Merchant K M, Dorsa D M
Geriatric Research, Education and Clinical Center, Seattle Veterans Administration Medical Center, WA 98108.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3447-51. doi: 10.1073/pnas.90.8.3447.
Precise neural mechanisms underlying the pathophysiology and pharmacotherapy of psychotic disorders remain largely unknown. Present studies investigated the effects of various antipsychotic drugs on expression of the gene encoding the purported endogenous antipsychotic-like peptide neurotensin (NT) in striatal regions of the rat brain. The results demonstrate that several clinically efficacious antipsychotic drugs selectively and specifically increase expression of NT/neuromedin N (NT/N) mRNA in the shell of the nucleus accumbens, a region of the forebrain associated with limbic systems. On the other hand, only typical antipsychotics that cause a high incidence of acute motor side effects increased the expression of NT/N mRNA in the dorsolateral striatum, an extrapyramidal region primarily involved in motor control. In addition, it appears that distinct mechanisms may be involved in the effects of antipsychotics on NT/N gene expression in the dorsolateral striatum versus the accumbal shell. Thus neuroleptic-induced increases in NT/N mRNA expression in the dorsolateral striatum were preceded by a rapid and transient activation of c-fos mRNA, whereas none of the antipsychotics affected c-fos mRNA expression in the accumbal shell. The anatomical characteristics of NT/N gene expression induced by typical versus atypical antipsychotics raise the possibility that increased activity of specific NT neurons may contribute to the therapeutic effects (NT neurons in the accumbal shell) or motor side effects (NT neurons in the dorsolateral striatum) of these drugs.
精神障碍的病理生理学和药物治疗背后的确切神经机制在很大程度上仍然未知。目前的研究调查了各种抗精神病药物对大鼠脑纹状体区域中编码所谓内源性抗精神病样肽神经降压素（NT）的基因表达的影响。结果表明，几种临床有效的抗精神病药物选择性且特异性地增加了伏隔核壳中NT/神经介素N（NT/N）mRNA的表达，伏隔核壳是前脑与边缘系统相关的一个区域。另一方面，只有那些会导致高发性急性运动副作用的典型抗精神病药物增加了背外侧纹状体中NT/N mRNA的表达，背外侧纹状体是一个主要参与运动控制的锥体外系区域。此外，抗精神病药物对背外侧纹状体与伏隔核壳中NT/N基因表达的影响似乎涉及不同的机制。因此，在背外侧纹状体中，抗精神病药物诱导的NT/N mRNA表达增加之前会出现c-fos mRNA的快速短暂激活，而没有一种抗精神病药物会影响伏隔核壳中的c-fos mRNA表达。典型与非典型抗精神病药物诱导的NT/N基因表达的解剖学特征增加了一种可能性，即特定NT神经元活性的增加可能有助于这些药物的治疗效果（伏隔核壳中的NT神经元）或运动副作用（背外侧纹状体中的NT神经元）。
