The neurobiological mechanisms underlying the addictive property of ethanol remain obscure. It is generallyaccepted that the addictive property of ethanol is associated with its ability to increase the activity ofdopaminergic neurons in the ventral tegmental area (VTA) in the brain. These neurons are under the powerfulcontrol of synaptic inputs. Thus, the synaptic regulation of dopaminergic neurons is a key initial step in rewardmechanisms leading to alcohol addiction. The majority of the afferents to dopaminergic neurons are GABAergicand usually inhibitory. Some drugs of abuse, such as opioids, stimulate VTA-dopaminergic neurons throughsuppression of GABAergic transmission - that is by disinhibition. Emerging evidence indicates that therostromedial tegmental nucleus (RMTg), a newly defined structure with dense -opioid receptorimmunoreactivity, is a major GABAergic afferent to dopaminergic neurons, and a key structure in -opioidreceptor-dependent regulation of dopaminergic neurons. However, the functional mechanisms connecting theRMTg inputs to the dopaminergic neurons with alcohol drinking behavior remain obscure. Our long term goal isto understand the neurobiological mechanisms underlying alcohol addiction. The objective in this application is todefine RMTg's role in ethanol drinking behavior by identifying its contribution to ethanol-induced activation ofVTA dopaminergic neurons and determining the influence of RMTg neuronal activity on ethanol intake. Ourproposed experiments will specifically test the central hypothesis that the RMTg projection to VTA dopaminergiccells plays a key role in the control of regulating ethanol drinking behavior by strongly regulating ethanol-inducedenhancement of VTA-dopaminergic neuron activity. This central hypothesis will be tested in two separate butintegrated Aims.
Aim 1 will combine ex vivo electrophysiology, tract tracing experiments, targeted neuronalactivation/inactivation, molecular genetics and optogenetic techniques to functionally dissect a neuronal circuitimportant for acute ethanol's action on dopaminergic neurons.
Aim 2 will determine the effect of altering RMTgactivity on ethanol intake. To test the hypothesis that the RMTg plays a key role in ethanol drinking, we willmanipulate RMTg function by intra-RMTg infusion of relevant pharmacological agents and then studyconsequent changes in ethanol intake, using the intermittent 2-bottle choice paradigm. The studies aresignificant because they will advance our knowledge of the neural circuitries that determine excessive alcoholconsumption. The proposed studies are innovative, because they will characterize a previously understudiedeffect of ethanol on the RMTg neurons, and its subsequent indirect effect on VTA-dopaminergic neurons, as wellas the role of -opioid receptors in the RMTg in drinking behavior. The results of this project will provide valuableinformation on novel mechanisms underlying the addictive properties of alcohol and should identify novel cellulartargets for the development of improved treatment of alcoholism.
Excessive alcohol drinking is the third leading preventable cause of death in the United States; but the mechanisms driving excessive alcohol drinking behavior are not well understood. 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; there is; however; no direct evidence of a functional connection between the RMTg and ethanol-induced activation of dopamine neurons and alcohol drinking behavior. Identification of the RMTg role in alcohol-induced excitation of dopamine neurons in the ventral tegmental area and in the regulation of alcohol drinking behavior is expected to reveal novel targets for the development of improved pharmacotherapies to treat alcoholism.
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