Reid R T, Lloyd G K, Rao T S
SIBIA Neurosciences, Inc., La Jolla, California 92037-4641, USA.
Br J Pharmacol. 1999 Jul;127(6):1486-94. doi: 10.1038/sj.bjp.0702683.
In this study, the mechanism of nicotine-induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis. Systemic administration of nicotine (0.4 mg kg(-1), s.c.) increased the levels of ACh in hippocampal dialysates. The nicotine-induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg(-1), s.c.) and dihydro-beta-erythrodine (DHbetaE; 4.0 mg kg(-1), s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzaz epine; 0.3 mg kg(-1), s.c.). Local perfusion of mecamylamine (100 microM), DHbetaE (100 microM) or SCH-23390 (10 microM) through microdialysis probe did not increase basal hippocampal ACh release. Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg(-1), s.c.) was antagonized by local perfusion of SCH-23390 (10 microM), but not by MEC (100 microM) or DHbetaE (100 microM). Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co-perfusion of either mecamylamine (100 microM) or SCH-23390 (10 microM). These results suggest that nicotine-induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non-DA-ergic mechanism.
在本研究中，使用体内微透析技术检测了尼古丁诱导清醒、自由活动大鼠海马乙酰胆碱（ACh）释放的机制。皮下注射尼古丁（0.4 mg kg⁻¹）可增加海马透析液中ACh的水平。尼古丁诱导的海马ACh释放对神经元烟碱型乙酰胆碱受体（nAChR）拮抗剂美加明（3.0 mg kg⁻¹，皮下注射）和二氢-β-刺桐啶（DHβE；4.0 mg kg⁻¹，皮下注射）的预处理以及多巴胺（DA）D1受体拮抗剂SCH-23390（R-(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-苯并氮杂卓；0.3 mg kg⁻¹，皮下注射）的全身给药敏感。通过微透析探针局部灌注美加明（100 μM）、DHβE（100 μM）或SCH-23390（10 μM）不会增加海马基础ACh释放。皮下注射尼古丁（0.4 mg kg⁻¹）引起的海马ACh释放可被局部灌注SCH-23390（10 μM）拮抗，但不能被MEC（100 μM）或DHβE（100 μM）拮抗。直接灌注尼古丁（1 mM，但不是0.1 mM）可增加海马ACh水平；然而，这种效应相对不敏感于与美加明（100 μM）或SCH-23390（10 μM）共同灌注的阻断作用。这些结果表明，尼古丁诱导的海马ACh释放通过两种不同机制发生：（1）海马外nAChRs的激活导致DA释放以及随后涉及允许性DA突触的ACh释放，和（2）尼古丁在海马内的直接作用通过非DA能机制导致ACh释放。
