Neurotoxicity and persistent cognitive deficits induced by combined MDMA and alcohol exposure in adolescent rats

Recent trend assessments of drug consumption reveal an increase in the simultaneous use of several drugs at raves, clubs and college settings among youngsters and young adults. We studied in adolescent rats the effects of repeated exposure to cocaine and 3,4-methylenedioxymethanphetamine (MDMA, ecstasy), given alone or in combination with alcohol, on memory performance, adult hippocampal neurogenesis and neurotoxicity. Rats were trained two weeks after the drug treatments in the radial arm maze. The results showed that only rats exposed to combinations of alcohol and MDMA exhibited significant memory deficits. Alcohol, MDMA and combinations thereof significantly decreased 5-bromodeoxyuridine labeling in the dentate gyrus (DG), indicating reduced survival of neuronal precursors. None of the treatments altered the length of the dendritic arbors of doublecortin (DCX)-positive neurons or the number and length of DCX-negative gaps in the DG. Thus, changes in adult neurogenesis were not causally related to the cognitive alterations induced by the treatments. Only the combination of alcohol and MDMA significantly decreased the population of mature granule neurons in the DG and increased the presence of cluster of differentiation 11b+ reactive microglia in the bordering areas of the subgranular zone. Critically, memory impairment was correlated with granule cell depletion. These observations demonstrate that exposure to alcohol and MDMA during adolescence, at doses that do not provoke apparent cognitive impairment when given separately, causes neurotoxic alterations affecting the DG region as well as persistent memory deficits. The findings highlight the elevated risk associated with the concurrent recreational use of alcohol and MDMA.