Cognitive deficits are a core feature of
schizophrenia that may be linked to abnormalities in
GABA and
nitric oxide (NO). Subchronic treatment with
glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential
therapeutics. The present study investigated the effects of subchronic
MK-801 (intraperitoneally; 0.5 mg/kg twice daily for 7 days) on
amphetamine-induced locomotor activity and reversal learning in the water maze in rats, and the ability of the novel compound
GT 1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), containing dual pharmacophores producing NO- and
GABA-mimetic activity, to ameliorate these effects.
MK-801 enhanced locomotor responses to
amphetamine.
GT 1061 (0.1; not 0.0001, 0.001, 0.01, 1.0 mg/kg) further enhanced locomotion; the pro-
GABA drug chlormethiazole (0.1, 1.0 mg/kg) had no significant effect. In saline-pretreated rats
GT 1061 (0.1; not 0.0001, 0.001 mg/kg) increased
amphetamine-induced locomotion;
chlormethiazole (0.1, 1.0 mg/kg) had no effect. In the water maze,
MK-801 impaired reversal learning after platform relocation.
GT 1061 (0.001, 0.01, 0.1; not 0.0001 or 1.0 mg/kg) attenuated this impairment;
chlormethiazole had no significant effect. These ameliorative effects of
GT 1061 may be linked to the activation of NO- and
GABA-dependent signaling and suggests a new direction for treating
cognitive dysfunction in
schizophrenia.