Díaz-Mataix Llorenç, Scorza M Cecilia, Bortolozzi Analía, Toth Miklos, Celada Pau, Artigas Francesc
Department of Neurochemistry, Institut d' Investigacions Biomèdiques de Barcelona Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
J Neurosci. 2005 Nov 23;25(47):10831-43. doi: 10.1523/JNEUROSCI.2999-05.2005.
Atypical antipsychotics increase dopamine (DA) release in the medial prefrontal cortex (mPFC), an effect possibly involved in the superior effects of atypical versus classical antipsychotics on cognitive/negative symptoms. We examined the role of 5-HT1A receptors in the mPFC on the modulation of dopaminergic activity and the mesocortical DA release in vivo. The highly selective 5-HT1A agonist BAY x 3702 (BAY; 10-40 microg/kg, i.v.) increased the firing rate and burst firing of DA neurons in the ventral tegmental area (VTA) and DA release in the VTA and mPFC. The increase in DA release in both areas was potentiated by nomifensine coperfusion. The selective 5-HT1A antagonist WAY-100635 reversed the effects of BAY in both areas, and the changes in the VTA were prevented by frontocortical transection. The application of BAY in rat and mouse mPFC by reverse dialysis increased local extracellular DA at a low concentration (3 microM) and reduced it at a higher concentration (30 microM). Both effects disappeared in 5-HT1A knock-out mice. In the presence of bicuculline, BAY reduced DA release at all concentrations. The atypical antipsychotics clozapine, olanzapine, and ziprasidone (but not haloperidol) enhanced DA release in the mPFC of wild-type but not 5-HT1A knock-out mice after systemic and local (clozapine and olanzapine) administration in the mPFC. Likewise, bicuculline coperfusion prevented the elevation of DA release produced by local clozapine or olanzapine application. These results suggest that the activation of mPFC 5-HT1A receptors enhances the activity of VTA DA neurons and mesocortical DA release. This mechanism may be involved in the elevation of extracellular DA produced by atypical antipsychotics.
非典型抗精神病药物可增加内侧前额叶皮质（mPFC）中的多巴胺（DA）释放，这一效应可能与非典型抗精神病药物相对于经典抗精神病药物在认知/阴性症状方面的优势有关。我们研究了mPFC中5-HT1A受体在体内调节多巴胺能活性和中皮质DA释放中的作用。高度选择性的5-HT1A激动剂BAY x 3702（BAY；10-40微克/千克，静脉注射）可增加腹侧被盖区（VTA）中DA神经元的放电频率和爆发性放电，以及VTA和mPFC中的DA释放。诺米芬辛共灌注可增强这两个区域的DA释放增加。选择性5-HT1A拮抗剂WAY-100635可逆转BAY在这两个区域的作用，而前额叶皮质横断可阻止VTA中的变化。通过反向透析在大鼠和小鼠mPFC中应用BAY，在低浓度（3微摩尔）时可增加局部细胞外DA，而在高浓度（30微摩尔）时则降低。这两种效应在5-HT1A基因敲除小鼠中均消失。在存在荷包牡丹碱的情况下，BAY在所有浓度下均降低DA释放。在mPFC中进行全身和局部（氯氮平和奥氮平）给药后，非典型抗精神病药物氯氮平、奥氮平和齐拉西酮（但不是氟哌啶醇）可增强野生型小鼠而非5-HT1A基因敲除小鼠mPFC中的DA释放。同样，荷包牡丹碱共灌注可阻止局部应用氯氮平或奥氮平所产生的DA释放升高。这些结果表明，mPFC 5-HT1A受体的激活可增强VTA DA神经元的活性和中皮质DA释放。这一机制可能与非典型抗精神病药物所产生的细胞外DA升高有关。
