The Importance of Brainstem Cholinergic Neurons in the Pressor Response to Cocaine
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Abstract:
After intracisternal injection, 140 nmol (48 μg) of cocaine (but not lidocaine or procaine) evoked an increase in mean arterial pressure (MAP) of 41 mm Hg. The increase in MAP began within 1 min after injection and lasted 10 to 15 min. The pressor response to intracisternal injection of cocaine was not mediated through central α-adrenergic receptors, but intracisternal pretreatment with D1 or D2 dopamine receptor antagonists shortened the duration of the response. Pretreatment with intracisternal injection of hemicholinium-3 to deplete medullary acetylcholine produced a dose-dependent inhibition of the pressor and tachycardic responses to intracisternal injection of cocaine. Central pretreatment with hemicholinium-3 also inhibited the pressor response to intravenous injection of 0.5 mg/kg cocaine. Atropine pretreatment was only partly effective in blocking the pressor and tachycardic responses to intracisternal injection of cocaine. However, a single intracisternal injection of the nicotinic ganglionic receptor blocker hexamethonium inhibited the pressor response to cocaine administered intracisternally 24 h later, and on each of the following 4 days. The blocking effect of hexamethonium was not mimicked by the α7 selective antagonist methyllycaconitine or by the α4β2 subtype-preferring antagonist dihydro-β-erythroidine. The data suggest that the pressor response to cocaine is mediated by medullary acetylcholine release on to nicotinic receptors of the ganglionic type, enhancing the output of bulbospinal sympathetic premotor neurons. Our results provide new evidence for the prolonged inactivation of relevant central nicotinic receptors by nicotinic receptor antagonists, and suggest that such compounds might be used safely for cocaine overdose, as well as for antiabuse issues without the concern for autonomic side effects.Keywords:
Mecamylamine
Ganglionic blocker
Chlorisondamine
Hexamethonium and tetraethylammonium (TEA) produced parallel shifts (equilibrium blockade) of nicotine and dimethylphenylpiperazinium dose-response curves at all dose levels on isolated rabbit and guinea pig ileum preparations, while mecamylamine, pempidine, chlorisondamine and pentolinium produced parallel shifts at lower doses and nonparallel shifts (nonequilibrium blockade) at higher dose levels. Hexamethonium and TEA protected against the nonequilibrium blockade by mecamylamine, pempidine, chlorisondamine and pentolinium. Dose ratios for the combination of hexamethonium with TEA, with chlorisondamine or with pentolinium were consistent with competitive type of blockade. Dose ratios for the combination of hexamethonium with mecamylamine or with pempidine were not consistent with the noncompetitive type of blockade. It is concluded, that hexamethonium and TEA act as equilibrium competitive ganglion blockers while mecamylamine, pempidine, chlorisondamine and pentolinium act as nonequilibrium competitive ganglion blockers.
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Chlorisondamine
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The i.p. injection of nicotine produced several changes in regional catecholamine concentrations in rat brain. These changes were blocked by the centrally active nicotinic antagonist mecamylamine, but not by the quaternary nicotinic antagonist hexamethonium. An examination of the effects of various cholinergic agents on hypothalamic epinephrine concentrations revealed several interesting findings. Central muscarinic antagonism or peripheral muscarinic agonism decreased hypothalamic epinephrine concentrations. The anticholinesterase physostigmine decreased hypothalamic epinephrine concentrations and this effect was blocked by the centrally acting nicotinic antagonist mecamylamine, but not by hexamethonium, scopolamine or methscopolamine. These findings indicate an interaction of cholinergic receptors, both nicotinic and muscarinic, with hypothalamic epinephrine.
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Nicotinic Antagonist
Muscarinic antagonist
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Mecamylamine
Chlorisondamine
Ganglionic blocker
Hindlimb
Decamethonium
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Abstract It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced fluid secretion in the rat small intestine. This notion is, in part, derived from experiments on anaesthetized animals in which the response to cholera toxin was antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In the current study, such anti-secretory action of ganglionic blocking compounds was analysed in an experiment designed to minimize any possible negative effect of general anaesthesia on intestinal secretion. Rats were anaesthetized with ether for 5–10 min, during which time a jejunal loop (10–12 cm) was constructed. The loop was challenged with one of the secretagogues, cholera toxin, prostaglandin E1 (PGE1) or okadaic acid. Saline (control) or either of the ganglionic blockers, hexamethonium and chlorisondamine, was administered intravenously. The rats were killed 5 h (cholera toxin) or 1–5 h (PGE1 and okadaic acid) after challenge, and the amount of fluid accumulated in the loops was determined. Cholera toxin-induced secretion was unchanged by hexamethonium but reduced by approximately 80% by chlorisondamine. The difference in effect between the two blockers might relate to the duration of ganglionic blockade. Chlorisondamine blocked secretion induced by either PGE1 or okadaic acid by approximately 60%. It is suggested that the anti-secretory effect of ganglionic blocking compounds might be a result of blockade of secreto-motor nerves but other mechanisms, for example interference with haemodynamic factors, cannot be ruled out.
Chlorisondamine
Ganglionic blocker
Cholera toxin
Tetrodotoxin
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Mecamylamine
Cytisine
Nicotinic Antagonist
Epibatidine
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Mecamylamine
Chlorisondamine
Nicotinic Antagonist
Radial arm maze
Methyllycaconitine
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Mecamylamine
Nicotinic Antagonist
Ganglionic blocker
Epibatidine
Cytisine
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SummaryChlorisondamine dimethochloride is a new, very potent and long lasting ganglionic blocking agent. Its ganglionic blocking potency was about twice that of pentapyrrolidinium and hexamethonium, whereas its duration of action exceeded that of hexamethonium several times. Both sympathetic and parasympathetic ganglia were blocked by the drug to a similar extent.
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Blocking (statistics)
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Hexamethonium and tetraethylammonium (TEA) produced parallel shifts (equilibrium blockade) of nicotine and dimethylphenylpiperazinium dose-response curves at all dose levels on isolated rabbit and guinea pig ileum preparations, while mecamylamine, pempidine, chlorisondamine and pentolinium produced parallel shifts at lower doses and nonparallel shifts (nonequilibrium blockade) at higher dose levels. Hexamethonium and TEA protected against the nonequilibrium blockade by mecamylamine, pempidine, chlorisondamine and pentolinium. Dose ratios for the combination of hexamethonium with TEA, with chlorisondamine or with pentolinium were consistent with competitive type of blockade. Dose ratios for the combination of hexamethonium with mecamylamine or with pempidine were not consistent with the noncompetitive type of blockade. It is concluded, that hexamethonium and TEA act as equilibrium competitive ganglion blockers while mecamylamine, pempidine, chlorisondamine and pentolinium act as nonequilibrium competitive ganglion blockers.
Mecamylamine
Chlorisondamine
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The concentration of atropine was found to be of critical importance in demonstrating the nicotinic effects of acetylcholine in guinea pig atria. Differences were found between the concentrations of atropine needed to unmask positive chronotropic effects and those needed to unmask positive inotropic effects. In the presence of various concentrations of atropine, carbamylcholine was found to have nicotinic effects in isolated guinea pig atria, while methachohine did not. Hexamethonium produced a combination of surmountable and nonsurmountable inhibition of the nicotinic effects of nicotine, while mecamylamine produced a purely nonsurmountable block. On the basis of experiments (reserpine pretreatments, 1.5 and 3.0 mg/kg) in isolated guinea pig atria with intact sympathetic nerves, the stores from which nicotinic agents release catecholamines appear to resemble the stores released by sympathetic nerve stimulation but to differ from those stores released by tyramine.
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Reserpine
Nicotinic Antagonist
Phentolamine
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