BEHAVIORAL PHARMACOLOGY OF 2 NOVEL SUBSTITUTED QUINOXALINEDIONE GLUTAMATE ANTAGONISTS

Two novel quinoxalinedione glutamatergic antagonists, with in vitro se lectivity for the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primar ily designed to compare their effects to those of the noncompetitive N MDA antagonist phencyclidine (PCP). The compounds evaluated were 7-tri fluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and itro-6,7 -dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminat ive stimulus effects, although behavioral activity, in the form of res ponse rate suppression, was seen at the higher doses tested (6-25 mg/k g, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhes us monkeys trained to discriminate PCP from sham injection, although i n the monkeys minimal effects were observed on rates of responding eve n at the highest dose tested (10.2 mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial level s of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 pro duced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3 mg/kg, i.p.). ACEA-1021 was ineffective a s an antagonist of NMDA discrimination. Unlike results reported for PC P-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted pre pulse inhibition of the acoustic startle reflex in rats. It was not po ssible to establish ACEA-1021 (10 or 15.6 mg/kg) as a discriminative s timulus in rats. In conclusion, the novel glutamate antagonists ACEA-1 011 and ACEA-1021 did not produce a profile of behavioral effects simi lar to that of PCP-like noncompetitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonist s.