El Hage Cynthia, Bédard Anne-Marie, Samaha Anne-Noël
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada; CNS Research Group, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
Neuropharmacology. 2015 Dec;99:715-25. doi: 10.1016/j.neuropharm.2015.03.012. Epub 2015 Mar 27.
Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment.
长期接触某些抗精神病药物可导致对多巴胺受体刺激的超敏反应。这与临床预后恶化及抗精神病治疗失败有关。在此，我们研究了纹状体亚区[伏隔核（NAc）和尾状核 - 壳核（CPu）]在抗精神病药物诱导的多巴胺超敏反应表达中的作用。我们用氟哌啶醇（HAL）或奥氮平（OLZ）治疗大鼠，采用能实现纹状体D2受体占据的临床相关动力学的给药方案。在这些条件下，HAL会产生多巴胺超敏反应，而OLZ则不会。然后我们评估了多巴胺激动剂苯丙胺（AMPH）诱发的行为。我们要么将AMPH注射到纹状体中，要么在全身注射AMPH之前通过微量注射GABA受体激动剂来抑制纹状体功能。HAL治疗的大鼠对多巴胺超敏，表现为对全身AMPH诱导的运动活动增强和对条件性奖励（CR）的操作性反应增强敏感。在任何组中，向CPu内注射AMPH对这些行为均无影响。向NAc内注射AMPH增强了OLZ治疗组和对照组大鼠对CR的操作性反应，但在HAL治疗组大鼠中未增强。在HAL治疗的大鼠中，抑制NAc也未能破坏全身AMPH诱导的对CR的操作性反应增强。此外，虽然向NAc内注射AMPH增强了HAL治疗组和对照组动物的运动，但抑制NAc仅在对照组大鼠中破坏了全身AMPH诱导的运动。因此，抗精神病药物诱导的多巴胺超敏反应持续破坏NAc功能，使得一些正常依赖NAc多巴胺的行为不再如此。这对于理解接受慢性抗精神病治疗的患者中多巴胺介导行为的功能障碍具有重要意义。
