Chronic clozapine administration, unlike mood stabilizers, does not block NMDA- and D2-like receptor-mediated brain signaling via arachidonic acid in rats

Wednesday, November 06, 2013 — Poster Session I
4:00 p.m. – 6:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIA	NEURO-25

Authors

H R Modi
E Ramadan
M Basellin
L Chang
M Chein
K Ma
SI Rapoport

Abstract

Hyperdopaminergic and hyperglutamatergic signaling, and an upregulated brain arachidonic acid (AA) cascade may contribute to bipolar disorder (BD). Lithium, carbamazepine, valproate, and lamotrigine, FDA-approved for the treatment of BD, attenuate brain dopaminergic D2-like (D2, D3, and D4) and glutamatergic N-methyl-D-aspartate (NMDA) receptor signaling involving AA when given chronically to awake rats. We hypothesized that chronic clozapine, with efficacy in acute mania and mood-stabilizing properties, would also reduce the D2-like- and NMDA-mediated signaling via AA. An acute dose of quinpirole (1 mg/kg), NMDA (25 mg/kg) or saline was administered to unanesthetized rats that had been treated for 30 days with clozapine (10 mg/kg/day) or vehicle. Regional brain AA incorporation coefficients, k*, and incorporation rates, Jin, markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-14C]AA infusion. Chronic clozapine had a positive main effect on k* for AA in many regions including the cortex. On the other hand, chronic clozapine did not alter the k* responses to NMDA and quinpirole seen in chronic saline-treated rats. These data show that, unlike drugs effective in BD, clozapine does not block NMDA- and D2-like receptor-mediated brain signaling via AA in rats.