Memantine Improves Social Behavior and Prevents Developmental Retardation in Rats Exposed Prenatally to Valproic Acid
Journal Title: The 1st Annual Meeting of Georgian Center for Neuroscience Research - Year 2020, Vol 2, Issue 20
Abstract
Autism spectrum disorders (ASD) is a group of neurodevelopmental disorders which are characterized by impairments in communication and social interaction, repetitive behaviors and a limited repertoire of interests and activities. The etiology of autism is not known, but there is evidence to suggest that it has strong genetic and environmental components. Although the number of patients has strikingly increased, therapeutic agents to ameliorate the ASD core symptoms are very limited. Rats prenatally exposed to valproic acid (VPA) showed autistic behaviors. In this study, we investigated therapeutic potential of memantine for ASD using VPA-induced autistic animal model. Memantine is uncompetitive antagonist of glutamatergic NMDA receptors. In addition, memantine has been demonstrated to act as an antagonist of nicotinic acetylcholine receptors. Hyperactivity of the excitatory glutamate system and dysregulation of acetylcholine (ACh) has been theorized to have a causal role in the development of behavioral symptoms in autism. Female outbred white rats were mated overnight, and the morning when spermatozoa were found was designated as the first day of gestation. Females received a single intraperitoneal injection of 500 mg/kg sodium VPA on the 12.5 day after conception, and control females were injected with physiological saline at the same time. The offspring were weaned on postnatal day (PND) 28. Experiments were carried out on male offspring. Control and VPA rats were divided into 2 subgroups and memantine (5 mg/kg) or saline was administered via intraperitoneal injection from PND 14 to 35, once daily. Weight gain was controlled on PNDs 7, 14, 23 and 30. Eye opening was observed from days 12 to 16. Sociability was evaluated in a three-chamber apparatus. Our results showed maturational delay - later eye opening and lower body weight in VPA group. Statistical analysis revealed lower body weight in VPA group on PNDs 23, 30, with no difference on PNDs 7 and 14. Memantine treatment prevents developmental retardation. Our studies showed marked decreases in social interaction in VPAtreated rats. In the sociability test, VPA rat stayed more time in the empty space than rat in other groups and their staying time in the compartment with a conspecific rat was significantly lower than control rat suggesting the deficits in sociability. Interestingly, VPA group treated with memantine stayed more time in the compartment with a conspecific rat which showed improved social interaction by the memantine. From our results, we might assume that modulation of glutamatergic and cholinergic transmission by subchronic treatment of memantine may at least in part contribute to the observed therapeutic effects in VPA rats. Our results bring further support to the validity of the proposed VPA animal model of autism and reinforce the importance of this model for the preclinical investigation of new therapeutic drugs. (Supported by the funding from the SRNSFG: Grant # - FR-18-14029.)
Authors and Affiliations
L. Kruashvili, M. Burjanadze, M. Chighladze, N. Chkhikvishvili, M. Dashniani
Keywords
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- EP ID EP677933
- DOI 10.29088/GCNR-2020.24
- Views 287
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