The antipsychotic drug brexpiprazole reverses phencyclidine-induced disruptions of thalamocortical networks

摘要

Abstract Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5‐HT 1A and D 2 receptors and antagonist at α 1B - and α 2C -adrenergic and 5-HT 2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; 1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at α 1B -adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT 1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α 1B -, α 2C -adrenergic and 5-HT 2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT 1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.