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Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism

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Abstract

Rationale

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and cognitive behaviors. Histamine H3 receptor (H3R) antagonists are considered as therapeutic factors for treating cognitive impairments.

Objectives

The aim of the present study was to evaluate the effects of the H3R antagonist, ciproxifan (CPX), on cognition impairment especially, spatial learning memory, and synaptic plasticity in the CA1 region of the hippocampus in autistic rats.

Methods

Pregnant rats were injected with either valproic acid (VPA) (600 mg/kg, i.p.) or saline on an embryonic day 12.5 (E12.5). The effects of the H3R antagonist, ciproxifan (CPX) (1, 3 mg/kg, i.p.), were investigated on learning and memory in VPA-exposed rat pups and saline-exposed rat pups using Morris water maze (MWM) and social interaction tasks. The H2R antagonist, famotidine (FAM) (10, 20, 40 mg/kg, i.p.), was used to determine whether brain histaminergic neurotransmission exerted its procognitive effects through the H2R. In addition, synaptic reinforcement was evaluated by in vivo field potential recording.

Results

The results showed that VPA-exposed rat pups had significantly lower sociability and social memory performance compared to the saline rats. VPA-exposed rat pups exhibited learning and memory impairments in the MWM task. In addition, VPA caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results demonstrated that CPX 3 mg/kg improved VPA-induced cognitive impairments and FAM 20 mg/kg attenuated cognitive behaviors as well as electrophysiological properties.

Conclusions

CPX 3 mg/kg improved VPA-induced impairments of LTP as well as learning and memory deficits through H2R.

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Acknowledgements

This study was supported by the Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.

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  1. Khadijeh Esmaeilpour and Gholamreza Sepehri contributed equally to this work.

Authors and Affiliations

  1. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Farahnaz Taheri, Khadijeh Esmaeilpour, Gholamreza Sepehri, Vahid Sheibani & Marzieh Maneshian

  2. Physics and Astronomy Department, University of Waterloo, Waterloo, Ontario, Canada

    Khadijeh Esmaeilpour

  3. Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Islamabad, Pakistan

    Naeem ur Rehman

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  1. Farahnaz Taheri
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Taheri, F., Esmaeilpour, K., Sepehri, G. et al. Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism. Psychopharmacology 239, 2673–2693 (2022). https://doi.org/10.1007/s00213-022-06155-z

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