Some central effects of kynurenic acid, 7-chlorokynurenic acid and 5,7- dichloro-kynurenic acid, glycine site antagonists.

Strychnine-insensitive glycine site is one of a few binding sites of NMDA receptor complex. The aim of these study was to find out whether compounds regarded as glycine antagonists-kynurenic acid (KA), 7-chlorokynurenic acid (7-CKA), 5,7-dichlorokynurenic acid (5,7-DCKA) evoke the effects analogous to those of the NMDA receptor antagonist, CGP 37849 (or MK-801) and/or can modulate the effects of the last compounds in rats. KA (but not 7-CKA, given ip) inhibited electroshock-induced seizures and increased the anticonvulsant effect of CGP 37849. CGP 37849-induced locomotor hyperactivity was enhanced by KA, 7-CKA (icv but not ip) and 5,7-DCKA. D-Amphetamine-induced hyperactivity was inhibited by KA as well as 7-CKA. In monoamine-depleted rats 7-CKA (but not KA) increased the antiakinetic effect of clonidine; the antiakinetic effect of L-DOPA was enhanced by 7-CKA and 5,7-DCKA, but not by KA. KA and 7-CKA did not change the spiperone-induced catalepsy but they attenuated the anticataleptic effect of CGP 37849; the studied drugs did not change the anticataleptic effect of MK-801. 7-CKA given icv did not influence the spiperone-induced catalepsy as well as the anticataleptic effect of CGP 37849. In the forced swimming test KA, given once, prolonged (50 mg/kg) or did not change (200 and 300 mg/kg) the immobility time. 7-CKA did not affect the immobility time in this model. When given three times KA (200 mg/kg) and 7-CKA (20 mg/kg) reduced the immobility time; the lower doses of KA and 7-CKA prolonged or did not change the immobility time, respectively. Joint injection with imipramine and KA (or 7-CKA) induced the decrease of immobility time (vs imipramine alone or glycine antagonist alone); in the case of joint injection with citalopram + KA (or 7-CKA), the time of immobility was prolonged or not changed. In conclusion, the obtained results point to similarities between glycine antagonists (kynurenine derivatives) and CGP 37849 and to the possibility of positive cooperation between the NMDA- and glycine-sites antagonists.