv1.2 currents and reduced excitability while attenuating psychomotor sensitization to cocaine—a process that may contribute to the development of addiction. Moreover, NAcSh-specific overexpression of Kv1.2 subunits, which mimics cocaine-induced neuronal hypoactivity, amplifies sensitization to cocaine. We hypothesize that psychostimulant drugs act through a common DA-independent pathway that leads to σ1-dependent upregulation of Kv1.2 in NAcSh MSNs to promote addiction, in addition to DA-dependent signaling effects. Using cocaine self-administration (SA) procedures in mice, this research will determine whether the formation of σ1-Kv1.2 protein complexes and firing rate depression is associated with the incubation of cocaine craving after prolonged abstinence from cocaine SA (Aim 1). This research also will employ: (i) a combination of molecular approaches only available in cell culture models including multiphoton confocal cell imaging to track Kv1.2 trafficking following in vitro cocaine exposure, and (ii) a pharmacological approach targeting key endocytic/recycling machinery to validate a similar approach in NAcSh slices (Aim 2). To provide behavioral relevance to this novel mechanism of cocaine action, we will determine how NAcSh-specific σ1 and Kv1.2 modulations during cocaine SA alter subsequent stages of the addiction cycle, including drug seeking after withdrawal (Aim 3). Together, our work will provide a multipronged functional investigation of this mechanism of drug addiction, from intracellular signaling to cell firing and relevant measures of addictive behavior. These studies could pave the way for new and complementary pharmacotherapies to combat psychostimulant abuse.