Early and late behavioral consequences of ethanol withdrawal: focus on brain indoleamine 2,3 dioxygenase activity

Anxiety and depression are symptoms associated with ethanol withdrawal that lead individuals to relapse. In the kynurenine pathway, the enzyme indoleamine 2,3 dioxygenase (IDO) is responsible for the conversion of tryptophan to kynurenine, and dysregulation of this pathway has been associated with psychiatric disorders, such as anxiety and depression. The present study evaluated the early and late behavioral and biochemical effects of ethanol withdrawal in rats. Male Wistar rats were submitted to increasing concentrations of ethanol in drinking water during 21 days. In experiment 1, both control and withdrawal groups were submitted to a battery of behavioral tests 3, 5, 10, 19, and 21 days following ethanol removal. In experiment 2, animals were euthanized 3 days (short-term) or 21 days (long-term) after withdrawal, and the brains were dissected altogether, following kynurenine concentration analysis in prefrontal cortex, hippocampus, and striatum. Short-term ethanol withdrawal decreased the exploration of the open arms in the elevated plus-maze. In the forced swimming test, long-term ethanol-withdrawn rats displayed higher immobility time than control animals. Ethanol withdrawal altered neither locomotion nor motor coordination of rats. In experiment 2, kynurenine concentrations were increased in the prefrontal cortex after a long-term period of withdrawal. In conclusion, short-term ethanol withdrawal produced anxiety-like behaviors, while long-term withdrawal favored depressive-like behaviors. Long-term ethanol withdrawal elevated kynurenine levels, specifically in the prefrontal cortex, suggesting that the depressive-like responses observed after long-term withdrawal might be related to the increased IDO activity.