Angulo J A, Cadet J L, Woolley C S, Suber F, McEwen B S
Columbia University, Department of Neurology, College of Physicians and Surgeons, New York, New York.
J Neurochem. 1990 Jun;54(6):1889-94. doi: 10.1111/j.1471-4159.1990.tb04887.x.
We measured proenkephalin (PEK) mRNA levels in the anterior and medial aspects of the caudate-putamen (CPU) and in the nucleus accumbens (NAc) of the rat by in situ hybridization histochemistry after chronic treatment for 21 days with typical (haloperidol and prolixin) and atypical (molindone, thioridazine, and clozapine) neuroleptics. Chronic administration with these drugs resulted in PEK mRNA levels that were 60-80% higher than controls in the anterior and medial aspects of the CPU but only 25-30% over controls in the NAc. All three atypical neuroleptics studied increased PEK mRNA in the following order: anterior-CPU, thioridazine greater than clozapine and molindone; medial-CPU, thioridazine and molindone greater than clozapine; and NAc, thioridazine much greater than molindone and clozapine. Chronic treatment with the specific dopamine D2 antagonist sulpiride also caused elevation in PEK mRNA levels in all three brain regions studied whereas the specific serotonin S2 receptor blocker, cinanserin, had no significant effects on PEK mRNA levels. These results are consistent with the hypothesis that elevated levels of the enkephalins in the mesolimbic system may be necessary for antipsychotic activity. They also support the idea that the undesirable motoric signs and symptoms observed after chronic treatment with typical neuroleptics may not be the result of increased levels of enkephalins in the basal ganglia because atypical neuroleptics which are almost totally devoid of these side effects caused similar increases in PEK mRNA in the CPU.
在用典型抗精神病药（氟哌啶醇和丙氯拉嗪）和非典型抗精神病药（吗茚酮、硫利达嗪和氯氮平）对大鼠进行21天的慢性治疗后，我们通过原位杂交组织化学法测量了大鼠尾状核-壳核（CPU）前部和内侧以及伏隔核（NAc）中前脑啡肽原（PEK）mRNA的水平。用这些药物进行慢性给药导致CPU前部和内侧的PEK mRNA水平比对照组高60 - 80%，但在NAc中仅比对照组高25 - 30%。所研究的三种非典型抗精神病药均使PEK mRNA增加，顺序如下：前部CPU，硫利达嗪大于氯氮平和吗茚酮；内侧CPU，硫利达嗪和吗茚酮大于氯氮平；NAc，硫利达嗪远大于吗茚酮和氯氮平。用特异性多巴胺D2拮抗剂舒必利进行慢性治疗也导致所研究的所有三个脑区的PEK mRNA水平升高，而特异性5-羟色胺S2受体阻滞剂西那色林对PEK mRNA水平无显著影响。这些结果与以下假设一致，即中脑边缘系统中脑啡肽水平升高可能是抗精神病活性所必需的。它们还支持这样一种观点，即在用典型抗精神病药进行慢性治疗后观察到的不良运动体征和症状可能不是基底神经节中脑啡肽水平升高的结果，因为几乎完全没有这些副作用的非典型抗精神病药在CPU中导致了类似的PEK mRNA增加。
