Fuller R W
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind. 46285.
J Clin Psychiatry. 1991 May;52 Suppl:52-7.
Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.
血清素神经药理学的多项进展对精神疾病具有重要意义，并且已经开始影响其治疗。血清素摄取的选择性抑制剂通过阻止血清素经膜转运体从突触间隙清除来增强血清素能功能，已被用于治疗抑郁症，并且可能对其他疾病有效。前体加载可增加突触间隙中的血清素浓度，色氨酸（在健康食品店和药店均可买到）越来越多地被用于抑郁症、失眠和经前综合征的自我治疗。色氨酸向血清素的转化并非其主要代谢途径，细胞外血清素少量增加时，其他色氨酸代谢产物（如喹啉酸，一种高浓度时具有兴奋性毒性的物质）会大幅增加。近期与色氨酸相关的嗜酸性粒细胞增多性肌痛综合征的流行，现在看来是由于单一制造商生产的产品中存在微量污染物所致。血清素药理学的一项重大进展是对血清素受体异质性的阐明。在大脑中已鉴定出至少七种受体亚型（5-HT1A、5-HT1B、5-HT1C、5-HT1D、5-HT2、5-HT3、5-HT4）。直接作用的激动剂和拮抗剂可对特定受体亚型具有选择性亲和力。选择性激活5-HT1A受体似乎会产生抗焦虑作用，可能还有抗抑郁作用。5-HT2或5-HT3受体的选择性拮抗剂可能有助于治疗焦虑症和精神分裂症。增强血清素能功能的药物可抑制动物的攻击行为，但具体涉及的受体亚型尚不清楚。血清素药理学的进展将有助于明确这种脑内神经递质在精神疾病和其他疾病中的作用，有望带来进一步的治疗进展。
