title: Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol.
abstract: Prolonged exposure of the brain to ethanol is a prerequisite for developing ethanol dependence, but the underlying neural adaptations are unknown. Here we demonstrate that rats subjected to repeated cycles of intoxication and withdrawal develop a marked and long-lasting increase in voluntary ethanol intake. Exposure-induced but not spontaneous alcohol intake is antagonized by acamprosate, a compound clinically effective in human alcoholism. Expression analysis of cingulate cortex and amygdala reveals a set of long-term up-regulated transcripts in this model. These include members of pathways previously implicated in alcohol dependence (glutamatergic, endocannabinoid, and monoaminergic neurotransmission), as well as pathways not previously thought to be involved in this disorder (e.g., members of the mitogen-activated protein kinase pathway). Thus, alternating periods of ethanol intoxication and withdrawal are sufficient to induce an altered functional brain state, which is likely to be encoded by long-term changes in gene expression. These observations may have important implications for how alcoholism is managed clinically. Novel clinically effective treatments may be possible to develop by targeting the products of genes found to be regulated in our model.
authors.affiliation: NEUROTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.forename: Christina
authors.initials: C
authors.lastname: Arlinde
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sommer
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000077443:Acamprosate; D000222:Adaptation, Physiological; D000427:Alcohol Deterrents / Q000494:pharmacology; D000437:Alcoholism / Q000378:metabolism*; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D003216:Conditioning, Operant; D003345:Corticosterone / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005625:Frontal Lobe / Q000378:metabolism; D020869:Gene Expression Profiling; D007700:Kinetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D000427:Alcohol Deterrents; D063385:Cannabinoid Receptor Modulators; D013654:Taurine; D000431:Ethanol; D000077443:Acamprosate; D003345:Corticosterone