The propensity to drink alcohol can be thought of as a balance between ethanol's rewarding (use-promoting) and aversive (use-limiting) properties. Accordingly, individuals who experience fewer negative effects of alcohol are more likely to drink heavily and develop alcohol use disorders. In addition, alcohol dependence is associated with increased tolerance to the aversive properties of alcohol, which is likely to facilitate continued drinking in addicts and relapse during abstinence. While a significant body of research has focused on the use- promoting properties of alcohol and their involvement in addiction, much less has been done to investigate the neurobiological correlates of alcohol's use-limiting properties and their role in the progression to dependence. Recently, however, a midbrain region known as the rostromedial tegmental nucleus (RMTg) was identified and characterized for its involvement in negative reward prediction error and the behavioral response to aversive stimuli through its prominent inhibitory control over dopamine neurons. Interestingly, the prelimbic (PrL) cortex, which is involved in signaling the salience of environmental stimuli, sends a very dense projection to the RMTg. The present proposal will test a novel hypothesis that the PrL cortex relays information about the aversive properties of conditioned environmental stimuli --- including information related to the aversive actions of alcohol --- via its projection to the RMTg. It is further hypothesized that modulation of aversive signals by the RMTg plays an important role in modulating alcohol drinking, and that the normal processing of aversive properties of alcohol by the RMTg is altered by chronic alcohol exposure. An innovative set of studies is proposed to examine the role of the role of the RMTg in mediating the aversive properties of alcohol.
Aim 1 will examine Fos induction following ethanol-induced conditioned taste aversion (CTA) using retrograde tract tracing in combination with immunohistochemistry to confirm the involvement of the PrL-RMTg pathway in signaling alcohol's aversive actions. These studies will also examine the effect of inhibition of this pathway on the development of ethanol-induced CTA using in vivo optogenetics to inhibit RMTg-projecting PrL neurons.
Aim 2 will investigate the effect of inhibition of the PrL-RMTg pathway on ethanol-seeking and drinking behavior using in vivo optogenetics procedures in combination with operant behavior.
Aim 3 will determine the effect of alcohol dependence on the synaptic response of RMTg neurons to input from PrL cortex. The results of these studies will provide new insights into the role of the RMTg in alcohol drinking and dependence and will help to address the gap in our understanding of the neurobiological mechanisms that contribute to the addictive process.

Public Health Relevance

While it is well known that the rewarding properties of alcohol critically contribute to its addictive potential, there is increasing appreciation that alcohol's aversive properties also significantly impact the transition from controlled recreational use to excessive and uncontrolled use. The neurobiological correlates that signal the aversive properties of alcohol are currently unknown, but recent work has identified a midbrain nucleus known as the rostromedial tegmental nucleus (RMTg) in the processing of aversive stimuli. The project proposed in the current application will examine the role of the RMTg and its inputs in processing information about alcohol's aversive properties and its involvement in alcohol-seeking and drinking behavior.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Health Services Research Review Subcommittee (AA)
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Cui, Changhai
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Medical University of South Carolina
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