Therapeutic effects of aniracetam on cognitive deficits induced by ethanol teratogenicity: A novel treatment approach through synaptic AMPA receptor modulation

Abstract

Ethanol exposure during fetal development can adversely affect the outcome of the offspring. Numerous mechanisms are likely to contribute to these damaging effects of ethanol on the fetus and particularly the developing central nervous system. The hippocampus which is critically involved in learning and memory formation is most vulnerable to ethanol exposure in utero, resulting in persistent memory and learning deficits commonly observed in fetal alcohol syndrome (FAS). FAS is assumed to be mediated partially via alterations in glutamatergic synaptic transmission. The a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors plays a crucial role in learning and memory. However, the damaging effects of ethanol on AMPAR-mediated synaptic transmission in the hippocampus are not well studied. Therefore, this study investigated the hypothesis that in utero exposure to alcohol can impair the AMPAR function, altering the normal neurobehavioral function and targeting the AMPARs would provide a new therapeutic approach in the treatment of FAS. The identification of this new mechanism and its contribution to ethanol-induced fetal damage led to the development of a rational approach using aniracetam that targets AMPARs, for the treatment of alcohol-related cognitive deficits associated with FAS. Developmental reflexes, plus-maze test and active avoidance tests were carried out to assess the behavioral teratogenicity in Sprague Dawley rat offspring exposed to moderate ethanol (4 g/kg/24h; 38% v/v), throughout pregnancy. The whole-cell-patch clamp technique and bilayer reconstitution of synaptosomal AMPARs were used to study the AMPAR-mediated currents in the hippocampus. Growth retardation, impairments in learning and memory, and enhancement of anxiety were noticed after ethanol exposure. Significant reduction of AMPAR-mediated currents suggested impairment of post synaptic AMPARs as well as glutamate release from presynaptic nerve terminals. Ten day aniracetam treatment (50 mg/kg) during preadolescence effectively ameliorated the neurobehavioral deficits of ethanol exposure in utero. The results of this study clearly demonstrate for the first time that the AMPAR-mediated synaptic transmission is impaired by moderate prenatal ethanol exposure, which results at least partially in behavioral teratogenicity in FAS. Our findings emphasize the importance of targeting AMPARs using aniracetam in developing an effective intervention approach to address this major public health problem.