University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada.
Eur Neuropsychopharmacol. 2012 Jul;22(7):518-26. doi: 10.1016/j.euroneuro.2011.11.005. Epub 2011 Dec 10.
Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT(2C), 5-HT(2A) receptors and α₁- and α₂-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 or 14 days. Administration of trazodone for 2 and 14 days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT(2C) receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2 days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14 days enhanced the tonic activation of postsynaptic α₂-adrenoceptors, as indicated by the disinhibitory effect of the α₂-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT(1A) receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT(2A) agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT(2A) receptors. The enhancement in α₂-adrenergic transmission by trazodone, and its 5-HT(2A) and 5-HT(2C) receptor antagonism may contribute to its therapeutic action in major depression.
先前的研究已经记录了抗抑郁药曲唑酮对 5-羟色胺（5-HT）系统的长期影响。本研究探讨了持续曲唑酮对腹侧被盖区（VTA）多巴胺（DA）和蓝斑（LC）去甲肾上腺素（NE）神经元放电活动的影响，并描述了其对 5-HT（2C）、5-HT（2A）受体和α₁-和α₂-肾上腺素能受体的作用。在麻醉大鼠中进行了电生理记录。皮下植入的微量泵输送载体或曲唑酮（10mg/kg/天），持续 2 或 14 天。曲唑酮给药 2 天和 14 天都不会改变 DA 神经元的放电活动。然而，曲唑酮的全身注射逆转了 5-HT（2C）受体激动剂 Ro 60,0175 对 DA 神经元放电的抑制作用，表明曲唑酮在该受体上具有拮抗作用。曲唑酮给药 2 天可显著增强 NE 神经元的放电。尽管在 14 天曲唑酮后，NE 神经元的放电率恢复到基线，但该方案增加了神经元爆发放电的比例。曲唑酮给药 14 天增强了突触后α₂-肾上腺素能受体的紧张性激活，如α₂-肾上腺素能受体拮抗剂伊达唑啉对海马锥体神经元放电的抑制作用所示。曲唑酮对背侧中缝核（DR）5-HT 神经元放电的抑制作用被证明是通过 5-HT（1A）受体。曲唑酮的全身注射逆转了 5-HT（2A）激动剂 DOI 对 NE 神经元放电率的抑制作用，表明其在 5-HT（2A）受体上具有拮抗作用。曲唑酮增强α₂-肾上腺素能传递，以及其 5-HT（2A）和 5-HT（2C）受体拮抗作用，可能有助于其在重度抑郁症中的治疗作用。
