Positive and Negative Selective Allosteric Modulators of α5 GABA_A Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease

Article type: Research Article

Authors: Aranđelović, Jovana^a | Santrač, Anja^a | Batinić, Bojan^b | Todorović, Lidija^c | Ahmed Khan, Md Zubair^d | Rashid, Farjana^d | Poe, Michael M.^d | Obradović, Aleksandar^a | Cook, James M.^d | Savić, Miroslav M.^{a; *}

Affiliations: [a] Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia | [b] Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia | [c] Laboratory for Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia | [d] Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

Correspondence: [*] Correspondence to: Miroslav M. Savić, Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia. Tel.: +381 11 3951280; Fax: +381 11 3972840; E-mail: [email protected].

Abstract: Background:Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective:The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods:The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results:MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion:Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.

Keywords: 5xFAD, α5 GABA_A receptors, Alzheimer’s disease, emotionality, motor function, motivation, negative allosteric modulation, positive allosteric modulation

DOI: 10.3233/JAD-215079

Journal: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1291-1302, 2021