The goal of this application is to explore the role that neurons in the Lateral Habenula (LHb) play in regulating ethanol intake. Aversive, negative sensory input is processed by the habenular complex, an epithalamic structure involved in fear, anxiety, depression, stress and reward. The LHb receives inputs primarily from the basal ganglia and sends outputs mainly to dopaminergic (DA) and serotonergic neurons. The LHb provides an important source of negative reinforcing signals to midbrain DA cells. This profound and consistent inhibitory influence involves a disynaptic connection from glutamate neurons in the LHb to the GABA cells in the Rostromedial Mesopontine Tegmental Nucleus (RMTg) that, in turn, innervates DA neurons. Much work has shown that the habenula plays a key role in nicotine addiction and withdrawal and in the regulation of morphine self-administration, as well as cocaine seeking behavior. However, the role of LHb in ethanol addiction has not been well explored. It is well accepted that the DA system, including the ventral tegmental area (VTA), is involved in ethanol seeking and relapse. Although ethanol acutely activates mesolimbic DA transmission, withdrawal from chronic ethanol exposure leads to substantial decrements in VTA DA neuronal activities and extracellular levels of dopamine in the nucleus accumbens. It is believed that this dopamine hypofunction leads to a dysphoric state that drives drug seeking to restore dopamine to normal, drug-na?ve levels. However, the mechanisms causing dopamine hypofunction are not well understood. Our proposed experiments will therefore specifically test the central hypothesis that over-activity of LHb neurons in alcohol dependent animals drives inhibitory RMTg neurons which reduce firing of VTA DA neurons. These inhibitory effects may underlie the dopamine hypofunction and aversive state that may substantially contribute to excessive drinking. We will test this hypothesis by the use of a rat model of chronic intermittent ethanol self-administration (CIESA) and a multidisciplinary approach, including state-of-the-art optogenetic techniques in the following two separate but integrated Specific Aims.
Specific Aim 1 will test the hypothesis by assessing changes in voluntary ethanol drinking while the function of the LHb neurons is manipulated by electrical/light stimulation or pharmacologically. We will also measure changes caused by CIESA on the activity of neurons in the LHb and RMTg by means of Fos immunoreactivity, on protein levels of glutamate receptors using Western blotting, and extracellular levels of glutamate in the LHb and RMTg using microdialysis techniques.
Specific Aim 2 will examine the cellular mechanisms underlying LHb regulation of ethanol drinking behaviors by electrophysiological recording in brain slices of alcohol dependent animals. We will characterize changes caused by CIESA in the activity of, and glutamatergic synaptic transmissions to, neurons in the LHb and RMTg. These studies will provide important new information that will significantly advance our understanding of the role of LHb and RMTg in alcohol use disorders. These studies could also provide insight into the cellular mechanisms governing negative reinforcement-associated drinking in human alcoholics.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-Q (03))
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Cui, Changhai
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Rutgers University
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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
Xie, Zijing; Li, Guohui; Ye, Jiang-Hong (2013) Acute effects of ethanol on GABAA and glycine currents in the lateral habenula neurons of young rats. Open J Neurosci 3:

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