Aniracetam Reversed Learning and Memory Deficits Following Prenatal Ethanol Exposure by Modulating Functions of Synaptic AMPA Receptors

Abstract

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 (a-amino-3 hydro-5 methyl-isoxazole propionic acid) receptormediated miniature excitatory postsynaptic responses (mEPSCs) in the hippocampus. Administration of aniracetam for 10 days (postnatal 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.

Effects of Developmental Alcohol Exposure on Potentiation and Depression of Visual Cortex Responses

“…Studies using a variety of alcohol doses, regimens and time periods showed unequivocally that alcohol can disrupt LTP in hippocampus (Izumi et al, 2005; Puglia and Valenzuela, 2010b; Puglia and Valenzuela, 2010a; Richardson et al, 2002; Savage et al, 2010; Sutherland et al, 1997). Interestingly, in this region, pharmacological potentiation of AMPA receptor responses reverses the deficits of alcohol exposed animals in the Morris water maze, a behavior that is dependent on LTP in the hippocampus (Vaglenova et al, 2008). Surprisingly, few studies have investigated the effects of alcohol on LTD.…”

Aniracetam Does Not Alter Cognitive and Affective Behavior in Adult C57BL/6J Mice

“…Aniracetam positively impacts the pharmacological profile associated with learning and memory by elevating hippocampal acetylcholine, serotonin, glutamate, and dopamine levels [12], [19], [20]. In addition, aniracetam significantly facilitates long-term potentiation (LTP) formation in the hippocampus [21], reverses memory loss [22], reduces anxiety [12], and reverses ethanol-induced brain damage [23], [24]. An important caveat for some of the above behavioral studies is that they were performed in rodent models of disease or using experimentally induced learning deficits and did not explicitly address impacts in healthy subjects.…”

GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice

“…Interestingly, our data indicate that the combination of the high dose of MU and the low dose of MK has an anxiogenic effect only in females. Similarly, Sprague-Dawley adult females, but not males, prenatally exposed to ethanol presented an increase in anxiety-like behaviors as compared to controls (Osborn et al, 1998;Vaglenova et al, 2008). A gender difference was also observed in humans prenatally exposed to ethanol, with females showing higher rates of anxiety than males (Famy et al, 1998).…”