Effects of benzoyltropine and tropacocaine on several cholinergic processes in the rat brain
Meyer, E.M.; Potter, L.T.; De Vane, C.L.; Irwin, I.; MacKay, S.L.; Miller, R.; Ruttenber, A.J.
Journal of Pharmacology and Experimental Therapeutics 254(2): 584-590
1990
ISSN/ISBN: 0022-3565 PMID: 1974643 Document Number: 363921
Benzoyltropine and tropacocaine are two contaminants of street-cocaine reported to have parasympatholytic activity. Because the mechanism underlying this activity is obscure, we investigated the effects of these compounds on several cholinergic processes: sodium-dependent choline uptake, sodium-independent choline uptake, acetylcholine synthesis, acetylcholine release (spontaneous and veratridine-induced) and binding of [3H]quinuclidinyl benzylate to muscarinic receptors. These studies used rat cerebral cortical synaptosomes, except for the receptor-binding studies, which used whole brain plasma membranes. Benzoyltropine and tropacocaine each inhibited sodium-dependent choline uptake and acetylcholine synthesis in a dose-related manner that was competitive with extracellular choline. Benzoyltropine was 4 to 5 times more potent in both actions than tropacocaine. Sodium-independent choline uptake was not affected by either compound. Benzoyltropine (30 .mu.M) had no effect on the sodium-dependent uptake of norepinephrine, .gamma.-aminobutyric acid, glutamate or serotonin; tropacocaine (30 .mu.M) inhibited only norepinephrine uptake at this concentration. Benzoyltropine and tropacocaine each inhibited the spontaneous and veratridine-induced release of newly synthesized acetylcholine, but not via activation of presynaptic muscarinic receptors. Instead, each compound was able to attenuate the oxotremorine-induced inhibition of the release of acetylcholine, suggesting antimuscarinic activity. Binding experiments showed that benzoyltropine and tropacocaine were, respectively, about 1,000- and 10,000-fold less potent than scopolamine as receptor antagonists. Finally, we demonstrated that benzoyltropine accumulates in the rat brain after its peripheral injection (10 mg/kg i.p.) and remains there with a half-life similar to that of cocaine. These results suggest that: 1) benzoyltropine exerts a novel pattern of anticholinergic effects; 2) anticholinergic agents may be counter-indicated in patients suffering cardiac arrest in response to street-cocaine overdose; and 3) these compounds may contribute to the toxicity of street-cocaine.