Weikop P, Kehr J, Scheel-Krüger J
Department of Microdialysis, NeuroSearch A/S, Ballerup, Denmark.
J Psychopharmacol. 2004 Sep;18(3):395-403. doi: 10.1177/026988110401800311.
The role of adrenergic alpha1- and alpha2-adrenoreceptors in augmentation of venlafaxine-induced elevation of extracellular serotonin (5-HT),noradrenaline (NA) and dopamine (DA) levels in the rat prefrontal cortex (PFC) and hippocampus (HIPP) was studied by in vivo microdialysis in anaesthetized rats. The alpha1-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The alpha2-adrenoreceptor antagonist idazoxan (1.5 mg/kg, s.c.) causes moderate increases in the levels of 5-HT and DA in the PFC. The mixed 5-HT and NA reuptake inhibitor venlafaxine (10 mg/kg, i.p.) increased the efflux of 5-HT, NA and DA almost equally, to approximately 200% of the control levels in the PFC. The levels of 5-HT increased to 310%, an effect approximately twice the effect on NA in the HIPP. Venlafaxine also produced a moderate increase in DA levels in the PFC but had no effect in the HIPP. Pre-treatment with prazosin caused a significant attenuation of the venlafaxine induced 5-HT effect in the PFC, and a moderate increase in DA levels in the HIPP. Prazosin had no significant effect on the venlafaxine-induced increase of the NA levels in PFC or HIPP. A combined treatment of venlafaxine with idazoxan increased the venlafaxine NA and DA effects in PFC by a factor of two and resulted in a very robust five-fold augmentation of NA and DA concentrations in the HIPP. In summary, idazoxan was found to produce a potent enhancement of the venlafaxine effect to increase extracellular NA and DA levels in the PFC and, in particular, in the HIPP. Idazoxan had no effect on venlafaxine-induced elevation of extracellular 5-HT levels in either PFC or HIPP and prazosin induced a decrease of 5-HT in the PFC. The present data suggest that blockade of alpha2-adrenoreceptors may play an important role in augmentation of the effects of mixed monoamine reuptake inhibitors.
通过对麻醉大鼠进行体内微透析，研究了肾上腺素能α1和α2肾上腺素受体在增强文拉法辛诱导的大鼠前额叶皮质（PFC）和海马体（HIPP）细胞外5-羟色胺（5-HT）、去甲肾上腺素（NA）和多巴胺（DA）水平升高中的作用。单独给予α1肾上腺素受体拮抗剂哌唑嗪（0.3mg/kg，皮下注射）仅引起海马体5-HT和NA水平适度降低。α2肾上腺素受体拮抗剂咪唑克生（1.5mg/kg，皮下注射）使PFC中5-HT和DA水平适度升高。5-HT和NA再摄取抑制剂文拉法辛（10mg/kg，腹腔注射）几乎同等程度地增加了5-HT、NA和DA的流出量，使PFC中的流出量达到对照水平的约200%。HIPP中5-HT水平升高至310%，该效应约为对NA效应的两倍。文拉法辛还使PFC中DA水平适度升高，但对HIPP无影响。哌唑嗪预处理导致文拉法辛诱导的PFC中5-HT效应显著减弱，HIPP中DA水平适度升高。哌唑嗪对文拉法辛诱导的PFC或HIPP中NA水平升高无显著影响。文拉法辛与咪唑克生联合治疗使文拉法辛在PFC中的NA和DA效应增加了两倍，并导致HIPP中NA和DA浓度非常显著地增加了五倍。总之，发现咪唑克生能有效增强文拉法辛增加PFC尤其是HIPP中细胞外NA和DA水平的效应。咪唑克生对文拉法辛诱导的PFC或HIPP中细胞外5-HT水平升高无影响，而哌唑嗪导致PFC中5-HT降低。目前的数据表明，阻断α2肾上腺素受体可能在增强混合单胺再摄取抑制剂的作用中起重要作用。
