丙酸睾丸酮改变发育早期的行为及DA能、5-HT能神经体系在行为改变中的参与

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by motor tics, and one or more vocal tics, as well as several comorbid behavioral abnormalities. It occurs more often in boys than in girls, with a ratio of about 3-9:1, even up to 10.6:1 in China. TS has a distinctive natural history with onset of tics in childhood, common exacerbation of tics before and around the onset of puberty, and frequent remission or moderation of tics as TS patients enter adulthood. Androgen antagonists improved markedly the symptoms in a case of adult TS. It is suggested that androgen brain signaling disturbance might be involved in TS pathophysiology..Increased dopamine transporter (DAT) binding sites have been observed in vivo using SPECT in medication-na?ve TS children. Abnormal activity of DOPA decarboxylase was reported in unmedicated adolescents with TS by PET study. Amphetamine-induced release of dopamine (DA) within the striatum was increased in TS patients. In addition to DA, abnormalities of serotonergic function have also been demonstrated, such as the cortical and subcortical abnormalities of tryptophan metabolism and reduction in serotonin transporter (SERT) binding potential in the midbrain and striatum of subjects with TS..The influence of anabolic androgenic steroids (AAS) on central dopaminergic and serotonergic activity has been reported in animal studies. AAS increase in DAT density and dopaminergic metabolism in male rat brain. The decreased DA concentration in the nucleus accumbens following castration of male rats can be reversed by testosterone. Testosterone treatment leads to an immediate increase in DA and serotonin levels in adult rats and prevented the decreased number of SERT mRNA-expressing cells in the dorsal raphe nucleus from castration..Based on the distinctive natural history of TS, the significant boy predominance of TS, abnormalities of dopaminergic and serotonergic systems in TS and the effects of androgen on dopaminergic and serotonergic systems, we presume the some developmentally regulated changes is possibly related to TS. An altered timing or magnitude of the development of the dopaminergic and serotonergic systems seems plausible in TS, which are due to the disturbed level of testosterone. Therefore, in the present project, we aimed to assess the effects of early androgen treatment on brain function during development by analyzing the open field behavior of rats, and investigate whether dopaminergic and serotonergic systems is involved in pathophysiology of altered behaviors. In our preliminary experiment, the several parameters of open field behavior and the labeled markers of dopaminergic and serotonergic system (such as DAT, SERT etc) were found to be changed at 3 weeks and at 7 weeks of age. Further studies on the findings of our preliminary experiment would provide some experimental clues to search for the evidence of TS pathophysiology.

研究发现抽动-秽语综合征（TS）多发生于男童，虽其发病机制目前尚不清楚，但根据发病人群存在的明显性别差异以及青春期加重的特点，推测其发病可能与体内雄激素水平紊乱有关。基于多巴胺（DA）能和5羟色胺（5-HT）能神经体系在行为活动调控中的作用，以及TS患者脑内普遍存在着两神经体系的神经影像变化。本项目以大鼠为实验对象，观察丙酸睾丸酮（TP）对发育过程中行为的影响，探讨脑内DA能和5-HT能神经体系在TP改变行为过程中的参与。预实验发现TP早期处理的乳鼠在幼年和青春期两发育阶段均表现出不同程度的旷场行为改变，以及脑内DA能和5-HT能神经体系多个指标的变化。进一步深入这一研究，揭示雄激素在发育过程中对行为的影响及其机制，分析DA能和5-HT能神经体系改变在这一过程中所起的作用，期望所获结果能为探寻TS的发病提供一定的实验依据。

研究项目内容已于2013年完成。本课题发现丙酸睾丸酮（TP）早期处理显著改变3周龄和7周龄大鼠的旷场行为，即增加静止闻嗅行为；增加探索行为的Walking、Climbing、Rearing 和Sniffing参数；增加运动行为的Vertical activity、Horizontal activity和Total path length三个参数，以及理毛行为的Number of grooming 和Duration of grooming两个参数。雄激素拮抗剂flutamide早期干预仅改变7 周龄大鼠旷场的少数行为，即降低了探索行为的Walking 和Sniffing两个参数。拮抗剂flutamide预处理能够改善丙酸睾丸酮早期处理所致大鼠3周龄和7周龄时改变的旷场行为，与TP早期处理组相比Immobile-sniffing、Walking、Climbing、Rearing 、Sniffing 、Vertical activity、Horizontal activity 和Total path length以及Number of grooming 和Duration of grooming均得到缓解。TP早期处理增加3周龄、7周龄大鼠尾壳核与伏核DA和5-HT以及相关代谢产物DOPAC与5-HIAA的含量；增加3周龄、7周龄大鼠尾壳核及7周龄大鼠伏核代谢产物HVA的含量。拮抗剂flutamide早期干预仅降低3周龄大鼠尾壳核与伏核DA 的含量及增加7周龄大鼠尾壳核HVA的含量，未改变3周龄、7周龄大鼠尾壳核与伏核5-HT及其代谢产物5-HIAA的含量；拮抗剂flutamide预处理能够缓解TP早期处理所致3周龄大鼠尾壳核DA、DOPAC 和HVA，以及5-HT 和5-HIAA含量的增加；缓解3周龄大鼠伏核DA 、DOPAC和5-HT以及7周龄大鼠伏核DA、5-HT含量的增加。三种早期处理方式未改变6月龄大鼠的旷场行为，以及尾壳核与伏核神经递质DA和5-HT及其代谢产物的表达。本课题所获结果揭示了雄激素对发育早期行为的影响及DA能与5-HT能神经体系在行为改变中的参与，为探寻抽动秽语综合症的发病机制提供了一定的实验依据。