harman and beta-carboline-3-carboxylic-acid-ethyl-ester

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)

Topics: Animals; Carbolines; Diazepam; Discrimination Learning; Harmine; Male; Picrotoxin; Rats; Rats, Inbred F344

Compounds from both the beta-carboline (BC) and xanthine groups have been suggested to be the natural ligands for benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and caffeine, 1,3,7-trimethylxanthine, on the binding of 3H-flunitrazepam (3H-FZ) and beta-3H-carboline-3-carboxylic acid ethyl ester (3H-BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion-producing doses of caffeine (120 mg/kg intravenously) and harmane (30 mg/kg intravenously) lowered the specific binding of 3H-FZ in vivo by 12-31%. A tremorogenic dose of harmaline (30 mg/kg intravenously) increased binding by 31%. Caffeine and harmane also slightly decreased the in vivo binding of 3H-BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors. Harmaline stimulated the binding of 3H-BCCE only in the forebrain. Both harmaline and harmane increased by 41-111% the amount of 3H-BCCE that was distributed to the brain. In vitro BC's and caffeine displaced 3H-FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 microM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were harmaline and caffeine in the forebrain: both exhibited curvilinear plots for 3H-FZ binding. Harmaline increased the binding, and caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both harmaline and caffeine inhibited binding and produced linear plots. BC-induced tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during harmaline-induced tremor the affinity of some BZ receptors is increased, while harmane-induced convulsions are connected to direct occupation of BZ receptors.

Topics: Animals; Brain; Caffeine; Carbolines; Flunitrazepam; Harmaline; Harmine; Indoles; Male; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A; Seizures; Tremor