Behavioral and molecular effects of α2A-adrenergic receptor activation in the triple-hit Lisket rat model of schizophrenia.

Authors

Gyongyi Horvath, Szonja Bianka Plesz, Eszter Ducza, Peter Szatmári, Emese Solymos, Tibor Nyári, Gabriella Kekesi

Published in

Neuropharmacology. Pages 111190. Sep 16, 2026. Epub Sep 16, 2026.

Abstract

Dysregulation of the noradrenergic system has been implicated in the pathophysiology of schizophrenia. Although α2-adenergic receptor (α2-AR) agonists may alleviate positive symptoms, their effects on cognitive and negative symptoms remain controversial. This study aimed to characterize the dose-dependent effects of repeatedly administered α2A-AR agonist, guanfacine, on behavioral activity, cognition, and cerebral α2A-AR mRNA expression in male Long Evans rats and their schizophrenia-like substrain (Lisket). Animals received guanfacine (0.02; 0.1, and 0.5 mg/kg intraperitoneally) or vehicle for 11 days. Behavioral performance was assessed using the reward-based Ambitus test before treatment and during treatment (days 8-11). Guanfacine produced dose-dependent impairments following an inverted-U pattern in several exploration- and cognition-related parameters particularly in Lisket animals. However, guanfacine did not influence the number of collected rewards, attention-related parameters, reference memory, or overall data variability. Vehicle treated Lisket rats showed reduced α2A-AR mRNA expression in the prefrontal cortex and increased expression in the brainstem and a similar trend in the hippocampus compared with controls. Guanfacine produced region-specific effects, including decreased prefrontal and increased subcortical α2A-AR expression. These findings provide new insights into the expression of cerebral α2A-AR mRNA in a complex schizophrenia model and subsequent effects of guanfacine. They reveal that this compound has a detrimental or ineffective impact on behavioral outcomes. The results highlight the complexity of noradrenergic modulation in schizophrenia and suggest that α2A-AR agonist therapy alone is unlikely to alleviate cognitive or negative symptoms associated with the disorder. This emphasizes the need for more integrative therapeutic strategies that target multiple neuromodulator systems.

PMID:
42749215
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.

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