title: Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats.
abstract: The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, USA. Electronic address: moorman@cns.umass.edu.
authors: David E
authors: DE
authors: Moorman
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia. Electronic address: morgan.james@rutgers.edu.
authors: Morgan H
authors: MH
authors: James
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
authors: Elisabeth A
authors: EA
authors: Kilroy
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, USA.
authors: Gary
authors: G
authors: Aston-Jones
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000378:metabolism; D019973:Alcohol-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D021461:Animals, Outbred Strains; D001583:Benzoxazoles / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D002492:Central Nervous System Depressants; C578627:Hcrtr1 protein, rat; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000431:Ethanol; D014508:Urea
keywords: Alcoholism; Individual differences; Lateral hypothalamus; Motivation; Neuropeptide; Reward