Oxytocin Induces Retrograde Metaplasticity to Attenuate CocainePreference Behavior

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PROJECT SUMMARY/ABSTRACT A growing number of studies have demonstrated that oxytocin (OXT) provides an attenuating effect on cocaine reward behaviors in rodents and therefore may be investigated as a potential modulator of cocaine reward processes. Despite this, the specific mechanism through which OXT exerts this modulatory effect on cocaine- related behaviors remains unclear. The present research project proposes that OXT attenuates cocaine- associated preference via a two-fold mechanism on dopamine (DA) neurons within the ventral tegmental area (VTA). Recent evidence suggests that OXT receptors (OXTRs) on VTA DA neurons both increase tonic firing of the DA neuron and decreases excitatory inputs, likely affecting phasic activation of the DA neuron. This decrease in excitatory inputs has been shown to be mediated by an OXT interaction with presynaptic CB1 receptors (CB1Rs) on glutamatergic terminals. This project investigates the functional relevance of this effect using a novel combination of transgenic rat and virally-delivered shRNA to silence VTA DA OXTRs or presynaptic glutamatergic CB1Rs. First, OXTRs on DA VTA neurons will be silenced in male and female rats using a transgenic Cre rat and Cre-dependent knockdown of OXTRs to determine the effect of OXT-mediated DA firing rate. Behaviorally, OXT attenuates cocaine preference behaviors, and it is expected that silencing of OXTRs on VTA DA neurons will diminish this effect. Second, to further elucidate the specific mechanism through which OXT attenuates cocaine preference via VTA DA neurons, CB1Rs on VTA glutamatergic inputs will be silenced using a combination of transgenic Cre rat and shRNA silencing of CB1R in the absence of Cre expression. OXT is known to reduce neuronal excitation through production of endocannabinioids (eCB) that retrogradely reduce presynaptic input via CB1 receptors. Through this, the effect of glutamatergic CB1R silencing will be assessed on OXT-mediated VTA DA phasic neuronal firing. Behaviorally, this demonstrates that OXT-mediated reduction of VTA DA phasic firing underlies OXT-mediated attenuation of cocaine-associated preference. Overall, this project will utilize a novel combination of tools to investigate the specific neural mechanism through which OXT attenuates cocaine reward and offer insight into the use of OXT as a therapeutic target for cocaine-related disorders in males and females.