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.
AuthorsRichard J Beninger, Jennifer K Forsyth, Michael Van Adel, James N Reynolds, Roland J Boegman, Khem Jhamandas
JournalPharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 91 Issue 4 Pg. 495-502 (Feb 2009) ISSN: 0091-3057 [Print] United States
PMID18834899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Central Nervous System Stimulants
  • Excitatory Amino Acid Antagonists
  • GT 061
  • Hypnotics and Sedatives
  • Nitrates
  • Chlormethiazole
  • Dizocilpine Maleate
  • Amphetamine
  • Amphetamine (pharmacology)
  • Animals
  • Behavior, Animal (drug effects)
  • Central Nervous System Stimulants (pharmacology)
  • Chlormethiazole (therapeutic use)
  • Cognition Disorders (chemically induced, psychology)
  • Data Interpretation, Statistical
  • Dizocilpine Maleate (antagonists & inhibitors, toxicity)
  • Excitatory Amino Acid Antagonists (toxicity)
  • Hypnotics and Sedatives (therapeutic use)
  • Male
  • Maze Learning (drug effects)
  • Motor Activity (drug effects)
  • Nitrates (therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Reversal Learning (drug effects)

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