The neurobiological mechanisms underlying the addictive property of ethanol remain obscure. It is generally accepted that the addictive property of ethanol is associated with its ability to increase the activity of dopaminergic neurons in the ventral tegmental area (VTA) in the brain. These neurons are under the powerful control of synaptic inputs. Thus, the synaptic regulation of dopaminergic neurons is a key initial step in reward mechanisms leading to alcohol addiction. The majority of the afferents to dopaminergic neurons are GABAergic and usually inhibitory. Some drugs of abuse, such as opioids, stimulate VTA-dopaminergic neurons through suppression of GABAergic transmission - that is by disinhibition. Emerging evidence indicates that the rostromedial tegmental nucleus (RMTg), a newly defined structure with dense ?-opioid receptor immunoreactivity, is a major GABAergic afferent to dopaminergic neurons, and a key structure in ?-opioid receptor-dependent regulation of dopaminergic neurons. However, the functional mechanisms connecting the RMTg inputs to the dopaminergic neurons with alcohol drinking behavior remain obscure. Our long term goal is to understand the neurobiological mechanisms underlying alcohol addiction. The objective in this application is to define RMTg's role in ethanol drinking behavior by identifying its contribution to ethanol-induced activation of VTA dopaminergic neurons and determining the influence of RMTg neuronal activity on ethanol intake. Our proposed experiments will specifically test the central hypothesis that the RMTg projection to VTA dopaminergic cells plays a key role in the control of regulating ethanol drinking behavior by strongly regulating ethanol-induced enhancement of VTA-dopaminergic neuron activity. This central hypothesis will be tested in two separate but integrated Aims.
Aim 1 will combine ex vivo electrophysiology, tract tracing experiments, targeted neuronal activation/inactivation, molecular genetics and optogenetic techniques to functionally dissect a neuronal circuit important for acute ethanol's action on dopaminergic neurons.
Aim 2 will determine the effect of altering RMTg activity on ethanol intake. To test the hypothesis that the RMTg plays a key role in ethanol drinking, we will manipulate RMTg function by intra-RMTg infusion of relevant pharmacological agents and then study consequent changes in ethanol intake, using the intermittent 2-bottle choice paradigm. The studies are significant because they will advance our knowledge of the neural circuitries that determine excessive alcohol consumption. The proposed studies are innovative, because they will characterize a previously understudied effect of ethanol on the RMTg neurons, and its subsequent indirect effect on VTA-dopaminergic neurons, as well as the role of ?-opioid receptors in the RMTg in drinking behavior. 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 the development of improved treatment of alcoholism.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA022292-05
Application #
9210577
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02)M)
Program Officer
Liu, Qi-Ying
Project Start
2014-02-03
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
5
Fiscal Year
2017
Total Cost
$301,722
Indirect Cost
$111,960
Name
Rutgers University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Kang, Seungwoo; Li, Jing; Zuo, Wanhong et al. (2017) Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula. Neuropsychopharmacology 42:1813-1824
Li, Jing; Kang, Seungwoo; Fu, Rao et al. (2017) Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats. Neuropharmacology 126:108-120
Fu, Rao; Mei, Qinghua; Zuo, Wanhong et al. (2017) Low-dose ethanol excites lateral habenula neurons projecting to VTA, RMTg, and raphe. Int J Physiol Pathophysiol Pharmacol 9:217-230
Li, Jing; Fu, Caihong; Liu, Hongwei et al. (2017) Electroacupuncture Attenuates Hyperalgesia in Rats Withdrawn from Chronic Alcohol Drinking via Habenular Mu Opioid Receptors. Alcohol Clin Exp Res 41:637-643
Zuo, Wanhong; Fu, Rao; Hopf, Frederic Woodward et al. (2017) Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons. Addict Biol 22:103-116
Xie, Guiqin; Zuo, Wanhong; Wu, Liangzhi et al. (2016) Serotonin modulates glutamatergic transmission to neurons in the lateral habenula. Sci Rep 6:23798
Fu, Rao; Chen, Xing; Zuo, Wanhong et al. (2016) Ablation of ? opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors. Neuropharmacology 107:58-67
Guan, Y-Z; Ye, J-H (2016) Glycine blocks long-term potentiation of GABAergic synapses in the ventral tegmental area. Neuroscience 318:134-42
Zuo, Wanhong; Xiao, Cheng; Gao, Ming et al. (2016) Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms. Sci Rep 6:32937
Fu, Rao; Zuo, Wanhong; Gregor, Danielle et al. (2016) Pharmacological Manipulation of the Rostromedial Tegmental Nucleus Changes Voluntary and Operant Ethanol Self-Administration in Rats. Alcohol Clin Exp Res 40:572-82

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