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Título

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

Autorvan den Munkhof, Hanna; Arnt, Jørn; Celada, Pau ; Artigas, Francesc
Palabras claveAntipsychotic drugs
NMDA receptor antagonists
Oscillations
Phencyclidine
Prefrontal cortex
Thalamocortical circuit
Fecha de publicacióndic-2017
EditorElsevier
CitaciónEuropean Neuropsychopharmacology 27(12): 1248-1257 (2017)
ResumenBrexpiprazole (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‐HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A 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; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5 mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2 mg/kg), perhaps due to antagonism at α1B-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-HT1A 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 α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A 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.
Versión del editorhttps://doi.org/10.1016/j.euroneuro.2017.10.034
URIhttp://hdl.handle.net/10261/159391
DOI10.1016/j.euroneuro.2017.10.034
ISSN0924-977X
E-ISSN1873-7862
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