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

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.