title: Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors.
abstract: There has been increasing interest in the rostromedial tegmental nucleus (RMTg), given its potential regulatory role in many aversion-related behaviors. The RMTg contains mostly GABAergic neurons, sends a dense inhibitory projection to dopamine neurons in the midbrain, and is rich with μ-opioid receptors (MOR). Like most addictive drugs, ethanol has both aversive and rewarding properties. However, the cellular mechanisms underlying the effects of ethanol, particularly the aversive effect that limits its intake are not well understood. Recent studies have linked aversion with synaptic inhibition of dopamine neurons in the ventral tegmental area. To determine a potential role that the RMTg plays in the effect of ethanol, in this study, we employed a neurotoxin, dermorphin-saporin (DS), to lesion RMTg neurons prior to assessing ethanol-related behaviors. Rats were infused with DS bilaterally into the RMTg. This manipulation substantially increased the intake and preference for ethanol but not sucrose. It also reduced the number of neurons with MOR and glutamic acid decarboxylase 67 immunoreactivity within the RMTg. These changes did not occur after intra-RMTg infusion of blank saporin or vehicle. Importantly, intra-RMTg DS infusion significantly enhanced expression of conditioned place preference induced by ethanol (2 g/kg, i.p.), and slowed the extinction process. These results suggest that MOR-expressing GABAergic neurons in the RMTg contribute significantly to the regulation of ethanol consumption and related behaviors.
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Rao
authors.initials: R
authors.lastname: Fu
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Wanhong
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Seungwoo
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China, (LHZ).
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhou
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Siegel
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bekker
authors.affiliation: Departments of Anesthesiology, Pharmacology and Physiology, (RF, XC, WZ, JL, SK, AB JHY), Psychiatry (AS) Rutgers-New Jersey Medical School, Newark, NJ, USA. Electronic address: ye@njms.rutgers.edu.
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Ye
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism* / Q000473:pathology; D019973:Alcohol-Related Disorders / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018847:Opioid Peptides; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D002492:Central Nervous System Depressants; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D054789:Ribosome Inactivating Proteins, Type 1; C431163:dermorphin-saporin; D000431:Ethanol; D000076985:Saporins; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Conditioning place preference; Dermorphin-saporin; Ethanol; Intracranial infusion; Rat