Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5−9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT_1A receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release.

先前的研究表明，美加明是一种非竞争性和非特异性的烟碱型乙酰胆碱受体 (nAChR) 阻滞剂，可刺激中缝背核 (DRN) 血清素能神经元的活性和 DRN 血清素 (5-HT) 的释放。在本研究中，使用电生理学和钙成像研究检查了这些美加明诱导作用所涉及的机制，两者均在 Wistar 大鼠中脑切片中进行。Mecamylamine (0.5-9 μM)，在浴中给药后，在 3 μM 时，已识别的 5-HT DRN 神经元的放电频率最多增加了 5%。这种效应伴随着 5-HT DRN 神经元自发兴奋性突触后电流的频率增加了 112%。它被 AMPA/红藻氨酸受体阻滞剂 CNQX (10 μM) 和特定的 α4β2 nAChRs 阻滞剂二氢-β-红氨酸 (100 nM) 阻断，但不受河豚毒素 (TTX，500 nM) 的影响。同时，美加明使 GABA 能自发抑制性突触后电流的频率降低了 58%，这种效果不受 TTX 的影响。钙成像研究通过显示美加明 (3 μM) 增加位于 DRN 中线的细胞群的活性来支持电生理学研究的结果，该细胞群对 8-OH-DPAT 的抑制作用敏感，是一种5-HT 激动剂_1A受体。假设美加明在低浓度下可作为存在于谷氨酸能 DRN 末端的 α4β2 nAChR 的激动剂，从而增加中缝内谷氨酸盐的释放。这种刺激作用通过 DRN GABA 释放的减少得到加强，这取决于美加明对位于 DRN GABA 能末端的 α7 nAChR 的阻断。我们假设抑郁症动物模型中描述的美加明抗抑郁作用的至少一部分是由 DRN 5-HT 释放的增加介导的。