The Importance of Brainstem Cholinergic Neurons in the Pressor Response to Cocaine

Abstract

After intracisternal injection, 140 nmol (48 g) 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 ␣-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 ␣7 selective antagonist methyllycaconitine or by the ␣4␤2 subtype-preferring antagonist dihydro-␤-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.The ability of cocaine to increase systemic blood pressure usually is considered to be commensurate with drug's pharmacological classification as an indirect-acting sympathomimetic amine. Whereas cocaine conforms to this classification both in the peripheral and central nervous systems, the role of the CNS in terms of blood pressure alterations has been debated (Knuepfer et al., 1993;Gillis et al., 1995;Bernards, 1996). In fact, agonists at central ␣ 2 -adrenergic receptors such as clonidine and ␣-methyldopa are effective antihypertensive drugs; and levodopa and other dopaminergic antiParkinson agents often produce orthostatic hypotension as a side effect. Also, systemic administration of cocaine has been reported to decrease sympathetic nervous activity (Knuepfer and Branch, 1992;Gillis et al., 1995;Abrahams et al., 1996). Yet, there have been instances when cocaine has been administered directly into the CNS, usually via the cerebrospinal fluid, that the drug elicits an increase in arterial blood pressure. However, based upon the requirement for relatively high doses to elicit a pressor response via the lateral ventricular route (Knuepfer et al., 1993), it is unlikely that forebrain str...

β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon

“…Excess catecholamines from reuptake inhibition in the CNS and peripheral circulation 4,17 a-Stimulation resulting in vasoconstriction 4,17,92,93,94 b-Stimulation resulting in tachycardia and increased risk of dysrhythmia 4,17,95 Blockade of sodium and potassium channels with increased risk of dysrhythmia 96 Increased risk of thrombosis from platelet activation 97 Increased intracellular calcium and increased risk of dysrhythmia 96,98 Inhibition of peripheral arterial baroreceptors with altered baroreflex [99][100][101][102] Acceleration of coronary arterial disease and enhanced vasoconstriction in diseased segments 92 Enhanced coronary microvascular disease 94,103 Additive vasoconstrictive effects in the presence of cigarette smoking 93 Generation of reactive oxygen and nitrogen species altering autoregulation of cardiac blood flow 104,105 Stimulation of the vasoconstrictor endothelin 106,107 Inhibition of NO production and associated vasodilation 106,107 Damage to coronary endothelium with increased sensitivity to vasoconstrictors 108 Direct cardiomyotoxicity from membrane oxidative damage and early apoptosis 104,105,109,110 Alteration of parasympathetic response with decreased heart rate variability 111,112 Abbreviations: CNS, central nervous system; NO, nitric oxide. potential unique adverse effects, and risk/benefit ratio must be taken into consideration by the prescribing clinician.…”

“…111,112 Cocaine may not elicit hypertension and tachycardia due to direct catecholamine effects but instead by altering CNSmediated parasympathetic acetylcholinergic responses, sympathetic nerve activity, and baroreflex inhibition. [99][100][101][102] Sympathetic activation and sodium and potassium-channel blockade by cocaine increases propensity for life-threatening and unpredictable dysrhythmias, which may be an important factor in prehospital cocaine-related deaths. 96 Finally, cocaine increases platelet activation, von Willebrand factor and a-granule release, and microaggregate formation with potential for sudden, unpredictable coronary arterial thrombosis.…”

Contribution of baroreflex sensitivity and vascular reactivity to variable haemodynamic responses to cocaine in conscious rats

“…It has been argued that the pressor response to cocaine may also depend on central cholinergic receptors because intracisternal administration of hemicholinium-3 attenuates the pressor response to intravenous cocaine administration. 55 The present study suggests that there may be differences in the cardiac response to muscarinic agonists, but it is unclear whether the action is mediated centrally or peripherally.…”

Diazepam Protects Against the Enhanced Toxicity of Cocaine Adulterated With Atropine

“…injection, atropine had no effect on acute cocaineinduced lethality at doses that are effective in preventing parasympathetic effects and lethality of oxotremorine in rats (10). Pre-treatment with relatively high doses of atropine partially reduced the pressor and tachycardiac response to intracisternal injection of cocaine in rats (11). Pretreatment with pirenzepine, the muscarinic M 1 -receptor antagonist, when given at low doses, reduced cocaine-induced lethality in mice, while the nonselective muscarinic antagonist atropine, administered systematically by i.p.…”