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Author Contact: hkwon02@wesleyan.edu
Local Identifier: 1244.pdf
PID: ir:3283"},{"label":"Author-supplied Keywords","value":["Sex differences","Acute","Chronic","Neurobiology","Locomotion","Sensitization","Ethanol","Alcohol","Ventral tegmental area","Dopamine","GABA","Plasticity","CNO","Chemogenetics","Neurons"]},{"label":"Degree","value":["Master of Arts"]},{"label":"Description","value":"

Alcohol sensitization is an enhanced stimulant response to the same dose of alcohol following repeated use. Individuals who develop sensitization acquire a sensitized neural circuit responsible for regulating incentive salience of stimuli, which confers vulnerability to alcohol use disorder. However, the neurobiological basis of sensitization remains unknown. Here we show that acute inhibition of GABAergic neurons in the ventral tegmental area causes persistent, synaptic changes sufficient to induce ethanol sensitization without prior exposure to the drug in a sex-dependent manner. We found that two weeks after acute chemogenetic inhibition of GABAergic neurons, males showed heightened baseline and ethanol-induced locomotion, indicating the presence of sensitization, while females displayed no increases in baseline and ethanol-induced locomotion. However, both males and females exhibited enhanced baseline locomotion one week after acute chemogenetic inhibition of GABAergic neurons. Our results demonstrate that VTA GABAergic neurons express persistent plasticity to a greater extent in males than females and undergo sex-dependent neuroadaptations responsible for the induction of sensitization following chronic ethanol exposure. We anticipate our results to contribute to the identification of a novel therapeutic molecular target for treating alcohol addiction associated with the pattern of chronic use that leads to behavioral sensitization.

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