Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain

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• 作者：Ramez Ghanbari^a ; Mostafa El Mansari^a ; Pierre Blier^a ; ^b ; ^{pierre.blier@theroyal.ca}
• 关键词：5-HT ; 5-hydroxytryptamine (serotonin) ; NE ; norepinephrine ; DA ; dopamine ; SSRI ; selective serotonin reuptake inhibitor ; WAY100 ; 635 ; N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride ; DOI ; [1-(2 ; 5-dimethox
• 刊名：European Neuropsychopharmacology
• 出版年：2012
• 期刊代码：95_0924977x
• 类别：med
• 出版时间：July, 2012
• 卷：22
• 期：7
• 页码：518-526
• 文件大小：861 K

摘要

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 伪₁- and 伪₂-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 伪₂-adrenoceptors, as indicated by the disinhibitory effect of the 伪₂-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 伪₂-adrenergic transmission by trazodone, and its 5-HT_2A and 5-HT_2C receptor antagonism may contribute to its therapeutic action in major depression.