Bissette G, Dauer W T, Kilts C D, O'Connor L, Nemeroff C B
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710.
Neuropsychopharmacology. 1988 Dec;1(4):329-35.
The prevailing hypothesis concerning the mechanism of antipsychotic drug action is principally based on the striking correlation between their clinical potency and their potency in blockade of D2 dopamine receptors. However, most of these compounds also have effects at serotonin, acetylcholine, histamine, and alpha-adrenergic receptors and have recently been shown to alter the concentrations of certain neuropeptides in the rat brain after chronic drug administration. One such neuropeptide that is increased in concentration in dopamine terminal regions by clinically effective neuroleptic drugs is neurotensin (NT). Neurotensin is closely associated with dopamine neurons, as demonstrated by evidence derived from anatomic, physiologic, and pharmacologic studies. In this report, we determined the effects of chronic administration of the potent D2 receptor antagonist (+)-butaclamol and its inactive (-) stereoisomer on regional brain NT content. Moreover, we sought to determine whether the effects of haloperidol on NT concentrations can be antagonized by concomitant administration of an indirect dopamine agonist, d-amphetamine. Neurotensin content in the caudate nucleus and nucleus accumbens of the rat were significantly increased by 3 weeks of daily injections of haloperidol or (+)-butaclamol, but not (-)-butaclamol. d-Amphetamine did not alter this effect of haloperidol on NT concentrations in either the nucleus accumbens or caudate nucleus. These data are concordant with the hypothesis that D2 receptor blockade is required for NT concentration increases after antipsychotic drug treatment and that the increase in synaptic cleft dopamine content produced by d-amphetamine cannot reverse this effect of dopamine receptor antagonists.
关于抗精神病药物作用机制的主流假说是，主要基于其临床效力与其阻断D2多巴胺受体的效力之间显著的相关性。然而，这些化合物中的大多数对5-羟色胺、乙酰胆碱、组胺和α-肾上腺素能受体也有作用，并且最近已显示，在长期给药后，它们会改变大鼠脑中某些神经肽的浓度。一种在多巴胺终末区域经临床有效的抗精神病药物作用后浓度升高的神经肽是神经降压素（NT）。解剖学、生理学和药理学研究的证据表明，神经降压素与多巴胺神经元密切相关。在本报告中，我们确定了强效D2受体拮抗剂（+）-丁酰苯及其无活性的（-）立体异构体长期给药对脑区NT含量的影响。此外，我们试图确定，同时给予间接多巴胺激动剂d-苯丙胺是否可以拮抗氟哌啶醇对NT浓度的影响。每日注射氟哌啶醇或（+）-丁酰苯3周后，大鼠尾状核和伏隔核中的神经降压素含量显著增加，但（-）-丁酰苯则不然。d-苯丙胺并未改变氟哌啶醇对伏隔核或尾状核中NT浓度的这一作用。这些数据与以下假说一致：抗精神病药物治疗后NT浓度升高需要阻断D2受体，并且d-苯丙胺产生的突触间隙多巴胺含量增加不能逆转多巴胺受体拮抗剂的这一作用。
