Buccafusco Jerry J, Davis Jerry A, Shuster Laura C, Buccafusco Christopher J, Gattu Mahanandeeshwar
Alzheimer's Research Center, Department of Pharmacology and Toxicology, 1120-15th St., Augusta, GA 30912-2300, USA.
J Pharmacol Exp Ther. 2005 Jan;312(1):179-91. doi: 10.1124/jpet.104.073619. Epub 2004 Aug 24.
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.
脑池内注射后，140 nmol（48微克）可卡因（而非利多卡因或普鲁卡因）可使平均动脉压（MAP）升高41毫米汞柱。MAP升高在注射后1分钟内开始，持续10至15分钟。脑池内注射可卡因引起的升压反应并非通过中枢α-肾上腺素能受体介导，但脑池内预先使用D1或D2多巴胺受体拮抗剂可缩短反应持续时间。脑池内注射半胱氨酸3以耗尽延髓乙酰胆碱进行预处理，可产生剂量依赖性抑制脑池内注射可卡因引起的升压和心动过速反应。脑池内预先使用半胱氨酸3也可抑制静脉注射0.5毫克/千克可卡因引起的升压反应。阿托品预处理仅部分有效阻断脑池内注射可卡因引起的升压和心动过速反应。然而，单次脑池内注射烟碱型神经节受体阻滞剂六甲铵可抑制24小时后及随后4天内脑池内给予可卡因的升压反应。六甲铵的阻断作用不能被α7选择性拮抗剂甲基lycaconitine或α4β2亚型偏好拮抗剂二氢-β-刺桐碱模拟。数据表明，对可卡因的升压反应是由延髓乙酰胆碱释放到神经节型烟碱受体上介导的，增强了延髓脊髓交感神经运动前神经元的输出。我们的结果为烟碱受体拮抗剂对相关中枢烟碱受体的长期失活提供了新证据，并表明此类化合物可安全用于可卡因过量以及抗滥用问题，而无需担心自主神经副作用。
