Hussain N, Flumerfelt B A, Rajakumar N
Department of Anatomy and Cell Biology, The University of Western Ontario, Ontario, N6A 5C1, London, Canada.
Neuroscience. 2001;102(2):391-9. doi: 10.1016/s0306-4522(00)00487-5.
Acute administration of haloperidol induces the expression of the immediate-early gene c-fos in the striatum and nucleus accumbens via dopamine D(2) receptor antagonism. Dopaminergic transmission in the striatum and nucleus accumbens is modulated by glutamate via N-methyl-D-aspartate (NMDA) receptors. Indeed, haloperidol-induced c-fos expression is dependent on NMDA receptor activation in the dorsolateral part of the striatum. However, the role that NMDA receptors play in haloperidol-induced c-fos expression in other functionally distinct areas of the striatum and nucleus accumbens has not yet been established. Therefore, in the present study the entire rostrocaudal extent of the rat striatum and nucleus accumbens was examined to determine the role that NMDA receptors play in haloperidol-induced c-fos expression. Pretreatment with MK-801, a non-competitive antagonist of NMDA receptors, significantly reduced the number of neurons showing c-fos immunoreactivity in the rostral aspect of the dorsolateral striatum and the entire rostrocaudal extent of the ventrolateral striatum following an acute injection of haloperidol. However, the same treatment did not modify the pattern of haloperidol-mediated c-fos expression in the medial or central parts of the striatum. Similarly, MK-801 pretreatment significantly suppressed the number of neurons expressing c-fos immunoreactivity following haloperidol injection in the entire rostrocaudal extent of the shell region of nucleus accumbens, but not in the core region. The results indicate that haloperidol-induced c-fos expression is dependent on NMDA receptors only in the rostral aspect of the dorsolateral striatum and the rostrocaudal extent of the ventrolateral striatum, the areas involved in motor function. The differential role that NMDA receptors play in modulating haloperidol-mediated dopamine D(2) receptor antagonism between motor and associative areas of the striatum may contribute to the development of extrapyramidal symptoms following chronic haloperidol treatment. Furthermore, the attenuation of the haloperidol-induced c-fos expression by MK-801 was restricted to the nucleus accumbens shell, an area often implicated in the therapeutic effect of haloperidol. Therefore, the NMDA-dopamine D(2) receptor interaction may also play a role in mediating the therapeutic effects of haloperidol.
急性给予氟哌啶醇通过拮抗多巴胺D(2)受体诱导纹状体和伏隔核中即早基因c-fos的表达。纹状体和伏隔核中的多巴胺能传递通过谷氨酸经由N-甲基-D-天冬氨酸（NMDA）受体进行调节。实际上，氟哌啶醇诱导的c-fos表达依赖于纹状体背外侧部分的NMDA受体激活。然而，NMDA受体在氟哌啶醇诱导的纹状体和伏隔核其他功能不同区域的c-fos表达中所起的作用尚未明确。因此，在本研究中，对大鼠纹状体和伏隔核的整个前后范围进行了检查，以确定NMDA受体在氟哌啶醇诱导的c-fos表达中所起的作用。用NMDA受体的非竞争性拮抗剂MK-801进行预处理，在急性注射氟哌啶醇后，显著减少了背外侧纹状体前部和腹外侧纹状体整个前后范围内显示c-fos免疫反应性的神经元数量。然而，相同的处理并未改变氟哌啶醇介导的纹状体内侧或中央部分c-fos表达模式。同样，MK-801预处理显著抑制了氟哌啶醇注射后伏隔核壳区整个前后范围内表达c-fos免疫反应性的神经元数量，但在核心区域未观察到这种抑制。结果表明，氟哌啶醇诱导的c-fos表达仅在背外侧纹状体前部和腹外侧纹状体前后范围（涉及运动功能的区域）依赖于NMDA受体。NMDA受体在调节纹状体运动和联合区域之间氟哌啶醇介导的多巴胺D(2)受体拮抗作用中所起的不同作用，可能导致慢性氟哌啶醇治疗后锥体外系症状的发生。此外，MK-801对氟哌啶醇诱导的c-fos表达的减弱作用仅限于伏隔核壳区，该区域常与氟哌啶醇的治疗效果有关。因此，NMDA-多巴胺D(2)受体相互作用也可能在介导氟哌啶醇的治疗作用中发挥作用。
