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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
6R01AA022292-02
Application #
8813027
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Liu, Qi-Ying
Project Start
2014-02-03
Project End
2019-01-31
Budget Start
2014-02-03
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$335,247
Indirect Cost
$124,400
Name
Rutgers University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Fu, Rao; Chen, Xing; Zuo, Wanhong et al. (2016) Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors. Neuropharmacology 107:58-67
Li, Jing; Zuo, Wanhong; Fu, Rao et al. (2016) High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats. Int J Neuropsychopharmacol :
Xie, Guiqin; Zuo, Wanhong; Wu, Liangzhi et al. (2016) Serotonin modulates glutamatergic transmission to neurons in the lateral habenula. Sci Rep 6:23798
Guan, Y-Z; Ye, J-H (2016) Glycine blocks long-term potentiation of GABAergic synapses in the ventral tegmental area. Neuroscience 318:134-42
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
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
Zuo, Wanhong; Zhang, Yong; Xie, Guiqin et al. (2016) Serotonin stimulates lateral habenula via activation of the post-synaptic serotonin 2/3 receptors and transient receptor potential channels. Neuropharmacology 101:449-59
Zuo, Wanhong; Fu, Rao; Hopf, Frederic Woodward et al. (2015) Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons. Addict Biol :
Fu, Rao; Gregor, Danielle; Peng, Zengliu et al. (2015) Chronic intermittent voluntary alcohol drinking induces hyperalgesia in Sprague-Dawley rats. Int J Physiol Pathophysiol Pharmacol 7:136-44