Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Int J Neuropsychopharmacol. 2018 Mar 1;21(3):305-310. doi: 10.1093/ijnp/pyy007.
Ketamine rapidly elicits antidepressive effects in humans and mice in which serotonergic activity is involved. Although α4β2 nicotinic acetylcholine receptor (α4β2 nAChR) in the dorsal raphe nucleus plays a key role in the ketamine-induced prefrontal serotonin release, the source of cholinergic afferents, and its role is unclear.
Prefrontal serotonin levels after ketamine injection were measured by microdialysis in rats. Electrolytic lesion of pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus was made with constant direct current.
Bilateral lesion of the pedunculopontine tegmental nucleus, but not laterodorsal tegmental nucleus, attenuated prefrontal serotonin release induced by systemic ketamine. Intra-pedunculopontine tegmental nucleus, but not intra-laterodorsal tegmental nucleus ketamine perfusion, increased prefrontal serotonin release. This increase was attenuated by intra-dorsal raphe nucleus injection of dihydro-β-erythroidine, an α4β2 nAChR antagonist, or NBQX, an AMPA receptor antagonist.
These results suggest the ketamine-induced serotonin release in medial prefrontal cortex is mediated by cholinergic neurons projecting from pedunculopontine tegmental nucleus to dorsal raphe nucleus via α4β2 nAChRs.
氯胺酮能迅速在人类和小鼠中产生抗抑郁作用，其中涉及到 5-羟色胺能活性。尽管背缝核中的α4β2 烟碱型乙酰胆碱受体（α4β2 nAChR）在氯胺酮诱导的前额叶 5-羟色胺释放中起着关键作用，但胆碱能传入的来源及其作用尚不清楚。
通过微透析测量大鼠注射氯胺酮后前额叶 5-羟色胺水平。用恒直流电进行脑桥被盖脚间核和外侧被盖核的电解损伤。
双侧脑桥被盖脚间核损伤，但不是外侧被盖核损伤，减弱了全身氯胺酮诱导的前额叶 5-羟色胺释放。脑桥被盖脚间核内，而不是外侧被盖核内的氯胺酮灌流，增加了前额叶 5-羟色胺的释放。这种增加被背缝核内注射二氢-β-erythroidine（一种 α4β2 nAChR 拮抗剂）或 NBQX（一种 AMPA 受体拮抗剂）所减弱。
这些结果表明，氯胺酮诱导的内侧前额叶皮质 5-羟色胺释放是由投射到背缝核的来自脑桥被盖脚间核的胆碱能神经元通过 α4β2 nAChRs 介导的。
