Anxiogenic effect of disulfiram evaluated in an animal model.
The present experiment was designed to determine whether disulfiram produced an interoceptive discriminative stimulus (IDS) in rats similar to that exhibited by the anxiogenic drug pentylenetetrazol (PTZ). Rats were trained to discriminate PTZ (20 mg/kg IP) from saline, according to an FR10 schedule of food reinforcement. After training criteria had been met, discrimination testing revealed that disulfiram (100 mg/kg, IP) produced a PTZ-like IDS that fully substituted for PTZ 4 hours after injection, decaying to baseline values by the third day. The metabolite of disulfiram, diethyl dithiocarbamate (100 mg/kg, IP), followed much the same temporal pattern, but only showed partial substitution for PTZ. When ethanol (1 g/kg, gavage) or the monoamine oxidase inhibitor pargyline (50 mg/kg, IP) were administered in combination with disulfiram, no significant change of the PTZ-like stimulus was observed. Pargyline (100 mg/kg, IP) or acetaldehyde (200 mg/kg, IP), given alone, did not significantly substitute for PTZ. These data show that disulfiram produces an IDS in rats similar to that produced by other anxiogenic drugs. These data also suggest that the mechanism by which disulfiram produces its anxiogenic effect may not be entirely based upon the disulfiram metabolite diethyl dithiocarbamate, elevated acetaldehyde levels or stimulation of the catecholaminergic system.
Department of Pharmacology, Texas College of Osteopathic Medicine, Fort Worth 76107.
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Bhadra
P L
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Prather
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Elkhayat
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D
Benjamin
C M
CM
Harris
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Lal
D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001143:Arousal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D004221:Disulfiram / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005239:Fear / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D010293:Pargyline / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats
D000431:Ethanol; D004050:Ditiocarb; D010293:Pargyline; D000079:Acetaldehyde; D004221:Disulfiram; D010433:Pentylenetetrazole