title: The "first hit" toward alcohol reinforcement: role of ethanol metabolites.
abstract: This review analyzes literature that describes the behavioral effects of 2 metabolites of ethanol (EtOH): acetaldehyde and salsolinol (a condensation product of acetaldehyde and dopamine) generated in the brain. These metabolites are self-administered into specific brain areas by animals, showing strong reinforcing effects. A wealth of evidence shows that EtOH, a drug consumed to attain millimolar concentrations, generates brain metabolites that are reinforcing at micromolar and nanomolar concentrations. Salsolinol administration leads to marked increases in voluntary EtOH intake, an effect inhibited by mu-opioid receptor blockers. In animals that have ingested EtOH chronically, the maintenance of alcohol intake is no longer influenced by EtOH metabolites, as intake is taken over by other brain systems. However, after EtOH withdrawal brain acetaldehyde has a major role in promoting binge-like drinking in the condition known as the "alcohol deprivation effect"; a condition seen in animals that have ingested alcohol chronically, are deprived of EtOH for extended periods, and are allowed EtOH re-access. The review also analyzes the behavioral effects of acetate, a metabolite that enters the brain and is responsible for motor incoordination at low doses of EtOH. Also discussed are the paradoxical effects of systemic acetaldehyde. Overall, evidence strongly suggests that brain-generated EtOH metabolites play a major role in the early ("first-hit") development of alcohol reinforcement and in the generation of relapse-like drinking.
authors.affiliation: Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Yedy
authors.initials: Y
authors.lastname: Israel
authors.forename: María Elena
authors.initials: ME
authors.lastname: Quintanilla
authors.forename: Eduardo
authors.initials: E
authors.lastname: Karahanian
authors.forename: Mario
authors.initials: M
authors.lastname: Rivera-Meza
authors.forename: Mario
authors.initials: M
authors.lastname: Herrera-Marschitz
mesh_terms: D000079:Acetaldehyde / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology*; D007546:Isoquinolines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000085:Acetates; D007546:Isoquinolines; D000431:Ethanol; C036617:salsolinol; D000079:Acetaldehyde
keywords: Acetaldehyde; Acetate; Alcohol Deprivation Effect; Reinforcement; Salsolinol; Self-Administration