title: A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence.
abstract: In human alcoholics, abstinence is often self-imposed, despite alcohol availability, because of the negative consequences of excessive use. During abstinence, relapse is often triggered by exposure to contexts associated with alcohol use. We recently developed a rat model that captures some features of this human condition: exposure to the alcohol self-administration environment (context A), after punishment-imposed suppression of alcohol self-administration in a different environment (context B), provoked renewal of alcohol seeking in alcohol-preferring P rats. The mechanisms underlying context-induced renewal of alcohol seeking after punishment-imposed abstinence are unknown. Here, we studied the role of the lateral hypothalamus (LH) and its forebrain projections in this effect. We first determined the effect of context-induced renewal of alcohol seeking on Fos (a neuronal activity marker) expression in LH. We next determined the effect of LH reversible inactivation by GABAA + GABAB receptor agonists (muscimol + baclofen) on this effect. Finally, we determined neuronal activation in brain areas projecting to LH during context-induced renewal tests by measuring double labeling of the retrograde tracer cholera toxin subunit B (CTb; injected in LH) with Fos. Context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with increased Fos expression in LH. Additionally, renewal was blocked by muscimol + baclofen injections into LH. Finally, double-labeling analysis of CTb + Fos showed that context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with selective activation of accumbens shell neurons projecting to LH. The results demonstrate an important role of LH in renewal of alcohol seeking after punishment-imposed abstinence and suggest a role of accumbens shell projections to LH in this form of relapse.
authors.affiliation: Behavioral Neuroscience Research Branch and Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia, nathan.marchant@nih.gov yavin.shaham@nih.gov.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Marchant
authors.affiliation: Behavioral Neuroscience Research Branch and.
authors.forename: Rana
authors.initials: R
authors.lastname: Rabei
authors.affiliation: Behavioral Neuroscience Research Branch and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kaganovsky
authors.affiliation: Behavioral Neuroscience Research Branch and.
authors.forename: Daniele
authors.initials: D
authors.lastname: Caprioli
authors.affiliation: Behavioral Neuroscience Research Branch and.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bossert
authors.affiliation: Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, Solomon H. Snyder Department of Neuroscience and Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21287.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Behavioral Neuroscience Research Branch and nathan.marchant@nih.gov yavin.shaham@nih.gov.
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D064829:Alcohol Abstinence / Q000523:psychology*; D000428:Alcohol Drinking / Q000503:physiopathology / Q000523:psychology*; D000818:Animals; D016739:Behavior, Addictive / Q000523:psychology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D011678:Punishment / Q000523:psychology*; D051381:Rats; D012008:Recurrence; D012055:Reinforcement Schedule; D012646:Self Administration
keywords: alcohol; context; lateral hypothalamus; nucleus accumbens; punishment; relapse