Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.
Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.
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发表时间：
1993-05
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通讯作者：
H. Criswell;K. Johnson;R. Mueller;G. Breese
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作者：
H. Criswell;K. Johnson;R. Mueller;G. Breese
在未损伤对照组和新生儿6-羟基多巴胺（OHDA）损伤大鼠中检查了全身给予N-甲基-D-天冬氨酸受体拮抗剂MK-801 [（+）-5-甲基-10，11-二羟基-5H-二苯并（a，d）环庚烯-5，10-亚胺;地佐环平]后的行为激活。发现新生6-OHDA损伤动物比对照大鼠更敏感，雌性大鼠比雄性大鼠对MK-801诱导的行为激活更敏感。竞争性NMDA拮抗剂CGS-19755也增加了脑损伤动物的活性。MK-801给药后，通过α-甲基酪氨酸预处理，降低了脑损伤大鼠增加的活性水平，但未消除，表明内源性儿茶酚胺是MK-801这一作用的部分原因。此外，D1-或D2-多巴胺拮抗剂在减少MK-801诱导的行为激活方面均不完全有效，但当两种多巴胺拮抗剂联合给药时，MK-801诱导的活性降低至α-甲基酪氨酸后观察到的水平。与这些结果相反，α-甲基酪氨酸几乎消除了成年病变大鼠中MK-801诱导的活性。在新生6-OHDA损伤大鼠中检查MK-801诱导的个体行为时，MK-801未产生与L-二羟基苯丙氨酸或D1或D2多巴胺激动剂相同的行为。然而MK-801对特异性D1或D2多巴胺激动剂诱导的大多数行为没有重大影响，它阻断了L-二羟基苯丙氨酸给药后产生的一些行为，包括自伤行为。重复MK-801治疗导致运动活动增加，但这与D1-多巴胺受体致敏性增加无关。为了支持MK-801的区域作用，MK-801在大脑皮质中诱导c-fos样免疫反应，但在延髓核或纹状体中不诱导。MK-801增加大脑皮质中c-fos样免疫反应性的作用被SCH-23390降低，但未被阻断。此外，MK-801减少，但没有消除，D1-多巴胺激动剂诱导的c-fos样免疫反应在纹状体。这些数据表明，MK-801不仅可以促进特定脑区域内的多巴胺释放，而且具有不同于多巴胺激动剂的行为和功能作用。
Behavioral activation following systemic administration of the N-methyl-D-aspartic acid receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclohepten-5,10-imine; dizocilpine] was examined in unlesioned control and in neonatal-6-hydroxydopamine (OHDA) lesioned rats. Neonatal-6-OHDA lesioned animals were found more sensitive than control rats and female rats more sensitive than males to this MK-801-induced behavioral activation. CGS-19755, a competitive NMDA antagonist, also increased activity in neonatally lesioned animals. The increased activity level following MK-801 administration to neonatally lesioned rats was reduced, but not eliminated, by pretreatment with alpha-methyltyrosine, indicating that endogenous catecholamines were partially responsible for this action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antagonist was totally effective alone in reducing MK-801-induced behavioral activation in the neonatally lesioned rats, but MK-801-induced activity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contrast to these results, alpha-methyltyrosine virtually eliminated the MK-801-induced activity in adult-lesioned rats. When individual behaviors induced by MK-801 were examined in neonatal-6-OHDA lesioned rats, MK-801 did not produce the same behaviors as L-dihydroxyphenylalanine or a D1- or D2-dopamine agonist. Whereas MK-801 had no major effect on most behaviors induced by specific D1- or D2-dopamine agonists, it blocked some behaviors produced after L-dihydroxyphenylalanine administration, including the self-injurious behavior. Repeated MK-801 treatment resulted in increasingly greater motor activity, but this was not related to increased D1-dopamine receptor sensitization. In support of a regional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. The action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-801 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-like immunoreactivity in striatum. These data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.