THE FIRST ALCOHOL DRINK TRIGGERS MTORC1-DEPENDENT SYNAPTIC PLASTICITY IN NUCLEUS ACCUMBENS DOPAMINE D1 RECEPTOR NEURONS

Introduction: Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. This study investigates the impact of the first binge-drinking alcohol session on synaptic plasticity in nucleus accumbens (NAc) dopamine D1 receptor-expressing neurons (D1+ neurons) in mice. The NAc, particularly involved in the mesolimbic dopamine pathway, plays a crucial role in reinforcing the rewarding effects of alcohol. Understanding the molecular mechanisms behind these changes could provide insights into the initial stages of alcohol addiction.

Key Findings: The first binge-drinking alcohol session produced an enduring enhancement of excitatory synaptic transmission onto D1+ neurons in the NAc shell but not the core. This enhancement required dopamine D1 receptors (D1Rs) and a mechanistic target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference in subsequent drinking sessions, indicating its crucial role in reinforcement learning. The first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons, increasing synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Furthermore, stimulation of D1Rs alone was sufficient to activate mTORC1 in the NAc, promoting mTORC1-dependent translation of synaptic proteins GluA1 and Homer.

Innovative Tools: The researchers employed various creative methods to analyze the effects of the first alcohol-drinking session on synaptic plasticity and protein translation. Electrophysiology measured excitatory synaptic transmission, revealing the AMPAR/NMDAR ratio changes in D1+ and D2+ neurons. Western blotting was conducted to analyze protein phosphorylation and expression levels, explicitly focusing on mTORC1 pathway components and synaptic proteins. Immunohistochemistry provided insights into protein localization within NAc neurons, particularly the distribution of phosphorylated S6, a marker of mTORC1 activity. Additionally, two-bottle choice drinking paradigms were used to assess alcohol consumption and preference, establishing behavioral correlates to the biochemical findings.

Behavioral Assessments: Inhibition of mTORC1 during the first alcohol drinking session reduced alcohol consumption and preference in subsequent drinking sessions. This was evident from two-bottle choice drinking paradigms where mice treated with the mTORC1 inhibitor rapamycin showed decreased alcohol intake and preference. These findings suggest that mTORC1 activity is essential for reinforcement learning associated with the initial alcohol experience, as mTORC1 inhibition disrupted the reinforcing properties of alcohol, leading to reduced subsequent consumption.

Biochemical Analysis: The first alcohol session activated mTORC1 in NAc shell D1+ neurons, increasing synaptic expression of GluA1 and Homer proteins. This activation depended on D1R stimulation and was necessary for the enduring enhancement of excitatory synaptic transmission observed in D1+ neurons. Western blot analysis showed increased phosphorylation of mTORC1 downstream targets, including S6K and 4E-BP, indicating mTORC1 activation. Immunohistochemistry confirmed increased phospho-S6 levels in D1+ neurons but not D2+ neurons in the NAc shell, highlighting the specificity of this response. The increase in synaptic GluA1 and Homer proteins was associated with enhanced AMPAR-mediated synaptic currents, suggesting a postsynaptic mechanism for the observed synaptic plasticity.

Conclusions: The first binge-drinking alcohol session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission. This plasticity likely drives reinforcement learning associated with the first alcohol experience, promoting subsequent alcohol intake. These findings highlight the critical role of the D1R/mTORC1 pathway in the development of alcohol-induced behaviors. The study suggests that targeting the mTORC1 pathway could be a potential therapeutic strategy for preventing the transition from initial alcohol use to compulsive drinking. Further research is needed to explore the long-term effects of mTORC1 inhibition and its potential in treating alcohol use disorders.

Join the Discussion: We invite you to share your thoughts on the implications of these findings for understanding the neural mechanisms underlying alcohol reinforcement and addiction. How might targeting the D1R/mTORC1 pathway influence the development of therapeutic strategies for alcohol use disorders? What other molecular pathways could be involved in the initial stages of alcohol addiction? Join the conversation in the comments below and share your insights and ideas.

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Original Research: The original research, "The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons," is available on PubMed here.