Beta-carbolines as antagonists of the discriminative stimulus effects of diazepam in rats.
Rats were trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice procedure where responding was maintained under a fixed-ratio, 5-response schedule of stimulus shock termination. beta-Carboline-3-carboxylate-methyl ester (beta CCM), beta-carboline-3-carboxylate-ethyl ester (beta CCE) and beta-carboline-3-carboxylate-t-butyl ester (beta CCtB), compounds with alkylcarboxy substitutions on the 3-position of the beta-carboline ring structure, were effective antagonists of the discriminative effects of diazepam. The 3-hydroxymethyl-substituted compound (3HMC) was relatively ineffective in antagonizing the discriminative effects of diazepam. The order of potency in antagonizing the 1.0 mg/kg training dose of diazepam was beta CCtB greater than beta CCM greater than beta CCE much greater than 3 HMC. The greater potency of beta CCtB likely reflects its resistance to metabolism in vivo. beta CCE and beta CCtB produced dose-related, parallel shifts in the dose-response curve for the discriminative effects of diazepam, but the magnitude of the shifts was limited: the two highest doses of beta CCE and beta CCtB produced shifts that were not significantly different in magnitude. These latter results suggest that these beta-carbolines antagonize only a portion of the component(s) of action of diazepam in producing discriminative stimuli. In contrast, the 7-substituted beta-carbolines harmane, harmol and harmine were ineffective in antagonizing the discriminative effects of diazepam up to doses of the beta-carbolines which disrupted the ability of the animals to respond.(ABSTRACT TRUNCATED AT 250 WORDS)
Shannon
H E
HE
National Institute on Drug Abuse, Division of Research, Addiction Research Center, Lexington, Kentucky.
Hagen
T J
TJ
Guzman
F
F
Cook
J A
JA
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D002243:Carbolines; D003975:Diazepam; D006247:Harmine; D010852:Picrotoxin; C001326:harmol; C031516:3-hydroxymethyl-beta-carboline; C024915:beta-carboline-3-carboxylic acid ethyl ester; C005010:harman; C043232:tert-butyl beta-carboline-3-carboxylate; C036150:beta-carboline-3-carboxylic acid methyl ester