Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats.
Adolescent brain development seems to be important for the maturation of brain structures and behaviour. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage. Because we have demonstrated that chronic ethanol treatment induces inflammatory processes in the brain, we investigate whether intermittent ethanol intoxication enhances cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in adolescent rats, and whether these mediators induce brain damage and cause permanent cognitive dysfunctions. Adolescent rats were exposed to ethanol (3.0 g/kg) for two consecutive days at 48-h intervals over 14 days. Levels of COX-2, iNOS and cell death were assessed in the neocortex, hippocampus and cerebellum 24 h after the final ethanol administration. The following day or 20 days after the final injection (adult stage), animals were tested for different behavioural tests (conditional discrimination learning, rotarod, object recognition, beam-walking performance) to assess cognitive and motor functions. Our results show that intermittent ethanol intoxication upregulates COX-2 and iNOS levels, and increases cell death in the neocortex, hippocampus and cerebellum. Furthermore, animals treated with ethanol during adolescence exhibited behavioural deficits that were evident at the end of ethanol treatments and at the adult stage. Administration of indomethacin, a COX-2 inhibitor, abolishes the induction of COX-2 and iNOS expression and cell death, preventing ethanol-induced behavioural deficits. These findings indicate that binge pattern exposure to ethanol during adolescence induces brain damage by inflammatory processes and causes long-lasting neurobehavioural consequences. Accordingly, administering indomethacin protects against ethanol-induced brain damage and prevents detrimental ethanol effects on cognitive and motor processes.
Pascual
Maria
M
Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, Avda. Autopista del Saler, 16. 46013-Valencia, Spain.
Blanco
Ana M
AM
Cauli
Omar
O
Miñarro
Jose
J
Guerri
Consuelo
C
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D004347:Drug Interactions; D004660:Encephalitis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D000431:Ethanol; D007213:Indomethacin / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009483:Neuropsychological Tests; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D053148:Caspase 3; D007213:Indomethacin