Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061.
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.
Beninger
Richard J
RJ
Department of Psychology, Queen's University, Kingston ON, Canada K7L 3N6. beninger@queensu.ca
Forsyth
Jennifer K
JK
Van Adel
Michael
M
Reynolds
James N
JN
Boegman
Roland J
RJ
Jhamandas
Khem
K
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002719:Chlormethiazole / Q000627:therapeutic use; D003072:Cognition Disorders / Q000139:chemically induced* / Q000523:psychology*; D003627:Data Interpretation, Statistical; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009566:Nitrates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012193:Reversal Learning / Q000187:drug effects
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; C501053:GT 061; D006993:Hypnotics and Sedatives; D009566:Nitrates; D002719:Chlormethiazole; D016291:Dizocilpine Maleate; D000661:Amphetamine