title: The GABABPositive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats.
abstract: GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABABreceptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABABreceptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABABreceptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 (1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue- and stress-induced alcohol seeking were blocked by the GABABreceptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABABreceptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABABreceptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.
authors.affiliation: Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Augier
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Dulman
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Damadzic
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pilling
authors.affiliation: Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Hamilton
authors.affiliation: Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000081:Acetamides; D000427:Alcohol Deterrents; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003463:Cues; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism; D012008:Recurrence; D012646:Self Administration; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000494:pharmacology*; D014227:Triazines
chemical_list: C000592313:ADX71441; D000081:Acetamides; D000427:Alcohol Deterrents; D001426:Bacterial Proteins; D002492:Central Nervous System Depressants; D058786:GABA-B Receptor Agonists; D016760:Proto-Oncogene Proteins c-fos; D018080:Receptors, GABA-B; D014157:Transcription Factors; D014227:Triazines; D000431:Ethanol