Ichikawa Junji, Dai Jin, Meltzer Herbert Y
Department of Psychiatry, Vanderbilt University School of Medicine, The Psychiatric Hospital at Vanderbilt, Nashville, TN 37212, USA.
Brain Res. 2005 Jul 12;1049(2):182-90. doi: 10.1016/j.brainres.2005.05.005.
Anticonvulsant mood stabilizers, e.g., valproic acid and carbamazepine, and atypical antipsychotic drugs (APDs), e.g., clozapine, quetiapine, olanzapine, risperidone, and ziprasidone, have been reported to preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect partially or fully inhibited by WAY100635, a selective 5-HT(1A) antagonist. These atypical APDs have themselves been reported to be effective mood stabilizers, although the importance of increased cortical DA release to mood stabilization has not been established. The purpose of the present study was to determine whether zonisamide, another anticonvulsant mood stabilizer, as well as lithium, a mood stabilizer without anticonvulsant properties, also increases prefrontal cortical DA release and, if so, whether this release is also inhibited by 5-HT(1A) antagonism. As with valproic acid and carbamazepine, zonisamide (12.5 and 25 mg/kg) increased DA release in the mPFC, but not the NAC, an increase abolished by WAY100635 (0.2 mg/kg). However, lithium (100 and 250 mg/kg) decreased DA release in the NAC, an effect also attenuated by WAY100635 (0.2 mg/kg). Lithium itself had no effect in the mPFC but the combination of WAY100635 (0.2 mg/kg) and lithium (100 and 250 mg/kg) markedly increased DA release in the mPFC. Furthermore, M100907 (0.1 mg/kg), a selective 5-HT(2A) antagonist, abolished this increase in DA release in the mPFC. These results indicate that not all mood-stabilizing agents but only those, which have anticonvulsant mood-stabilizing properties, increase DA release in the cortex, and that the effect is dependent upon 5-HT(1A) receptor stimulation. However, the combination of lithium and 5-HT(1A) blockade may result in excessive 5-HT(2A) receptor stimulation, relative to 5-HT(1A) receptor stimulation, both of which can increase prefrontal cortical DA release.
据报道，抗惊厥情绪稳定剂，如丙戊酸和卡马西平，以及非典型抗精神病药物（APD），如氯氮平、喹硫平、奥氮平、利培酮和齐拉西酮，可优先增加大鼠内侧前额叶皮质（mPFC）中的多巴胺（DA）释放，选择性5-HT(1A)拮抗剂WAY100635可部分或完全抑制这种作用。这些非典型APD本身据报道是有效的情绪稳定剂，尽管皮质DA释放增加对情绪稳定的重要性尚未确定。本研究的目的是确定另一种抗惊厥情绪稳定剂唑尼沙胺以及无抗惊厥特性的情绪稳定剂锂是否也会增加前额叶皮质DA释放，如果是，这种释放是否也会被5-HT(1A)拮抗作用所抑制。与丙戊酸和卡马西平一样，唑尼沙胺（12.5和25mg/kg）增加了mPFC中的DA释放，但未增加伏隔核（NAC）中的DA释放，WAY100635（0.2mg/kg）可消除这种增加。然而，锂（100和250mg/kg）降低了NAC中的DA释放，WAY100635（0.2mg/kg）也减弱了这种作用。锂本身对mPFC没有影响，但WAY100635（0.2mg/kg）与锂（100和250mg/kg）的组合显著增加了mPFC中的DA释放。此外，选择性5-HT(2A)拮抗剂M100907（0.1mg/kg）消除了mPFC中DA释放的这种增加。这些结果表明，并非所有情绪稳定剂，只有那些具有抗惊厥情绪稳定特性的药物，才会增加皮质中的DA释放，且这种作用依赖于5-HT(1A)受体刺激。然而，相对于5-HT(1A)受体刺激，锂与5-HT(1A)阻断的组合可能会导致5-HT(2A)受体过度刺激，两者均可增加前额叶皮质DA释放。
