The transition from recreational drinking to development of alcohol use disorders (AUDs) is both an individual and societal concern. Along with adolescence, early adulthood is a period during which individuals are vulnerable for developing AUDs (Grant et al., 2001). Drinking behavior increases at this time (Chen et al., 2005), which is sometimes associated with deleterious consequences (Hingson et al., 2005). However, the mechanisms of ethanol (EtOH) that underlie an individual's response to the drug, as well as development of AUDs, are not entirely understood. It is known that EtOH alters neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA). EtOH increases the firing rate of dopamine (DA) neurons in the VTA, although research has shown that in vitro recordings require large concentrations of EtOH to elicit a response in firing rate. This observation could be due to the removal of afferents in slice, to a washout effect of whole-cell patch clamping, or to heterogeneity among VTA DA neurons. Recent research has shown that there is considerable heterogeneity among VTA DA neurons, and that classification of these neurons based on projection targets reveals differential roles in response to rewarding and aversive stimuli. Importantly, these recent findings emphasize that the traditional criteria fo identifying DA neurons in the VTA has led to the exclusion of several non-canonical DA neurons in electrophysiological studies. One goal of this proposed project is to investigate the response of subpopulations of VTA DA neurons to EtOH in an effort to uncover the most vulnerable population to EtOH. To accomplish this goal, retrograde tracing experiments will be performed by stereotactic delivery of retrobeads into discrete brain areas to which the VTA projects. Subsequent loose-seal cell-attached recordings of retrobead-labeled DA neurons in the VTA will be performed in the absence and presence of EtOH. This series of experiments will reveal the response of subpopulations of neurons to acute EtOH, hopefully identifying the most sensitive population of cells to the drug. In addition, neuroadaptations occur following repeated alcohol use. These adaptations are likely crucial in the development of AUDs. In order to determine the effect of repeated alcohol exposure on the VTA, a self- administration model will be used to produce escalated drinking in male mice at an age that corresponds to early adulthood in humans. Electrophysiological recordings will be performed in mice that undergo repeated drinking sessions and compared to alcohol-nave mice. This, in combination with retrograde tracing, will elaborate on findings from subpopulations of VTA DA neurons. These experiments will improve our understanding of VTA DA neurons and the neural adaptations following repeated alcohol exposure. This may reveal the most sensitive population of DA neurons to EtOH, allowing us to focus our efforts on uncovering the elements of these cells that dictate response to EtOH. This may ultimately reveal a target which could explain inter-individual variability in alcohol response and abuse potential.
The goal of the proposed research is to better understand the brain circuits involved in alcohol addiction, and the way these change following alcohol drinking over an extended period. The experiments will focus on an under-studied set of brain cells and their response to acute alcohol and to chronic drinking during early adulthood. The results from these experiments will improve our understanding of the circuits in the brain that respond to alcohol's effects, which could potentially reveal an effective target for treating alcoholism.
| Avegno, Elizabeth M; Salling, Michael C; Borgkvist, Anders et al. (2016) Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area. Neuropharmacology 110:386-395 |
