Gestational methylazoxymethanol acetate administration alters α5GABAA and NMDA receptor density: An integrated neuroimaging, behavioral and pharmacological study

Kiemes, A.; Gomes, F. V.; Cash, D.; Uliana, D. L.; Simmons, C.; Singh, N.; Vernon, A. C.; Turkheimer, F. E.; Davies, C.; Stone, J. M.; Grace, A. A.; Modinos, G.

doi:10.1101/2021.06.21.449343

bioRxiv · 10.1101/2021.06.21.449343

Gestational methylazoxymethanol acetate administration alters α5GABAA and NMDA receptor density: An integrated neuroimaging, behavioral and pharmacological study

Kiemes, A.·Gomes, F. V.·Cash, D.·Uliana, D. L.·Simmons, C.·Singh, N.·Vernon, A. C.·Turkheimer, F. E.·Davies, C.·Stone, J. M.·Grace, A. A.·Modinos, G.

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Abstract

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in dorsal hippocampus CA1, ventral hippocampus CA1, and in ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of 5 GABAA receptors (5GABAAR), [3H]-flumazenil to quantify 1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. 5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-Flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of 5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

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Kiemes, A., Gomes, F. V., Cash, D., Uliana, D. L., Simmons, C., Singh, N., Vernon, A. C., Turkheimer, F. E., Davies, C., Stone, J. M., Grace, A. A., Modinos, G.. 2021-06-22. Gestational methylazoxymethanol acetate administration alters α5GABAA and NMDA receptor density: An integrated neuroimaging, behavioral and pharmacological study. https://doi.org/10.1101/2021.06.21.449343

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