ABA(A) and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophreni

Author(s):Show less -

Kiemes, Amanda ^[1] ; Gomes, V, Felipe ; Cash, Diana ^[2] ; Uliana, Daniela L. ^{[3, 4, 5]} ; Simmons, Camilla ^[2] ; Singh, Nisha ^[6] ; Vernon, Anthony C. ^{[7, 8]} ; Turkheimer, Federico ^[2] ; Davies, Cathy ^[1] ; Stone, James M. ^[9] ; Grace, Anthony A. ^{[3, 4, 5]} ; Modinos, Gemma ^{[1, 2, 7]}

Affiliation

^[1] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London - England

^[2] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London - England

^[3] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA - USA

^[4] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA - USA

^[5] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 - USA

^[6] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford - England

^[7] Kings Coll London, MRC Ctr Neurodev Disorders, London - England

^[8] Kings Coll London, Dept Basic & Clin Neurosci, Inst Psychiat Psychol & Neurosci, London - England

^[9] Univ Sussex, Brighton & Sussex Med Sch, Brighton, E Sussex - England

• Document type: Journal article
• Source: NEUROPSYCHOPHARMACOLOGY; v. 47, n. 3 NOV 2021.
• Web of Science Citations: 0

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 GABA(A) 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 the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, {[}H-3]-Ro15-4513 was used to quantify the density of alpha 5GABA(A) receptors (alpha 5GABA(A)R), {[}H-3]-flumazenil to quantify alpha 1-3;5GABA(A)R, and {[}H-3]-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. alpha 5GABA(A)R density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 alpha 5GABA(A)R 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. {[}H-3]-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 alpha 5GABA(A)R and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia. (AU)

• FAPESP's process: 18/17597-3 - The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets
• Grantee: Felipe Villela Gomes
• Support Opportunities: Research Grants - Young Investigators Grants