Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2014020 | Pharmacology Biochemistry and Behavior | 2009 | 8 Pages |
Abstract
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; 0.5Â mg/kg twice daily for 7Â 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, 1.0Â mg/kg) further enhanced locomotion; the pro-GABA drug chlormethiazole (0.1, 1.0Â mg/kg) had no significant effect. In saline-pretreated rats GT 1061 (0.1; not 0.0001, 0.001Â mg/kg) increased amphetamine-induced locomotion; chlormethiazole (0.1, 1.0Â 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 1.0Â 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.
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Authors
Richard J. Beninger, Jennifer K. Forsyth, Michael Van Adel, James N. Reynolds, Roland J. Boegman, Khem Jhamandas,