Dobner P R, Fadel J, Deitemeyer N, Carraway R E, Deutch A Y
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):8048-53. doi: 10.1073/pnas.141042198. Epub 2001 Jun 26.
The peptide transmitter neurotensin (NT) exerts diverse neurochemical effects that resemble those seen after acute administration of antipsychotic drugs (APDs). These drugs also induce NT expression in the striatum; this and other convergent findings have led to the suggestion that NT may mediate some APD effects. Here, we demonstrate that the ability of the typical APD haloperidol to induce Fos expression in the dorsolateral striatum is markedly attenuated in NT-null mutant mice. The induction of Fos and NT in the dorsolateral striatum in response to typical, but not atypical, APDs has led to the hypothesis that the increased expression of these proteins is mechanistically related to the production of extrapyramidal side effects (EPS). However, we found that catalepsy, which is thought to reflect the EPS of typical APDs, is unaffected in NT-null mutant mice, suggesting that NT does not contribute to the generation of EPS. We conclude that NT is required for haloperidol-elicited activation of a specific population of striatal neurons but not haloperidol-induced catalepsy. These results are consistent with the hypothesis that endogenous NT mediates a specific subset of APD actions.
肽类递质神经降压素（NT）发挥着多种神经化学作用，这些作用类似于急性给予抗精神病药物（APD）后所观察到的作用。这些药物还能诱导纹状体中NT的表达；这一发现以及其他一些趋同的研究结果提示，NT可能介导了某些APD的作用。在此，我们证明，在NT基因敲除突变小鼠中，典型APD氟哌啶醇诱导背外侧纹状体中Fos表达的能力显著减弱。对典型而非非典型APD作出反应时，背外侧纹状体中Fos和NT的诱导表达引发了这样一种假说，即这些蛋白质表达的增加在机制上与锥体外系副作用（EPS）的产生有关。然而，我们发现，僵住症被认为反映了典型APD的EPS，但在NT基因敲除突变小鼠中并未受到影响，这表明NT对EPS的产生并无作用。我们得出结论，NT是氟哌啶醇引发特定纹状体神经元群体激活所必需的，但不是氟哌啶醇诱导僵住症所必需的。这些结果与内源性NT介导APD特定作用子集的假说一致。
