Serotonergic-Muscarinic Interaction within the Prefrontal Cortex as a Novel Target to Reverse Schizophrenia-Related Cognitive Symptoms.

Paulina Cieślik,Joanna M Wierońska,Adrianna Radulska,Leszek Kalinowski,Grzegorz Burnat

doi:10.3390/ijms22168612

Abstract

Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.

Highlights

Drugs were administered on two different schedules: (1) acute administration of compounds 45 min (WAY100635—5-HT1A antagonist) or 30 min (VU0357017, VU152100, VU0238429, and F15599) before MK-801; and (2) prolonged administration of the compounds and MK-801 with the last administration 24 h before the test (NOR test) or at the day of the test (Y-maze)
The subeffective doses of the compounds for acute administration in the novel object recognition (NOR) test were chosen based on our previous research while dose-dependent studies of the activity of the compounds in reversing disruptions in the Y-maze or after prolonged administration along with MK-801 were performed within this study
As the 5-HT1A receptor is postulated to play an essential role in cognition, here, we show that simultaneous, chronic activation of muscarinic, and 5-HT1A receptors may exert a therapeutic effect on some forms of learning at relatively low doses and offer a possibility to reduce the adverse effects observed for xanomeline or (R,S)-8-OH-DPAT alone, eliminating the need to use add-on drugs, e.g., trospium

Summary

Introduction

Deficits may appear premorbidly in children and adolescents or occur suddenly; they persist chronically and may worsen over time, affecting daily functioning [1,2,3]. In preclinical experiments with the use of rodent models of learning and memory (e.g., novel object recognition test—NOR) the administration of atypical neuroleptics reversed cognitive decline induced by the administration of open channel blockers (OCB) of NMDA receptor, such as MK-801 ( known as dizocilpine) or phencyclidine (PCP) [6,7,8,9]. Activation of the 5-HT1A receptor by atypical neuroleptics is responsible for their efficacy in reversing cognitive symptoms associated with schizophrenia [10,11]

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Conclusion