Effects of benzoyltropine and tropacocaine on several cholinergic processes in the rat brain.
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 microM) had no effect on the sodium-dependent uptake of norepinephrine, gamma-amino-butyric acid, glutamate or serotonin; tropacocaine (30 microM) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Meyer
E M
EM
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville.
Potter
L T
LT
De Vane
C L
CL
Irwin
I
I
MacKay
S L
SL
Miller
R
R
Ruttenber
A J
AJ
D000109:Acetylcholine / Q000096:biosynthesis; D000779:Anesthetics, Local / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007536:Isomerism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000779:Anesthetics, Local; D018377:Neurotransmitter Agents; D011976:Receptors, Muscarinic; C005862:tropacocaine; D011813:Quinuclidinyl Benzilate; D003042:Cocaine; D002794:Choline; D000109:Acetylcholine