Aniracetam reversed learning and memory deficits following prenatal ethanol exposure by modulating functions of synaptic AMPA receptors.

Specific pharmacological treatments are currently not available to address problems resulting from fetal ethanol exposure, described as Fetal Alcohol Syndrome or Fetal Alcohol Spectrum Disorders (FASD). The present study evaluated the therapeutic effects of aniracetam against cognitive deficits in a well-characterized and sensitive FASD Sprague-Dawley rat model. Ethanol, administered orally at a moderate dose (4 g/kg/24 h; 38% v/v) during the entire course of pregnancy, caused severe cognitive deficits in offspring. Furthermore, both progeny genders were affected by a spectrum of behavioral abnormalities, such as a delay in the development of the righting reflex, poor novelty seeking behavior, and high anxiety levels in female rats. Cognitive disabilities, monitored in adult rats by a two-way active avoidance task, correlated well with a significant reduction of AMPA (alpha-amino-3 hydro-5 methyl-isoxazole propionic acid) receptor-mediated miniature excitatory postsynaptic responses (mEPSCs) in the hippocampus. Administration of aniracetam for 10 days (post-natal days (PND) 18-27), at a dose of 50 mg/kg reversed cognitive deficits in both rat genders, indicated by a significant increase in the number of avoidances and the number of 'good learners'. After the termination of the nootropic treatment, a significant increase in both amplitude and frequency of AMPA receptor-mediated mEPSCs in hippocampal CA-1 pyramidal cells was observed. Significant anxiolytic effects on PND 40 also preceded acquisition improvements in the avoidance task. This study provides evidence for the therapeutic potential of aniracetam in reversing cognitive deficits associated with FASD through positive post-natal modulation of AMPA receptors.

An assessment of the long-term developmental and behavioral teratogenicity of prenatal nicotine exposure.

Maternal tobacco use during pregnancy adversely affects prenatal and postnatal growth and increases the risk of developmental and behavioral deficits in children and adolescents. In the present study, the effects of prenatal nicotine exposure (infused at 6mg/kg/day) and maternal withdraw during neonatal development, was examined in Sprague-Dawley rats on an array of behavioral tasks during different stages of ontogenesis. Offspring of both genders were monitored for exploratory, locomotor, and novelty-seeking activity, anxiety, and learning and memory in an active-avoidance task. Nicotine-exposed animals showed growth retardation, hyperactivity, and poor adaptation in a new environment, increased level of anxiety during the early adolescent period, and robust cognitive deficits in early adulthood. In addition, the deficits were generally more severe in the female nicotine-exposed offspring. Cross-fostering also revealed that while maternal behavior and nicotine withdraw did not affect postnatal somatic growth retardation or cognitive ability of the offspring; measures of exploration and adaptation in a new environment were impacted during the post-weanling and early adolescence period. Nicotine-exposed offspring, and the saline-treated offspring cross-fostered to nicotine-exposed mothers, showed higher measures of anxiety in the elevated plus-maze and decreased novelty-seeking behavior on the hole-board apparatus. These studies demonstrated that prenatal nicotine exposure produced significant long-term developmental and behavioral teratogenic effects. The study design provides a model system for studying the mechanism(s) responsible for the decline in central nervous system function following prenatal nicotine exposure, as well as that of other neurological and behavioral teratogens during pregnancy.

Ameliorating effects of preadolescent aniracetam treatment on prenatal ethanol-induced impairment in AMPA receptor activity.

Ethanol-induced damage in the developing hippocampus may result in cognitive deficits such as those observed in fetal alcohol spectrum disorder (FASD). Cognitive deficits in FASD are partially mediated by alterations in glutamatergic synaptic transmission. Recently, we reported that synaptic transmission mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is impaired following fetal ethanol exposure. This finding led us to develop a rational approach for the treatment of alcohol-related cognitive deficits using aniracetam, an allosteric AMPAR modulator. In the present study, 28 to 34-day-old rats exposed to ethanol in utero were treated with aniracetam, and subsequently exhibited persistent improvement in mEPSC amplitude, frequency, and decay time. Furthermore, these animals expressed positive changes in synaptic single channel properties, suggesting that aniracetam ameliorates prenatal ethanol-induced deficits through modifications at the single channel level. Specifically, single channel open probability, conductance, mean open and closed times, and the number and burst duration were positively affected. Our findings emphasize the utility of compounds which slow the rate of deactivation and desensitization of AMPARs such as aniracetam.