Guanosine ameliorates positive symptoms of schizophrenia via modulating 5-HT1A and 5-HT2A receptors

Yu Mao; Yao Xing; Jie Li; Dong Dong; Shoude Zhang; Zhenjiang Zhao; Jingli Xie; Rui Wang; Honglin Li

Guanosine ameliorates positive symptoms of schizophrenia via modulating 5-HT_1A and 5-HT_2A receptors

Am J Transl Res. 2021 May 15;13(5):4040-4054. eCollection 2021.

Authors

Yu Mao¹, Yao Xing¹, Jie Li¹, Dong Dong¹, Shoude Zhang^{1

2}, Zhenjiang Zhao¹, Jingli Xie³, Rui Wang¹, Honglin Li¹

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology Shanghai 200237, China.
² State Key Laboratory of Plateau Ecology and Agriculture, Department of Pharmacy, Medical College of Qinghai University, Qinghai University Qinghai 810016, China.
³ State Key Laboratory of Bioreactor Engineering, College of Bioengineering, East China University of Science & Technology Shanghai 200237, China.

PMID: 34149997
PMCID: PMC8205766

Abstract

Schizophrenia is a serious mental disorder characterized by hallucinations, delusions, and extremely disordered thinking and behavior. There are several hypotheses of pathogenesis in schizophrenia: dopaminergic, glutamatergic, or serotonergic hyperfunction. Guanosine reportedly protects the central nervous system by modulating the glutamatergic system. Thus, we assumed that guanosine may exert a positive effect on the pathophysiology of schizophrenia. Herein, we demonstrated that guanosine significantly reduced MK-801-induced hyperlocomotion and stereotyped behaviors, but showed no effect on hyperlocomotion induced by d-amphetamine, indicating that guanosine may directly affect the glutamatergic system. Guanosine dose-dependently reduced 5-HTP-induced wet dog shakes (WDS) and other serotonin syndromes (SS) behaviors, indicating that it might block serotonin 5-HT_1A or 5-HT_2A receptors. Finally, we confirm that that guanosine modulates serotonin 5-HT_1A and 5-HT_2A receptors and it might be anti-schizophrenic partly through pertussis toxin-sensitive G_i/o-coupled PI3K/Akt signaling. Collectively, this study provides possible compounds and mechanisms for therapeutic effects on schizophrenia.

Keywords: 5-HT1A receptor; 5-HT2A receptor; Guanosine; PI3K/Akt; schizophrenia.