Alcohol and D1R- and mTORC1-dependent plasticity

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): Alcohol (EtOH) consumption is a ubiquitous societal and cultural norm globally, and according to the most recent SAMSHA National Survey on Drug Use and Health, just over half of the United States population over 12 years old are current EtOH drinkers. The primary driver for such high levels of consumption is that EtOH is intrinsically a positively reinforcing stimulus, which is due to its pharmacological action that strongly activates mesolimbic dopamine (DA) neurons within the ventral tegmental area (VTA) leading to a transient burst of DA in the nucleus accumbens (NAc). While the reinforcing effects of EtOH are not detrimental per se, the self- reinforcing nature of EtOH can lead to chronic abuse, which profoundly alters neural circuits and produces psychopathology associated with alcohol-use disorders. It is unknown as to how EtOH transitions from a positive reinforcer to a stimulus that deleteriously shapes behavior. The NAc is primarily composed of GABAergic projection medium spiny neurons that express either DA D1Rs (D1R MSNs) or DA D2Rs (D2R MSNs). D1R activation within the NAc is a critical mediator of the development of alcohol-related behavior, and I recently found that a single challenge of mice to EtOH persistently enhances synaptic transmission selectively on NAc D1R MSNs. The goal of the research in this proposal is to characterize and determine the molecular mechanism underlying this novel form of EtOH-induced plasticity. Previous work from the Ron Lab has established that EtOH activates mammalian target of rapamycin complex 1 (mTORC1), a kinase that regulates local dendritic translation of select synaptic proteins involved in plasticity. Moreover, mTORC1 activation within the NAc mediates the development of alcohol-related behaviors. Preliminary results suggest that activation of D1R in the NAc increases the levels of proteins (GluA1, PSD95 and HOMER) whose translation is regulated by mTORC1. I therefore hypothesize that the EtOH-induced DA burst within the NAc and the concomitant activation of the D1R/mTORC1 pathway drives this form of long-lasting synaptic plasticity that ultimately underlies the enduring neural trace of reward. Aim 1 will test the hypothesis that EtOH-induced D1R activation triggers postsynaptic alterations that generate synaptic plasticity within D1R MSNs. I will also determine the duration and striatal subregion specificity of these EtOH-induced adaptations. Aim 2 will investigate: 1) if mTORC1 is activated by EtOH specifically in NAc D1R MSNs, 2) if EtOH induces the translation of GluA1, PSD95 and HOMER, and 3) whether mTORC1 activation is necessary for the EtOH-induced enhancement of excitatory synaptic strength. Collectively, my studies will shed light on a novel form of synaptic plasticity that may underlie the enduring neural trace for the rewarding effects of EtOH.