A novel role for midbrain glutamate co-transmitting neurons in alcohol drinking and motivated behaviors

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PROJECT SUMMARY Early adolescent alcohol use is one of the best predictors of risk for developing an alcohol use disorder (AUD) later in life. Generally, adolescents are more likely to report positive, rewarding effects of alcohol and fewer negative effects, which can lead to an increased propensity to consume larger volumes of alcohol. The molecular mechanisms underlying enhanced sensitivity to alcohol reward are poorly understood, but if identified, could lead to novel methods for reducing abuse liability and treating AUD in a manner that is uniquely tailored to adolescents and adults. Glutamate signaling is strongly implicated in the vulnerability to and pathogenesis of AUDs. Recent preclinical work has further refined this observation by showing that a population of neurons that express vesicular glutamate transporter 2 (VGLUT2) are strongly implicated in modulating drug reward. We have discovered that this distinct subpopulation of VGLUT2+ glutamatergic neurons is also dopaminergic. We also found glutamate potentiates activity-dependent vesicular dopamine loading and release. Thus, while glutamate and dopamine have both been individually implicated in the reinforcing effects of alcohol, glutamate and dopamine may also act synergistically to regulate sensitivity to alcohol. Notably, VGLUT2 expression is developmentally regulated, with expression peaking in adolescence and decreasing with age, which may explain why adolescents are particularly sensitive to the rewarding effects of alcohol. Additionally, we discovered strong sex differences in the expression of VGLUT2 including in glutamate/dopamine co-transmitting neurons, with females expressing more VGLUT2 relative to males. Thus, VGLUT2 expression may also explain why females are differentially sensitive to alcohol reward. Until recently, it has been difficult to functionally dissect subpopulations of glutamate neurons, including those that co-transmit dopamine, particularly in rats. However, we can now selectively control expression of a VGLUT2 in glutamate/dopamine neurons, and answer several key questions: 1) how does alcohol alter co-release of glutamate and dopamine from TH+/VGLUT2+ terminals in the mNAcSh?; 2) does manipulation of levels of VGLUT2 expression in mVTA glutamate/dopamine neurons modify alcohol reinforcement and motivation differentially in males and females and across key developmental stages (i.e., adolescence and adulthood)? Our central hypotheses are: i) Amount of glutamate/dopamine co- release will vary according to age and sex based on levels of VGLUT2 expression under basal conditions and in response to alcohol (Aim 1); ii) Manipulating levels of VGLUT2 expression will alter alcohol reinforcement and motivated behaviors (Aim 2). Using a combination of molecular, imaging, and behavioral tools, we will definitively identify the mechanistic role of subpopulations of midbrain glutamatergic neurons in alcohol reinforcement and motivation, and drive future development of new, more effective interventions for alcohol use disorder.