Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity:: Role in atypical antipsychotic action
Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity:: Role in atypical antipsychotic action
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DOI：
10.1523/jneurosci.2999-05.2005
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发表时间：
2005-11-23
影响因子：
5.3
通讯作者：
Artigas, F
中科院分区：
文献类型：
--
作者：
Díaz-Mataix, L;Scorza, MC;Artigas, F
非典型抗精神病药增加内侧前额叶皮质（mPFC）中多巴胺（DA）的释放，这种效应可能与非典型抗精神病药相对于经典抗精神病药对认知/阴性症状的上级效应有关。我们研究了mPFC中5-HT 1A受体对体内多巴胺能活性和皮质中膜DA释放的调节作用。高选择性5-HT 1A激动剂BAY x 3702（BAY; 10-40 μ g/kg，i. v.）增加腹侧被盖区（VTA）DA能神经元的放电频率和爆发放电以及VTA和mPFC的DA释放。诺米芬新共同灌注增强了这两个区域DA释放的增加。选择性5-HT 1A拮抗剂WAY-100635逆转BAY在这两个领域的影响，并在VTA的变化被阻止了frontocortical transsection.The应用BAY在大鼠和小鼠mPFC的反向透析增加了当地的细胞外DA在低浓度（3 μ M）和减少在较高浓度（30 μ M）。这两种效应在5-HT 1A基因敲除小鼠中消失。在荷包牡丹碱的存在下，BAY减少DA释放在所有浓度。非典型抗精神病药物氯氮平，奥氮平，齐拉西酮（但不是氟哌啶醇）增强DA释放的野生型，但不是5-HT 1A基因敲除小鼠后，全身和局部（氯氮平和奥氮平）管理的mPFC。同样，荷包牡丹碱共灌注防止局部氯氮平或奥氮平应用产生的DA释放升高。这些结果表明，激活mPFC 5-HT 1A受体增强VTADA神经元的活动和中皮层DA释放。这一机制可能与非典型抗精神病药引起的细胞外DA升高有关。
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 mu g/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 mu M) and reduced it at a higher concentration ( 30 mu M). 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 VTADA neurons and mesocortical DA release. This mechanism may be involved in the elevation of extracellular DA produced by atypical antipsychotics.