Excessive use and abuse of alcohol is the third leading preventable cause of death in the United States, but the mechanisms driving excessive drinking are not well understood. Although it is generally accepted that addictive properties of many drugs of abuse, including ethanol, are associated with their ability to activate dopamine (DA) neurons in the ventral tegmental area (VTA) of the brain, the neuronal circuits underlying ethanol's action on DA neurons have not been fully elucidated. The majority of the afferents to DA neurons are GABAergic and inhibitory. It is well known that some drugs of abuse, such as opioids, stimulate VTA-DA neurons through suppression of GABA-A IPSCs that inhibit DA neurons-that is by disinhibition. The opioid- sensitive cells that underlie this disinhibition were thought to be GABA-interneurons within the VTA. However, emerging evidence indicates that the rostromedial tegmental nucleus (RMTg) may play a more important role. The RMTg, also named the tail of the VTA, is a newly defined structure with dense MOR immunoreactivity, is a major GABA afferent to DA neurons, a potential control center for DA activity and also a key structure in MOR- dependent regulation of DA neurons. Many studies including our own have shown that MORs play a key role in ethanol addiction. However, the role of the RMTg in alcohol addiction has not been well explored. Our proposed experiments will specifically test the central hypothesis that the RMTg plays a critical role in ethanol activation of VTA-DA neurons and in the regulation of ethanol intake. This central hypothesis will be tested in two separate but integrated Aims. We will combine ex vivo electrophysiology, tract tracing experiments, targeted neuronal inactivation and the cutting-edge optogenetic techniques to dissect a neuronal circuit important for acute ethanol action on DA neurons in rats (Aim 1).
In Aim 2, we will selectively inactivate RMTg neurons by intra-RMTg injection of the conjugated neurotoxin dermorphin-saporin, which selectively ablates the RMTg neurons that express MORs, or naloxonazine, the selective, irreversible ?1-opioid receptor antagonist, and study consequent effect on ethanol addiction by measuring the changes in ethanol intake using the intermittent two-bottle choice procedure. This study is innovative, because it will characterize a previously little-investigated effect of ethanol on the RMTg neurons, and its subsequent indirect effect on VTA- DA neurons, as well as the role of MORs in the RMTg neurons in drinking behavior. The study is significant, because the proposed experiments will unequivocally address the role of the RMTg in ethanol activation of VTA-DA neurons and in alcohol drinking. The results of this project will provide valuable information on novel mechanisms underlying the addictive properties of alcohol and should identify novel cellular targets for development of improved therapies to treat alcoholism.
Excessive use and abuse of alcohol is the third leading preventable cause of death in the United States but the mechanisms driving excessive drinking behavior are not well understood. Although recent evidence demonstrates that the Rostromedial Tegmental Nucleus (RMTg) exerts a major GABAergic inhibition on dopaminergic neurons and plays an essential role in morphine induced excitation of dopaminergic neurons, the role of the RMTg in alcohol addiction has not been well explored. Identification of the role of the RMTg in alcohol-induced excitation of dopamine neurons in the ventral tegmental area and in the regulation of alcohol consumption is expected to reveal novel targets for development of improved pharmacotherapies to treat alcohol addiction.
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