Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide.
Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.
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MRC Neuropharmacology Research Group, School of Pharmacy, University of London, U.K.
Aranko
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D000818:Animals; D002707:Chlordiazepoxide / Q000494:pharmacology*; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D002707:Chlordiazepoxide