Brain control of the thermoregulatory cutaneous circulation: a window to the mind, and to the neurobiology of clozapine

精神分裂症患者从药物治疗中获益。发现药物发挥作用的大脑机制是最重要的。许多重要药物的作用已在实验动物中得到证实。对于抗精神分裂症药物来说，这是一项艰巨的任务，因为很难确定动物在想什么或感觉什么，而且动物是否患有精神分裂症也值得怀疑。因此，发现一种生理反应是非常有利的，例如在大鼠中可以测量的，可以作为动物对通常会引起焦虑的情况的情绪反应的标志。目前的资助是基于我实验室的一项发现，即压力刺激会导致大鼠尾部的血流突然福尔斯下降。我的实验室是世界上第一个测量有意识的老鼠尾部脉动血流的实验室，这就是我们发现的原因。我的实验室还发现，氯氮平（一种对精神分裂症治疗具有重要理论和实践意义的药物）可以抑制恐惧引起的尾动脉收缩。氯氮平与大脑中许多潜在的神经递质相互作用。这些相互作用的一些非常复杂的组合可能是药物在精神分裂症中独特的精神治疗作用的原因。我们发现氯氮平抑制恐惧引起的尾动脉收缩，这意味着我们将能够研究氯氮平的作用机制。我们的研究结果确实可能增加我们对氯氮平在精神分裂症中如何起作用的理解。这一信息也应该提供线索，目前神秘的大脑功能障碍的性质，导致精神分裂症。

Patients suffering from schizophrenia benefit from medication. Discovering the brain mechanisms whereby the medications work is most important. Action of many important drugs have been established in experimental animals. This is a difficult task for anti-schizophrenia drugs because it is difficult to establish what animals are thinking or feeling, and it is doubtful whether animals ever suffer from schizophrenia. Thus it would be very advantageous to discover a physiological response, measurable in, for example, rats, that can serve as a marker of the animal s emotional responses to situations that would normally prove anxiety-provoking. The present grant is based on the discovery, in my laboratory, that stressful stimuli cause sudden falls in blood flow to the tail in rats. My laboratory is the first in the world to measure pulsatile blood flow to the tail in conscious rats, and this is why we made our discovery. My laboratory also discovered that clozapine, a drug of major theoretical and practical importance for the treatment of schizophrenia inhibits fright-induced constriction of the tail artery. Clozapine interacts with many potential neurotransmitters in the brain. Some very complex combinations of these interactions are presumably responsible for the drug s unique psychotherapeutic action in schizophrenia. Our discovery that clozapine inhibits fright-induced constriction of the tail artery means that we will be able to investigate clozapine s mechanisms of action. Results of our findings are genuinely likely to increase our understanding of how clozapine works in schizophrenia. This information should also provide clues as to the nature of the presently mysterious brain malfunctions that result in schizophrenia.