Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE 68588-0308, USA.
Neuroscience. 2010 Apr 14;166(4):1043-55. doi: 10.1016/j.neuroscience.2010.01.023. Epub 2010 Jan 22.
Rat maternal behavior is a complex social behavior. Most antipsychotic drugs disrupt active maternal responses (e.g., pup retrieval, pup licking and nest building). Our previous work shows that typical antipsychotic haloperidol disrupts maternal behavior by blocking dopamine D(2) receptors, whereas atypical clozapine works by blocking 5-HT(2A/2C) receptors. The present study used c-Fos immunohistochemistry technique, together with pharmacological tools and behavioral observations, and delineated the neuroanatomical bases of the disruptive effects of haloperidol and clozapine. Postpartum female rats were treated with haloperidol (0.2 mg/kg sc) or clozapine (10.0 mg/kg sc), with or without pretreatment of quinpirole (a selective dopamine D(2)/D(3) agonist, 1.0 mg/kg sc) or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT(2A/2C) agonist, 2.5 mg/kg sc). They were then sacrificed 2 h later after a maternal behavior test was conducted. Brain regions that have been previously implicated in the regulation of rat maternal behavior and/or in the antipsychotic action were examined. Behaviorally, both haloperidol and clozapine disrupted pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, reversed the clozapine-induced deficits. Neuroanatomically, the nucleus accumbens (both the shell and core), dorsolateral striatum and lateral septum showed increased c-Fos expression to the treatment of haloperidol. In contrast, the nucleus accumbens shell showed increased expression of c-Fos to the treatment of clozapine. More importantly, pretreatment of quinpirole and DOI produced opposite response profiles in the brain regions where haloperidol and clozapine had an effect. Based on these findings, we concluded that haloperidol disrupts active maternal behavior primarily by blocking dopamine D(2) receptors in a neural circuitry involving the nucleus accumbens, dorsolateral striatum and lateral septum. In contrast, clozapine appears to disrupt maternal behavior mainly by blocking serotonin 5-HT(2A/2C) receptors in the nucleus accumbens shell.
大鼠的母性行为是一种复杂的社会行为。大多数抗精神病药物会破坏活跃的母性行为（例如，幼崽回收、幼崽舔舐和巢穴构建）。我们之前的工作表明，典型的抗精神病药氟哌啶醇通过阻断多巴胺 D2 受体来破坏母性行为，而非典型的氯氮平则通过阻断 5-HT2A/2C 受体起作用。本研究使用 c-Fos 免疫组织化学技术，结合药理学工具和行为观察，描绘了氟哌啶醇和氯氮平的破坏作用的神经解剖学基础。产后雌性大鼠接受氟哌啶醇（0.2 mg/kg sc）或氯氮平（10.0 mg/kg sc）治疗，并用或不用喹吡罗（一种选择性多巴胺 D2/D3 激动剂，1.0 mg/kg sc）或 2,5-二甲氧基-4-碘-苯丙胺（DOI，一种选择性 5-HT2A/2C 激动剂，2.5 mg/kg sc）预处理。在进行了一次母性行为测试后 2 小时，处死它们。检查了先前与调节大鼠母性行为和/或抗精神病作用有关的脑区。行为上，氟哌啶醇和氯氮平都破坏了幼崽的回收、幼崽的舔舐和巢穴的构建。喹吡罗预处理，但不是 DOI，逆转了氟哌啶醇引起的破坏。相反，DOI 预处理，但不是喹吡罗，逆转了氯氮平引起的缺陷。神经解剖学上，伏隔核（壳和核）、背外侧纹状体和外侧隔室在接受氟哌啶醇治疗后显示 c-Fos 表达增加。相反，伏隔核壳在接受氯氮平治疗后显示 c-Fos 表达增加。更重要的是，喹吡罗和 DOI 的预处理在氟哌啶醇和氯氮平产生影响的脑区产生了相反的反应模式。基于这些发现，我们得出结论，氟哌啶醇通过阻断涉及伏隔核、背外侧纹状体和外侧隔室的神经回路中的多巴胺 D2 受体，主要破坏活跃的母性行为。相比之下，氯氮平似乎主要通过阻断伏隔核壳中的 5-HT2A/2C 受体来破坏母性行为。
