The importance of brainstem cholinergic neurons in the pressor response to cocaine.
After intracisternal injection, 140 nmol (48 microg) 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 alpha-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 alpha7 selective antagonist methyllycaconitine or by the alpha4beta2 subtype-preferring antagonist dihydro-beta-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.
Buccafusco
Jerry J
JJ
Alzheimer's Research Center, Department of Pharmacology and Toxicology, 1120-15th St., Augusta, GA 30912-2300, USA. jbuccafu@mcg.edu
Davis
Jerry A
JA
Shuster
Laura C
LC
Buccafusco
Christopher J
CJ
Gattu
Mahanandeeshwar
M
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001933:Brain Stem / Q000166:cytology*; D002319:Cardiovascular System / Q000187:drug effects; D002802:Cholinesterases / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D006426:Hemicholinium 3 / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011311:Pressoreceptors / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000502:physiology; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000502:physiology
D000779:Anesthetics, Local; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D006426:Hemicholinium 3; D002802:Cholinesterases; D003042:Cocaine