摘要
抽动-秽语综合症(Tourette Syndrome,TS)是临床较为常见的儿童行为障碍综合征,是以面部、四肢以及躯干部肌肉不自主抽动伴有喉部异常发音即猥秽语言为特征的综合症候群,多发生于男童,男女发病比例为3-9:1,我国部分地区甚至高达10.6:1。TS患者常伴有至少一种行为或情绪障碍,大约1/3的病人伴有强迫症。研究发现TS具有较明显的病程特征,表现为儿童期发病,青春期病症加重,成年后运动症状逐渐好转,甚至消失。有研究报道,TS症状严重的患儿尿液含有较高水平的睾酮;可伴有雄激素增多症的表现;抗雄激素处理则显著缓解TS成年患者的症状。这些表明其发病可能和患儿体内雄激素水平紊乱有关。
近年来的临床资料暗示多巴胺(DA)能神经体系的功能障碍与TS密切相关。利用配基神经显像技术检测到TS患儿(6-12岁)新纹状体多巴胺转运体(DAT)信号增强,TS青少年患者(12-17岁)尾状核有异常的多巴脱羧酶活性增强。临床资料显示,安非他命可以增强TS患者壳及腹侧纹状体多巴胺的释放,多巴胺受体拮抗剂则具有抑制TS患儿抽动症状的功效。上述研究结果表明TS发病可能和脑内多巴胺能神经体系存在密切的关系。
睾酮在男性主要由睾丸间质细胞产生,具有脂溶性特点,可透过血脑屏障,作用于中枢神经系统。大量研究显示雄激素可以影响多巴胺能神经元的功能活动。胚胎期给予雄激素,可以导致成年期大鼠前额叶皮质多巴胺神经元功能活动增强;青春期给予雄激素可以明显引起大鼠的攻击行为增多以及下丘脑多巴胺D2受体表达增加;长期给予成年大鼠雄激素促进了纹状体DAT的表达。
脑内DA能神经元主要集中在中脑黑质致密部(SNc)及腹侧被盖区(VTA)等处。多巴胺黑质纹状体环路及VTA皮质环路分别参与躯体运动及认知、思维能力的调控。TS患儿发育过程中的异常行为是否与雄激素水平紊乱、进而改变了脑内多巴胺能神经体系的功能活动有关,目前尚不清楚。
因此,本研究以雄性Wistar乳鼠为实验对象,分别通过早期皮下注射丙酸睾酮(testosterone propionate, TP组)、雄激素受体抑制剂氟他胺(flutamide,Flu组)以及氟他胺+丙酸睾酮((Flu+TP组),建立大鼠实验动物模型。利用旷场实验、液相色谱-串联质谱、免疫印迹和RT-PCR技术观察3周龄(幼年)、7周龄(青春期)和6月龄(成年)实验大鼠的旷场行为以及中脑DA能神经元相关指标的表达变化,探讨雄激素在早期发育过程中对行为的影响及其机制,分析中脑DA能神经元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。第一部分:丙酸睾酮改变雄性大鼠发育早期的旷场行为
目的:探讨生后TP早期处理对雄性大鼠旷场行为的影响。
方法:利用旷场实验观察大鼠模型在3周龄、7周龄及6月龄旷场行为相关参数的变化;称量大鼠及其性腺器官和脑垂体的重量;以放射免疫法检测上述三个时间点大鼠模型血清睾酮、卵泡刺激素、黄体生成素含量的变化。
结果:
1通过旷场实验发现,在3周龄和7周龄时,与对照组相比,TP组各种静止闻嗅、运动行为、探索行为及理毛行为参数明显增加;而Flu+TP组旷场实验多项行为参数未表现明显改变,仅爬行的数量降低以及7周龄理毛次数增加。与TP组相比,Flu+TP组的静止闻嗅、运动行为、探索行为及理毛行为指标明显减低。TP早期处理和Flu早期干预对3周龄、7周龄以及6月龄大鼠的趋触行为无明显改变。6月龄时,各组大鼠行为均无明显改变。
2TP早期处理大鼠3周龄、7周龄及6月龄各组大鼠之间体重没有明显差异。
3TP早期处理大鼠精囊、垂体和睾丸重量的改变
在3周龄时,与对照组相比,TP组精囊的重量增加了1028%(P<0.01),睾丸的平均重量降低了24%(P<0.01);Flu组精囊的重量降低了16%(P<0.05);Flu+TP组精囊的重量增加了201%(P<0.01),睾丸的平均重量降低了60%(P<0.01)。与TP组相比,Flu+TP组精囊的重量和睾丸的平均重量分别降低了73%(P<0.01)和47%(P<0.01)。与Flu组相比,Flu+TP组精囊的重量增加了256%(P<0.01),睾丸的平均重量降低了62%(P<0.01)。各组垂体的重量无明显变化(P>0.05)。在7周龄时,与对照组相比,TP组睾丸的平均重量降低了25%(P<0.01),精囊腺没有差异;Flu组睾丸的平均重量无明显变化(P>0.05);Flu+TP组睾丸的平均重量降低了62%(P<0.01)。与TP组相比,Flu+TP组睾丸的平均重量降低了49%(P<0.01)。与Flu组相比,Flu+TP组睾丸的平均重量降低了58%(P<0.01)。各组精囊和垂体的重量无明显变化(P>0.05)。在6月龄时,各组精囊、垂体和睾丸重量无明显变化(P>0.05)。
4TP早期处理大鼠血清T、LH和FSH水平的改变
在3周龄时,与对照组相比,TP组血清T的浓度增加了4400%(P<0.01);Flu+TP组血清T的浓度增加了4229%(P<0.01)。与Flu组相比,Flu+TP组血清T的浓度增加了3996%(P<0.01)。各组血清LH和FSH水平无明显变化(P>0.05)。在7周龄时,与对照组相比,TP组血清T的浓度降低了53%(P<0.01);Flu+TP组血清T的浓度降低了88%(P<0.01)。与TP组相比,Flu+TP组血清T的浓度降低了74%(P<0.01)。与Flu组相比,Flu+TP组血清T的浓度低了88%(P<0.01)。各组血清LH和FSH水平无明显变化(P>0.05)。在6月龄时,各组血清T、LH和FSH水平无明显变化(P>0.05)
结论:
1皮下注射TP可使乳鼠保持在高水平的血睾状态。
2乳鼠TP早期处理导致幼年和青春期的旷场行为实验多项行为参数显著增加,暗示发育早期高水平的雄激素可能改变了脑内有关神经信号的传递。
第二部分:丙酸睾酮促进雄性大鼠发育早期中脑DA能神经元DA、DOPAC及HVA的表达
目的:观察生后TP早期处理对雄性大鼠黑质-尾壳核及腹侧被盖区-伏核DA能神经元神经递质DA及其代谢产物的影响,探讨TP改变发育早期旷场行为与DA信号传递变化可能存在的联系。
方法:利用液相色谱-串联质谱(LC-MS/MS)法检测3周龄、7周龄及6月龄实验大鼠中脑DA能神经元投射靶区尾壳核、伏核的DA、DOPAC和HVA的表达变化。结果:
与对照组相比,3周龄TP组尾壳核DA、DOPAC、 HVA以及伏核DA、DOPAC的表达显著增加。DOPAC+HVA/DA、DOPAC/DA和HVA/DA无明显变化;Flu组尾壳核和伏核DA的表达明显减低,尾壳核DOPAC+HVA/DA和DOPAC/DA的比值增加,伏核HVA/DA的比值增加;Flu+TP组尾壳核DA的表达降低,DOPAC+HVA/DA和DOPAC/DA的比值明显增加,伏核无显著改变。与TP组相比,Flu+TP组两个核团DA、DOPAC的浓度明显降低,伏核HVA降低不明显。
与对照组相比,7周龄TP组尾壳核和伏核DA、DOPAC和HVA的表达明显增加,DOPAC+HVA/DA、DOPAC/DA和HVA/DA的比值无明显变化;Flu组尾壳核HVA的表达增加了25%,伏核所有指标没有变化;Flu+TP组尾壳核各项指标均无明显变化。与TP组相比,Flu+TP组尾壳核各项指标均无明显变化,伏核DA的浓度降低了26%。
6月龄各组大鼠神经递质及代谢产物各项指标比值均无明显变化。
结论:乳鼠TP早期处理促进其幼年和青春期中脑DA能神经元DA、DOPAC及HVA的表达,给予Flu则抑制了外源性TP的这种作用。
第三部分:丙酸睾酮早期处理促进雄性大鼠发育早期中脑DA能神经元TH、DAT、MAOA、MAOB及COMT的表达
目的:观察乳鼠TP早期处理对中脑DA能神经元功能活动强弱相关指标表达的影响,探讨其表达变化与TP促进DA能神经元表达DA、DOPAC及HVA的相互关系。
方法:通过免疫印迹方法以及实时定量RT-PCR方法来检测丙酸睾酮处理后雄性大鼠黑质TH,DAT及其mRNA以及TH、DAT、MAOA、MAOB、COMT的mRNA的表达。
结果: TP早期处理对三个发育阶段黑质(SN)、尾壳核(CPu)、腹侧被盖区(VTA)和伏核(Acb)脑区TH和DAT的改变
在3周龄和7周龄时,与对照组相比,TP组大鼠处理黑质,尾壳核,腹侧被盖区及伏核TH和DAT表达均明显增加。黑质、腹侧被盖区TH mRNA和DAT mRNA表达升高。与TP组相比,Flu+TP组黑质,尾壳核,腹侧被盖区,伏核TH和DAT的表达明显减少。黑质、腹侧被盖区TH mRNA和DAT mRNA表达降低。在6月龄时,各组黑质,尾壳核,腹侧被盖区,伏核TH和DAT的表达无明显变化。
MAOA、MAOB及COMT mRNA的表达改变
在3周龄和在7周龄时,与对照组相比,TP组处理黑质和腹侧被盖区MAOA mRNA、MAOB mRNA以及COMT mRNA的表达均明显增加。与TP组相比,Flu+TP组黑质和腹侧被盖区MAOAmRNA、MAOBmRNA以及COMT mRNA的表达均明显降低。在6月龄时,各组黑质和腹侧被盖区MAOAmRNA、MAOBmRNA以及COMT mRNA的表达无明显变化。
结论:乳鼠TP早期处理改变其幼年和青春期中脑DA能神经元TH、DAT及其mRNA以及MAOA、MAOB、COMT mRNA的表达水平,表现为TP的增强效应;Flu能够抑制外源性TP的这种效应,暗示中脑DA神经元神经的信号传递的改变与TP调控神经递质DA代谢相关酶及DA转运体的表达有关。
Tourette Syndrome(TS) is a common children's behavior disordersyndrome in clinic. It is a comprehensive syndrome characterized byinvoluntary muscles twitch on the face, limbs and trunk with abnormallaryngeal pronunciation, thus dirty language. This disease occurred mosty inboys, and incidence ratio of men and women is3-9:1, while in parts of ourcountry it is even as high as10.6:1. Patients with this disease are accompaniedby at least one behavior or mood disorders, about a third of the patients withOCD. Many studies demonstrated that TS has obvious course characteristics,characterized by childhood-onset, illness is aggravating in adolescence andmotor symptoms gradually improve as an adult, even disappear. It has beenreported that urine of TS children with severe symptoms contains high level oftestosterone. Patients can be with hyperandrogenism performance.Antiandrogen treatment can significantly alleviate TS symptoms in adultpatients. These results showed the incidence may be related to androgen levelsdisorder in children.
Recent clinical data suggested that dysfunction of dopamine (DA)nervous system is closely related to the TS. By Genin neural imagingtechnology, TS children (6to12years of age) can be detected with newstriatal dopamine transporter (DAT) signal enhancement, and TS adolescentpatients (12to17years of age) can be detected with abnormal DOPAdecarboxylase activity enhancement in caudate nucleus. Clinical data showedthat amphetamine can enhance striatum dopamine release in putamen andveutro of TS patients, and dopamine receptor antagonist has inhibited twitchsymptoms of TS children. These results indicated that TS may have closerelationship with brain dopamine nervous system.
Most of testosterone in men is produced by leydig cells. Testosterone isan important form of androgen in the body, and has the characteristics offat-soluble. It can be used as a male steroid hormones (AAS), and can throughthe blood brain barrier and act on central nervous system. Researches showedthat abuse of AAS will lead to hyperactivity, lack of impulse control andemotional instability. In addition, the animal experiments also found thattestosterone can lead to the increase of motor behavior and excessivegrooming of normal adult male rats. The above experiments proved that AAShas affected the behavior changes in male rats.
DA neurons in the brain are mainly concentrated in the midbrainsubstantial nigra compacta (SNc) and ventral tegmental area (VTA), etc. Thesubstantia nigra-striatum and VTA-cortical dopaminergic neurons regulatemovement, cognition and thinking ability respectively. Whether the change ofandrogen levels are related to the abnormal behavior disorders in the TSchildren development or the function of the brain dopaminergic nerve system,it is not very clear.
Therefore, the study chose male Wistar rats as experimental object,respectively subcutaneous injection of testosterone propionate (testosteronepropionate, TP group), androgen receptor inhibitor flutamide (flutamide, Flugroup), and flutamide+testosterone propionate (Flu+TP group) to establishthe experimental animal model. The open field experiment, LC-MS/MS,western blot and RT-PCR technique are used to observe behaviors of theWistar rats and the related parameters of the midbrain DA neurons in3weeks(youth),7weeks of age (adolescence) and6months of age (adult). The aimsof the study are to explore the possible mechanisms in androgen acting ondopamine nervous system of rats in development, and it is expected thatprovide certain experiment basis for exploring the pathogenesis of TS.
Part1Effects of TP on male rats open field behaviors in the earlydevelopmental stage
Objective To study the effects of chronic administration of TP onmotor-related behaviors of male rats in the three developmental stages.
Methods Using open field test to observe rat behavior parameters in3weeks,7weeks and6months of age; Measuring the rat body weight, gonadorgans, pituitary weight. Radioimmunoassay (RIA) was used to detecttestosterone, follicle-stimulating hormone and luteinizing hormoneconcentration in serum after administration of TP.
Results
1At3weeks and7weeks, compared with the control group, TP groupimmobile-sniffing behavior, exploratory behavior, locomotor behavior andgrooming behavior were increased significantly. However, compared with thecontrol group, Flu+TP group open field behavior parameters showed noobvious change but the amount of Walking reduction at3weeks and7weeksand number of grooming increasing in7weeks. Compared with the TP group,TP group immobile sniffing, locomotor behavior, exploration behavior andgrooming behavior significantly reduced. The thigmotaxic behavior has noobvious change in TP or Flu group at3weeks,7weeks and6months. At6months, each behavior had no obvious change in all groups of rats.
2There were no significant differences between groups of rats weigh at3weeks,7weeks and6months.
3Effect of early TP administration on seminal vesicle, testis and pituitaryweight.
At3weeks, compared with the control group, average vesicle weight inTP group increases by1028%(P<0.01),average testis weight decreases by24%(P<0.05), average testis weight in Flu group decreases by16%(P<0.05),average seminal vesicle weight in Flu+TP group has increases by201%(P<0.01), average testis weight decreases by60%(P <0.01).Weight of averageseminal vesicle and testis weight in Flu+TP group compared with TPdecreases by73%(P <0.01) and47%(P <0.01). Average seminal vesicleweight in Flu+TP group Compared with Flu group has increases by256%(P<0.01), average testis weight has decreases by62%(P <0.01). Pituitary weightof each group has no obvious change (P>0.05)
At7weeks, compared with the control group,average testis weight decreases25%(P<0.01)in TP group,average testis weight in Flu group hasno obvious difference, average testis weight in Flu+TP group has decreasedby62%(P <0.01).Average weight of testis in Flu+T P group compared withTP reduce49%(P <0.01).Average weight of testis in Flu+TP groupcompared with Flu group decreases58%(P <0.01). Average pituitary weightof each group has no obvious change (P>0.05)
At6months, each above organ has no obvious change in all groups(P>0.05).
4Effect of Early TP administration on serum T, LH and FSH in threedevelopmental stages
At3weeks, compared with the control group, concentration of serumTin TP group increases4400%(P<0.01), serum T in Flu+TP group increases4229%(P<0.01). Serum T in Flu+TP group compared with Flu increases3996%(P<0.01). serum T, LH and FSH in each group has no obvious change(P>0.05).
At7weeks, compared with the control group,concentration of serum Tin TP group decreases53%(P<0.01), serum T in Flu+TP group decreases88%(P<0.01). Serum T in Flu+TP group compared with TP decreases74%(P<0.01).Serum T in Flu+TP group compared with Flu decreases88%(P<0.01). serum T, LH and FSH in each group has no obvious change(P>0.05).
At6months, concentration of serum T, LH and FSH has no obviouschange in all groups(P>0.05)
Conclusions:
1Subcutaneous administration of TP lead rats to remain at a high level ofblood testosterone.
2Early administration of TP on pup rats leads to open field behaviorparameters increasing significantly in childhood and puberty period,suggesting that high levels of androgens in the early development time maychange the brain neural signal transmission.
Part2Testosterone propionate promotes the expression of DA,DOPAC and HVA in the midbrain dopaminergic neurons in the earlydevelopment stage
Objective To observe the effect of TP on DA neurotransmitters and theirmetabolic products in the substantia nigr-caudate putamen and the ventraltegmental area-the nucleus accumbens neurons, discussed the relationshipbetween early behavior changes by administration of TP and dopaminergicnerve signal transmission
Methods Using LC-MS/MS to observe the expressions of DA, DOPACand HVA on rat corpus striatum and nucleus accumbens in3weeks,7weeksand6months.
Results
The changes of DA and metabolite in corpus striatum, nucleusaccumbens.
At3weeks, compared with control group, the expression of DA,DOPAC and HVA in corpus striatum are increased, the expression of DA,DOPAC in nucleus accumbens in TP group are increased(P<0.01), there is nosignificant change on DOPAC+HVA/DA, DOPAC/DA and HVA/DA. Theexpression of DA in corpus striatum and nucleus accumbens in Flu group aredecreased, the specific value of DOPAC+HVA/DA and DOPAC/DA incorpus striatum are increased(P<0.01), the specific value of corpus striatumHVA/DA is increased by40%. The expression of DA in corpus striatum inFlu+TP group is reduced by43%, the specific value of DOPAC+HVA/DAand DOPAC/DA are increased(P<0.01), there is no significant change oncorpus striatum. Compared with TP group, the expression of DA and DOPACin Flu+TP group is obviously decline. There is no obvious decreased onnucleus accumbens HVA.
At7weeks, compared with control group, the expression of DA,DOPAC and HVA in corpus striatum and nucleus accumbens in TP group areobviously increased(P<0.01), there is no significant change on the specificvalue of DOPAC+HVA/DA,DOPAC/DA and HVA/DA. The expression ofcorpus striatum HVA in Flu group are increased by25%, there is no change on all targets of nucleus accumbens; there is no obvious change on all targetsof corpus striatum in Flu+TP group. Compared with TP group. There is noobvious change on corpus striatum in Flu+TP group, the expression ofnucleus accumbens DA is reduced by26%.
At6months, there is no obvious change on DA neurotransmitter and itsmetabolite of male rats in each group.
Conclusion The early TP treatment on neonatal rats can promote themidbrain DA, DOPAC and HVA expression in childhood and adolescenceperiods, while administration of flutamide inhibited the effect of exogenousTP.
Part3Testosterone propionate early treatment increase theexpression of TH, DAT, MAOA and MAOB and COMT in midbraindopaminergic neurons of the male rats
Objective To observe the effect of TP administration on pup rats on therelevant activities indicators of the midbrain dopaminergic neurons. Then weexplore in depth the relationship between these effects and how TP canpromote DA, DOPAC and HVA expression
Methods Detecting the expressions of nigra TH, DAT protein, TH, DATof male rats, MAO, MAO and COMT mRNA after treating by testosteronepropionate by western blot and realtime RT-PCR.
Results The effect of TP’s earlier treatment on TH and DAT in SN,CPu, VTA, Acb.
1At3weeks and7weeks, compared with control group, the expressionsof TH, DAT in substantial nigra, ventral tegmental area and nucleusaccumbens in TP group are increased. Compared with TP group, theexpressions of TH, DAT in substantial nigra, ventral tegmental area andnucleus accumbens in Flu+TP group are obviously reduced.
At6months, there is no obviously change on the expressions ofsubstantial nigra, ventral tegmental area and nucleus accumbens TH, DAT ineach group.
2The effect of TP’s earlier treatment on TH, DAT, MAOA, MAOB, COMT gene in SN, VTA.
At3weeks and7weeks, compared with control group, the expressionsof TH mRNA, DAT mRNA, MAOA mRNA, MAOB mRNA and COMTmRNA in substantial nigra, ventral tegmental area are obviously increased inTP group. Compared with TP group, the expressions of TH mRNA,DATmRNA, MAOA mRNA, MAOB mRNA and COMT mRNA insubstantial nigra, ventral tegmental area are obviously reduced in Flu+TPgroup.
At6months, there is no obviously change on the expressions ofsubstantial nigra, ventral tegmental area TH mRNA, DATmRNA, MAOAmRNA, MAOB mRNA and COMT mRNA in each group.
Conclusion Early TP administration on pup rats leads to change on TH,DAT and its mRNA and MAOA and MAOB, COMT mRNA expression levelin childhood and adolescence midbrain DA neurons, which performance theenhancement effect of TP. Flu inhibited the effect of exogenous TP, whichsuggested that the midbrain neural signal transmission of DA changesassociated with TP regulation of neurotransmitter DA metabolic enzymes andthe expression of DA transporter.
引文
1Liu, S., et al., The Subjective Quality of Life in Young People WithTourette Syndrome in China. J Atten Disord,2014.(2):191-195
2Zhang G, Shi G, Tan H, et al. Intranasal administration oftestosterone increased immobile-sniffing, exploratory behavior, motorbehavior and grooming behavior in rats [J]. Horm Behav,2011,59(4):477-483
3Roemmich, R.T., et al., Effects of dopaminergic therapy on locomotoradaptation and adaptive learning in persons with Parkinson's disease.Behav Brain Res,2014.59(4):1301-1306
4Kailanto, S., A. Kankaanpaa, and T. Seppala, Subchronic steroidadministration induces long lasting changes in neurochemical andbehavioral response to cocaine in rats. Steroids,2011.76(12):1310-1316
5Buse, J., et al., Neuromodulation in Tourette syndrome: dopamine andbeyond. Neurosci Biobehav Rev,2013.37(6):1069-1084
6Mogwitz, S., et al., Clinical pharmacology of dopamine-modulatingagents in Tourette's syndrome. Int Rev Neurobiol,2013.112:281-349
7Thiblin, I., et al., Increased dopaminergic and5-hydroxytryptaminergicactivities in male rat brain following long-term treatment with anabolicandrogenic steroids. Br J Pharmacol,1999.126(6):1301-1306
8Purves-Tyson, T.D., et al., Testosterone regulation of sex steroid-relatedmRNAs and dopamine-related mRNAs in adolescent male rat substantianigra. BMC Neurosci,2012.13:95
9Biederman, J., et al., Sexually dimorphic effects of four genes (COMT,SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: apreliminary study. Am J Med Genet B Neuropsychiatr Genet,2008.147B(8):1511-1518
10Chen, K., et al., A spontaneous point mutation produces monoamineoxidase A/B knock-out mice with greatly elevated monoamines andanxiety-like behavior. J Biol Chem,2004.279(38):39645-39652
11Oreland, L., Y. Arai, and A. Stenstrom, The effect of deprenyl (selegiline)on intra-and extraneuronal dopamine oxidation. Acta Neurol ScandSuppl,1983.95:81-85
12Konkle, A.T. and M.M. McCarthy, Developmental time course ofestradiol, testosterone, and dihydrotestosterone levels in discrete regionsof male and female rat brain. Endocrinology,2011.152(1):223-235
13Forest, M.G., Plasma androgens (testosterone and4-androstenedione) and17-hydroxyprogesterone in the neonatal, prepubertal and peripubertalperiods in the human and the rat: differences between species. J SteroidBiochem,1979.11(1B):543-548
14Edinger, K.L. and C.A. Frye, Testosterone's anti-anxiety and analgesiceffects may be due in part to actions of its5alpha-reduced metabolites inthe hippocampus. Psychoneuroendocrinology,2005.30(5):418-430
15Frye, C.A., K. Edinger, and K. Sumida, Androgen administration to agedmale mice increases anti-anxiety behavior and enhances cognitiveperformance. Neuropsychopharmacology,2008.33(5):1049-1061
16Adler, A., et al., Gonadectomy in adult life increases tyrosinehydroxylase immunoreactivity in the prefrontal cortex and decreasesopen field activity in male rats. Neuroscience,1999.89(3):939-954
17Parrilla-Carrero, J., et al., The anabolic steroids testosterone propionateand nandrolone, but not17alpha-methyltestosterone, induce conditionedplace preference in adult mice. Drug Alcohol Depend,2009.100(1-2):122-127
18Egashira, N., et al., Depression-like behavior and reduced plasmatestosterone levels in the senescence-accelerated mouse. Behav BrainRes,2010.209(1):142-147
19Sanders, D.C., The Bethlem lines: genetic selection for high and lowrearing activity in rats. Behav Genet,1981.11(5):491-503
20Casarrubea, M., F. Sorbera, and G. Crescimanno, Multivariate analysis ofthe modifications induced by an environmental acoustic cue on ratexploratory behavior. Physiol Behav,2008.93(4-5):687-696
21Kalueff, A.V., et al., Analyzing grooming microstructure inneurobehavioral experiments. Nat Protoc,2007.2(10):2538-2544
22Kalueff, A.V. and P. Tuohimaa, Contrasting grooming phenotypes inthree mouse strains markedly different in anxiety and activity (129S1,BALB/c and NMRI). Behav Brain Res,2005.160(1):1-10
23Bourgeois, J.P., et al., Modulation of the mouse prefrontal cortexactivation by neuronal nicotinic receptors during novelty exploration butnot by exploration of a familiar environment. Cereb Cortex,2012.22(5):1007-1015
24Olivares, E.L., et al., Administration of an anabolic steroid during theadolescent phase changes the behavior, cardiac autonomic balance andfluid intake in male adult rats. Physiol Behav,2014.126:15-24
25Schwartzer, J.J. and R.H. Melloni, Jr., Dopamine activity in the lateralanterior hypothalamus modulates AAS-induced aggression through D2but not D5receptors. Behav Neurosci,2010.124(5):645-655
26Khakpai, F., The effect of opiodergic system and testosterone on anxietybehavior in gonadectomized rats. Behav Brain Res,2014.263:9-15
27Aikey, J.L., et al., Testosterone rapidly reduces anxiety in male housemice (Mus musculus). Horm Behav,2002.42(4):448-460
28Kailanto, S., A. Kankaanpaa, and T. Seppala, Subchronic steroidadministration induces long lasting changes in neurochemical andbehavioral response to cocaine in rats. Steroids,2011.76(12):1310-1316
29Scerbo, A.S. and D.J. Kolko, Salivary testosterone and cortisol indisruptive children: relationship to aggressive, hyperactive, andinternalizing behaviors. J Am Acad Child Adolesc Psychiatry,1994.33(8):1174-1184
30Hodosy, J., et al., The anxiolytic effect of testosterone in the rat ismediated via the androgen receptor. Pharmacol Biochem Behav,2012.102(2):191-195
31O'Neill, B., et al., Behavior of knock-in mice with a cocaine-insensitivedopamine transporter after virogenetic restoration of cocaine sensitivityin the striatum. Neuropharmacology,2014.79:626-633
32Weisz, J. and I.L. Ward, Plasma testosterone and progesterone titers ofpregnant rats, their male and female fetuses, and neonatal offspring.Endocrinology,1980.106(1):306-316
33Gerard, E. and B.S. Peterson, Developmental processes and brainimaging studies in Tourette syndrome. J Psychosom Res,2003.55(1):13-22
34Bingham, B., et al., Postnatal blockade of androgen receptors oraromatase impair the expression of stress hypothalamic-pituitary-adrenalaxis habituation in adult male rats. Psychoneuroendocrinology,2011.36(2):249-257
35Ravizza, T., J. Veliskova, and S.L. Moshe, Testosterone regulatesandrogen and estrogen receptor immunoreactivity in rat substantia nigrapars reticulata. Neurosci Lett,2003.338(1):57-61
36Foradori, C.D., M.J. Weiser, and R.J. Handa, Non-genomic actions ofandrogens. Front Neuroendocrinol,2008.29(2):169-181
37Baron, S., et al., Androgen receptor mediates non-genomic activation ofphosphatidylinositol3-OH kinase in androgen-sensitive epithelial cells. JBiol Chem,2004.279(15):14579-1486
38Li, J. and F. Al-Azzawi, Mechanism of androgen receptor action.Maturitas,2009.63(2):142-148
49Neri, R., et al., A biological profile of a nonsteroidal antiandrogen, SCH13521(4'-nitro-3'trifluoromethylisobutyranilide). Endocrinology,1972.91(2):427-437
40Murphy, J.C., S. Srinivas, and M.K. Terris, Flutamide administration at
500mg daily has similar effects on serum testosterone to750mg daily. JAndrol,2004.25(4):630-634
41Forest, M.G., E. De Peretti, and J. Bertrand,Hypothalamic-pituitary-gonadal relationships in man from birth topuberty. Clin Endocrinol (Oxf),1976.5(5):551-569
42Odell, W.D. and R.S. Swerdloff, The role of testicular sensitivity togonadotropins in sexual maturation of the male rat. J Steroid Biochem,1975.6(6):853-857
43Eldridge, J.C., J.C. McPherson,3rd, and V.B. Mahesh, Maturation of thenegative feedback control of gonadotropin secretion in the female rat.Endocrinology,1974.94(6):1536-1540
44Purves-Tyson, T.D., et al., Testosterone regulation of sex steroid-relatedmRNAs and dopamine-related mRNAs in adolescent male rat substantianigra. BMC Neurosci,2012.13:95
1Yu, Q., et al., Dopamine and serotonin signaling during two sensitivedevelopmental periods differentially impact adult aggressive and affectivebehaviors in mice. Mol Psychiatry,2014.8:293-303
2Bambico, F.R., et al., Father Absence in the Monogamous CaliforniaMouse Impairs Social Behavior and Modifies Dopamine and GlutamateSynapses in the Medial Prefrontal Cortex. Cereb Cortex,2013.6:281-349.
3Iakimovskii, A.F. and T.V. Kerko,[Comparative analysis of metabotropicand ionotropic glutamate striatal receptors blockade influence on ratslocomotor behaviour]. Ross Fiziol Zh Im I M Sechenova,2013.99(2):221-229
4Mileikovsky, B., S.V. Verevkina, and A.D. Nozdrachev, Effects ofstimulation of the frontoparietal cortex and parafascicular nucleus onlocomotion in rats. Physiol Behav,1994.55(2):267-271
5Butler, T.R., A.M. Chappell, and J.L. Weiner, Effect of beta3adrenoceptoractivation in the basolateral amygdala on ethanol seeking behaviors.Psychopharmacology (Berl),2014.231(1):293-303
6Gaszner, B., et al., The behavioral phenotype of pituitaryadenylate-cyclase activating polypeptide-deficient mice in anxiety anddepression tests is accompanied by blunted c-Fos expression in the bednucleus of the stria terminalis, central projecting Edinger-Westphalnucleus, ventral lateral septum, and dorsal raphe nucleus. Neuroscience,2012.202:283-299
7Grieb, B., et al., Decomposition of abnormal free locomotor behavior in arat model of Parkinson's disease. Front Syst Neurosci,2013.7:95
8O'Neill, B., et al., Behavior of knock-in mice with a cocaine-insensitivedopamine transporter after virogenetic restoration of cocaine sensitivity inthe striatum. Neuropharmacology,2014.79:626-633
9Mogwitz, S., et al., Clinical pharmacology of dopamine-modulating agentsin Tourette's syndrome. Int Rev Neurobiol,2013.112:281-349
10Berger, B.,[Central dopaminergic pathways]. Rev Prat,1988.38(25Suppl):11-16
11Kritzer, M.F., Long-term gonadectomy affects the density of tyrosinehydroxylase-but not dopamine-beta-hydroxylase-, cholineacetyltransferase-or serotonin-immunoreactive axons in the medialprefrontal cortices of adult male rats. Cereb Cortex,2003.13(3):282-296
15Shen, H., et al., Methamphetamine potentiates behavioral andelectrochemical responses after mild traumatic brain injury in mice. BrainRes,2011.1368:248-253
16Wei, X.L., et al., Agmatine inhibits morphine-induced locomotionsensitization and morphine-induced changes in striatal dopamine andmetabolites in rats. Eur Neuropsychopharmacol,2007.17(12):790-799
17de Souza Silva, M.A., et al., Dopaminergic and serotonergic activity inneostriatum and nucleus accumbens enhanced by intranasal administrationof testosterone. Eur Neuropsychopharmacol,2009.19(1):53-63
18Chen, R., et al., The role of exogenous testosterone in cocaine-inducedbehavioral sensitization and plasmalemmal or vesicular dopamine uptakein castrated rats. Neurosci Lett,2003.351(3):161-164
19Thiblin, I., et al., Increased dopaminergic and5-hydroxytryptaminergicactivities in male rat brain following long-term treatment with anabolicandrogenic steroids. Br J Pharmacol,1999.126(6):1301-1306
20McEwen, B.S., Non-genomic and genomic effects of steroids on neuralactivity. Trends Pharmacol Sci,1991.12(4):141-147
21Kurling, S., et al., The effect of sub-chronic nandrolone decanoatetreatment on dopaminergic and serotonergic neuronal systems in the brainsof rats. Brain Res,2005.1044(1):67-75
22Johansson, P., et al., Anabolic androgenic steroids affects alcohol intake,defensive behaviors and brain opioid peptides in the rat. PharmacolBiochem Behav,2000.67(2):271-279
23Steensland, P., et al., Amphetamine-induced aggression is enhanced in ratspre-treated with the anabolic androgenic steroid nandrolone decanoate.Steroids,2005.70(3):199-204
24Janne, O.A., Androgen interaction through multiple steroid receptors.NIDA Res Monogr,1990.102:178-186
25Masonis, A.E. and M.P. McCarthy, Direct effects of theanabolic/androgenic steroids, stanozolol and17alpha-methyltestosterone,on benzodiazepine binding to the. gamma-aminobutyric acid(a) receptor.Neurosci Lett,1995.189(1):35-38
26Kailanto, S., A. Kankaanpaa, and T. Seppala, Subchronic steroidadministration induces long lasting changes in neurochemical andbehavioral response to cocaine in rats. Steroids,2011.76(12):1310-1306
1Morris, R.W., et al., The effect of gonadectomy on prepulse inhibition andfear-potentiated startle in adolescent rhesus macaques.Psychoneuroendocrinology,2010.35(6):896-905
2Abreu, P., et al., Reproductive hormones control striatal tyrosinehydroxylase activity in the male rat. Neurosci Lett,1988.95(1-3):213-217
3Rogeness, G.A., et al., Biochemical differences in children with conductdisorder socialized and undersocialized. Am J Psychiatry,1982.139(3):307-311
4Tunbridge, E.M., et al., Catechol-o-methyltransferase inhibition improvesset-shifting performance and elevates stimulated dopamine release in therat prefrontal cortex. J Neurosci,2004.24(23):5331-5335
5Finberg, J.P., Update on the pharmacology of selective inhibitors ofMAO-A and MAO-B: Focus on modulation of CNS monoamineneurotransmitter release. Pharmacol Ther,2014.24(23):5331-5335
6Green, A.R. and M.B. Youdim, Effects of monoamine oxidase inhibitionby clorgyline, deprenil or tranylcypromine on5-hydroxytryptamineconcentrations in rat brain and hyperactivity following subsequenttryptophan administration. Br J Pharmacol,1975.55(3):415-422
7Saura, J., et al., Quantitative enzyme radioautography with3H-Ro41-1049and3H-Ro19-6327in vitro: localization and abundance ofMAO-A and MAO-B in rat CNS, peripheral organs, and human brain. JNeurosci,1992.12(5):1977-1999
8Brunner, H.G., Monoamine oxidase and behaviour. Ann Med,1995.27(4):431-432
9Yu, Q., et al., Dopamine and serotonin signaling during two sensitivedevelopmental periods differentially impact adult aggressive and affectivebehaviors in mice. Mol Psychiatry,2014.55(3):415-422
10Kindlundh, A.M., et al., Dopaminergic effects after chronic treatment withnandrolone visualized in rat brain by positron emission tomography. ProgNeuropsychopharmacol Biol Psychiatry,2002.26(7-8):1303-1308
11Galineau, L., et al., Ontogeny of the dopamine and serotonin transportersin the rat brain: an autoradiographic study. Neurosci Lett,2004.363(3):266-271
12Lewis, D.A., et al., Dopamine transporter immunoreactivity in monkeycerebral cortex: regional, laminar, and ultrastructural localization. J CompNeurol,2001.432(1):119-136
13Thiblin, I., et al., Increased dopaminergic and5-hydroxytryptaminergicactivities in male rat brain following long-term treatment with anabolicandrogenic steroids. Br J Pharmacol,1999.126(6):1301-1306
14Jeong, H., et al., Regulation of the transcriptional activity of the tyrosinehydroxylase gene by androgen receptor. Neurosci Lett,2006.396(1): p.57-561
15Purves-Tyson, T.D., et al., Testosterone regulation of sex steroid-relatedmRNAs and dopamine-related mRNAs in adolescent male rat substantianigra. BMC Neurosci,2012.13:95
16Ou, X.M., K. Chen, and J.C. Shih, Glucocorticoid and androgen activationof monoamine oxidase A is regulated differently by R1and Sp1. J BiolChem,2006.281(30):21512-21525
17Shih, J.C., K. Chen, and M.J. Ridd, Monoamine oxidase: from genes tobehavior. Annu Rev Neurosci,1999.22:197-217
18Brunner, H.G., et al., Abnormal behavior associated with a point mutationin the structural gene for monoamine oxidase A. Science,1993.262(5133):578-580
19Grimsby, J., et al., Increased stress response and beta-phenylethylamine inMAOB-deficient mice. Nat Genet,1997.17(2):206-210
20Chen, K., et al., A spontaneous point mutation produces monoamineoxidase A/B knock-out mice with greatly elevated monoamines andanxiety-like behavior. J Biol Chem,2004.279(38):39645-39652
21Biederman, J., et al., Sexually dimorphic effects of four genes (COMT,SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: apreliminary study. Am J Med Genet B Neuropsychiatr Genet,2008.147B(8):1511-1518
22Harrison, P.J. and E.M. Tunbridge, Catechol-O-methyltransferase(COMT): a gene contributing to sex differences in brain function, and tosexual dimorphism in the predisposition to psychiatric disorders.Neuropsychopharmacology,2008.33(13):3037-3045
23Strous, R.D., et al., Lack of association of a functionalcatechol-O-methyltransferase gene polymorphism in schizophrenia. BiolPsychiatry,1997.41(4):493-495
24Waldmeier, P.C., Amine oxidases and their endogenous substrates (withspecial reference to monoamine oxidase and the brain). J Neural TransmSuppl,1987.23:55-572
25Oreland, L., Y. Arai, and A. Stenstrom, The effect of deprenyl (selegiline)on intra-and extraneuronal dopamine oxidation. Acta Neurol Scand Suppl,1983.95:81-85
26Garrett, M.C. and P. Soares-da-Silva, Role of type A and B monoamineoxidase on the formation of3,4-dihydroxyphenylacetic acid (DOPAC) intissues from the brain of the rat. Neuropharmacology,1990.29(10):875-879
27Birgner, C., et al., Reduced activity of monoamine oxidase in the rat brainfollowing repeated nandrolone decanoate administration. Brain Res,2008.1219:103-110
28Cruz-Muros I, Afonso-Oramas D, Abreu P, et al. Aging effects on thedopamine transporter expression and compensatory mechanisms [J].Neurobiol Aging,2009,30(6):973-986
29Hernandez, L., et al., Testosterone modulates mesolimbic dopaminergicactivity in male rats. Neurosci Lett,1994.171(1-2):172-174
30Schwartzer, J.J., L.A. Ricci, and R.H. Melloni, Jr., Interactions betweenthe dopaminergic and GABAergic neural systems in the lateral anteriorhypothalamus of aggressive AAS-treated hamsters. Behav Brain Res,2009.203(1):15-22
31Datla, K.P., et al., Differences in dopaminergic neuroprotective effects ofestrogen during estrous cycle. Neuroreport,2003.14(1):47-50
32Kindlundh, A.M., et al., Increased dopamine transporter density in themale rat brain following chronic nandrolone decanoate administration.Neurosci Lett,2004.356(2):131-134
33Yeh, C.B., et al., Evaluating dopamine transporter activity with99mTc-TRODAT-1SPECT in drug-naive Tourette's adults. Nucl MedCommun,2006.27(10):779-784
1Schumacher, M., et al., Steroid hormones and neurosteroids in normal andpathological aging of the nervous system. Prog Neurobiol,2003.71(1):23-29
2Saldanha, P.A., et al., Long-and short-term effects of androgens in humanumbilical artery smooth muscle. Clin Exp Pharmacol Physiol,2013.40(3):181-9
3O'Shaughnessy, P.J., et al., Identification of Leydig cell-specific mRNAtranscripts in the adult rat testis. Reproduction,2014.147(5):671-682
4Pfeiffer, C.A. and A. Kirschbaum, Secretion of Androgen by the SparrowOvary Following Stimulation with Pregnant Mare Serum. Yale J Biol Med,1941.13(3):315-322
5Parker, C.R., Jr., et al., Development of adrenal cortical zonation andexpression of key elements of adrenal androgen production in thechimpanzee (Pan troglodytes) from birth to adulthood. Mol CellEndocrinol,2014.387(1-2):35-43.
6Forest, M.G., Plasma androgens (testosterone and4-androstenedione) and17-hydroxyprogesterone in the neonatal, prepubertal and peripubertalperiods in the human and the rat: differences between species. J SteroidBiochem,1979.11(1B):543-548
7Magoffin, D.A. and G.F. Erickson, Mechanism by which17beta-estradiolinhibits ovarian androgen production in the rat. Endocrinology,1981.108(3):962-969
8Celotti, F., R.C. Melcangi, and L. Martini, The5alpha-reductase in thebrain: molecular aspects and relation to brain function. FrontNeuroendocrinol,1992.13(2):163-215
9Kritzer, M.F. and L.M. Creutz, Region and sex differences in constituentdopamine neurons and immunoreactivity for intracellular estrogen andandrogen receptors in mesocortical projections in rats. J Neurosci,2008.28(38):9525-9535
10Rommerts FFG. Testosterone:an overview of biosynthesis, transport,metabolism and action. In Nieschlag E and Berber HM.(eds.)Testosterone Action. Deficiency sub situation. Springer-verlag.1990,1-22
11Weisz, J. and I.L. Ward, Plasma testosterone and progesterone titers ofpregnant rats, their male and female fetuses, and neonatal offspring.Endocrinology,1980.106(1):306-316
12Vermeulen, A., Clinical review24: Androgens in the aging male. J ClinEndocrinol Metab,1991.73(2):221-224
13Morley, J.E., et al., Longitudinal changes in testosterone, luteinizinghormone, and follicle-stimulating hormone in healthy older men.Metabolism,1997.46(4):410-413
14De La Piedra, C., et al., Daily or monthly ibandronate prevents or restoresdeteriorations of bone mass, architecture, biomechanical properties andmarkers of bone turnover in androgen-deficient aged rats. Aging Male,2011.14(4):220-230
15Zumoff, B., et al., Twenty-four-hour mean plasma testosteroneconcentration declines with age in normal premenopausal women. J ClinEndocrinol Metab,1995.80(4):1429-1430
16Lacroix, C., et al., Simultaneous radioimmunoassay of progesterone,androst-4-enedione, pregnenolone, dehydroepiandrosterone and17-hydroxyprogesterone in specific regions of human brain. J SteroidBiochem,1987.28(3):317-325
17Yu, W.H. and M.Y. McGinnis, Androgen receptors in cranial nerve motornuclei of male and female rats. J Neurobiol,2001.46(1):1-10
18Behan, M. and C.F. Thomas, Sex hormone receptors are expressed inidentified respiratory motoneurons in male and female rats. Neuroscience,2005.130(3):725-734
19Tetzlaff, J., L. Tanzer, and K.J. Jones, Cellular localization of androgenand estrogen receptors in mouse-derived motoneuron hybrid cells andmouse facial motoneurons. Dev Neurobiol,2007.67(10):1362-1370
20La Spada, A.R., et al., Androgen receptor gene mutations in X-linkedspinal and bulbar muscular atrophy. Nature,1991.352(6330): p.77-79
21Hajszan, T., N.J. MacLusky, and C. Leranth, Role of androgens and theandrogen receptor in remodeling of spine synapses in limbic brain areas.Horm Behav,2008.53(5):638-646
22Creutz, L.M. and M.F. Kritzer, Mesostriatal and mesolimbic projections ofmidbrain neurons immunoreactive for estrogen receptor beta or androgenreceptors in rats. J Comp Neurol,2004.476(4):348-362
23Kritzer, M.F., Long-term gonadectomy affects the density of tyrosinehydroxylase-but not dopamine-beta-hydroxylase-, cholineacetyltransferase-or serotonin-immunoreactive axons in the medialprefrontal cortices of adult male rats. Cereb Cortex,2003.13(3):282-296
24Aubele, T. and M.F. Kritzer, Gonadectomy and hormone replacementaffects in vivo basal extracellular dopamine levels in the prefrontal cortexbut not motor cortex of adult male rats. Cereb Cortex,2011.21(1):222-232
25Hannan, C.J., Jr., et al., Psychological and serum homovanillic acidchanges in men administered androgenic steroids.Psychoneuroendocrinology,1991.16(4):335-343
26Nishizaki, Y.,[The effects of exogenous and endogenous dopamine on thegastric microcirculation and their action sites in rat stomach]. NihonShokakibyo Gakkai Zasshi,1993.90(8):1639-1651
27Thiblin, I., et al., Increased dopaminergic and5-hydroxytryptaminergicactivities in male rat brain following long-term treatment with anabolicandrogenic steroids. Br J Pharmacol,1999.126(6):1301-1306
28De Vries, G.J. and G.C. Panzica, Sexual differentiation of centralvasopressin and vasotocin systems in vertebrates: different mechanisms,similar endpoints. Neuroscience,2006.138(3):947-955
29Karatsoreos, I.N., et al., A role for androgens in regulating circadianbehavior and the suprachiasmatic nucleus. Endocrinology,2007.148(11):5487-5495
30Simerly, R.B., et al., Influence of perinatal androgen on the sexuallydimorphic distribution of tyrosine hydroxylase-immunoreactive cells andfibers in the anteroventral periventricular nucleus of the rat.Neuroendocrinology,1985.40(6):501-510
31Chen, R., et al., The role of exogenous testosterone in cocaine-inducedbehavioral sensitization and plasmalemmal or vesicular dopamine uptakein castrated rats. Neurosci Lett,2003.351(3):161-164
32Bhatt, S.D. and D.E. Dluzen, Dopamine transporter function differencesbetween male and female CD-1mice. Brain Res,2005.1035(2):188-195.
33Battaner, E., et al., Gonadal influences on spinal cord and brainmonoamines in male rats. Brain Res,1987.425(2):391-394
34Johnson, A.E., et al., Testosterone modulates oxytocin binding in thehypothalamus of castrated male rats. Neuroendocrinology,1989.50(2):199-203
35Aubele, T. and M.F. Kritzer, Androgen influence on prefrontal dopaminesystems in adult male rats: localization of cognate intracellular receptorsin medial prefrontal projections to the ventral tegmental area and effects ofgonadectomy and hormone replacement on glutamate-stimulatedextracellular dopamine level. Cereb Cortex,2012.22(8):1799-1812
36Galea, L.A., et al., Sex, hormones and neurogenesis in the hippocampus:hormonal modulation of neurogenesis and potential functionalimplications. J Neuroendocrinol,2013.25(11):1039-1061
37Mahesh, V.B. and S.J. Nazian, Role of sex steroids in the initiation ofpuberty. J Steroid Biochem,1979.11(1B):587-591
38Dakin, C.L., et al., Neonatal stimulation of5-HT(2) receptors reducesandrogen receptor expression in the rat anteroventral periventricularnucleus and sexually dimorphic preoptic area. Eur J Neurosci,2008.27(9):2473-2480
39Malsbury, C.W. and K. McKay, Neurotrophic effects of testosterone on themedial nucleus of the amygdala in adult male rats. J Neuroendocrinol,1994.6(1):57-69
40Butler, R., P.N. Leigh, and J.M. Gallo, Androgen-induced up-regulation oftubulin isoforms in neuroblastoma cells. J Neurochem,2001.78(4):854-861
41Durham, H.D., S. Dahrouge, and N.R. Cashman, Evaluation of the spinalcord neuron X neuroblastoma hybrid cell line NSC-34as a model forneurotoxicity testing. Neurotoxicology,1993.14(4): p.387-395
42Cashman, N.R., et al., Neuroblastoma x spinal cord (NSC) hybrid celllines resemble developing motor neurons. Dev Dyn,1992.194(3):209-221
43Marron, T.U., et al., Androgen-induced neurite outgrowth is mediated byneuritin in motor neurones. J Neurochem,2005.92(1):10-20
44Pappas, S.S., et al., Neonatal androgen-dependent sex differences inlumbar spinal cord dopamine concentrations and the number of A11diencephalospinal dopamine neurons. J Comp Neurol,2010.518(13):2423-236
45Beyer, C., S.J. Green, and J.B. Hutchison, Androgens influence sexualdifferentiation of embryonic mouse hypothalamic aromatase neurons invitro. Endocrinology,1994.135(3):1220-1226
46Williams, M.R., et al., Neuropathological changes in the substantia nigrain schizophrenia but not depression. Eur Arch Psychiatry Clin Neurosci,2013.135(3):1220-1226
47Frye, C.A., K. Edinger, and K. Sumida, Androgen administration to agedmale mice increases anti-anxiety behavior and enhances cognitiveperformance. Neuropsychopharmacology,2008.33(5):1049-1061
48Parrilla-Carrero, J., et al., The anabolic steroids testosterone propionateand nandrolone, but not17alpha-methyltestosterone, induce conditionedplace preference in adult mice. Drug Alcohol Depend,2009.100(1-2):122-127
49Egashira, N., et al., Depression-like behavior and reduced plasmatestosterone levels in the senescence-accelerated mouse. Behav Brain Res,2010.209(1):142-147
50Sanders, D.C., The Bethlem lines: genetic selection for high and lowrearing activity in rats. Behav Genet,1981.11(5):491-503
51Casarrubea, M., F. Sorbera, and G. Crescimanno, Multivariate analysis ofthe modifications induced by an environmental acoustic cue on ratexploratory behavior. Physiol Behav,2008.93(4-5):687-696
52Kalueff, A.V., et al., Analyzing grooming microstructure inneurobehavioral experiments. Nat Protoc,2007.2(10):2538-44
53Kalueff, A.V. and P. Tuohimaa, Contrasting grooming phenotypes in threemouse strains markedly different in anxiety and activity (129S1, BALB/cand NMRI). Behav Brain Res,2005.160(1):1-10
54Olivares, E.L., et al., Administration of an anabolic steroid during theadolescent phase changes the behavior, cardiac autonomic balance andfluid intake in male adult rats. Physiol Behav,2014.126:15-24
55Schwartzer, J.J. and R.H. Melloni, Jr., Dopamine activity in the lateralanterior hypothalamus modulates AAS-induced aggression through D2butnot D5receptors. Behav Neurosci,2010.124(5):645-655
56Khakpai, F., The effect of opiodergic system and testosterone on anxietybehavior in gonadectomized rats. Behav Brain Res,2014.263:9-15.
57Aikey, J.L., et al., Testosterone rapidly reduces anxiety in male house mice(Mus musculus). Horm Behav,2002.42(4):448-460
58Kailanto, S., A. Kankaanpaa, and T. Seppala, Subchronic steroidadministration induces long lasting changes in neurochemical andbehavioral response to cocaine in rats. Steroids,2011.76(12):1310-1316
59Scerbo, A.S. and D.J. Kolko, Salivary testosterone and cortisol indisruptive children: relationship to aggressive, hyperactive, andinternalizing behaviors. J Am Acad Child Adolesc Psychiatry,1994.33(8):1174-1184
60Dela Cruz, C. and O.C. Pereira, Prenatal testosterone supplementationalters puberty onset, aggressive behavior, and partner preference in adultmale rats. J Physiol Sci,2012.62(2):123-131
61Hodosy, J., et al., The anxiolytic effect of testosterone in the rat ismediated via the androgen receptor. Pharmacol Biochem Behav,2012.102(2):191-195
62Gerard, E. and B.S. Peterson, Developmental processes and brain imagingstudies in Tourette syndrome. J Psychosom Res,2003.55(1):13-22
63Bingham, B., et al., Postnatal blockade of androgen receptors or aromataseimpair the expression of stress hypothalamic-pituitary-adrenal axishabituation in adult male rats. Psychoneuroendocrinology,2011.36(2):249-257
64Ravizza, T., J. Veliskova, and S.L. Moshe, Testosterone regulatesandrogen and estrogen receptor immunoreactivity in rat substantia nigrapars reticulata. Neurosci Lett,2003.338(1):57-61
65Stanton, S.J., S.H. Liening, and O.C. Schultheiss, Testosterone ispositively associated with risk taking in the Iowa Gambling Task. HormBehav,2011.59(2):252-256
66Welling, L.L., et al., Men report stronger attraction to femininity inwomen's faces when their testosterone levels are high. Horm Behav,2008.54(5):703-708
67Smith, J.T., et al., Differential regulation of KiSS-1mRNA expression bysex steroids in the brain of the male mouse. Endocrinology,2005.146(7):2976-2984
68Poletti, A., et al., Steroid binding and metabolism in the luteinizinghormone-releasing hormone-producing neuronal cell line GT1-1.Endocrinology,1994.135(6):2623-2628
69Pinter, O., et al., Seasonal changes in courtship behavior, plasma androgenlevels and in hypothalamic aromatase immunoreactivity in malefree-living European starlings (Sturnus vulgaris). Gen Comp Endocrinol,2011.172(1):151-157
70Wood, R.I. and S.W. Newman, Integration of chemosensory and hormonalcues is essential for mating in the male Syrian hamster. J Neurosci,1995.15(11):7261-7269
71Alekseyenko, O.V., M.J. Baum, and J.A. Cherry, Sex and gonadal steroidmodulation of pheromone receptor gene expression in the mousevomeronasal organ. Neuroscience,2006.140(4):1349-1357
72Hugdahl, K., T. Thomsen, and L. Ersland, Sex differences in visuo-spatialprocessing: an fMRI study of mental rotation. Neuropsychologia,2006.44(9):1575-1583
73Jia, J., et al., Amelioratory effects of testosterone treatment on cognitiveperformance deficits induced by soluble Abeta1-42oligomers injected intothe hippocampus. Horm Behav,2013.64(3):477-486
74O'Connor, D.B., et al., Activational effects of testosterone on cognitivefunction in men. Neuropsychologia,2001.39(13):1385-1394
75Maheu, F.S., et al., Steroid abnormalities and the developing brain:declarative memory for emotionally arousing and neutral material inchildren with congenital adrenal hyperplasia. Psychoneuroendocrinology,2008.33(2):238-245
76Celec, P., et al., The circalunar cycle of salivary testosterone and thevisual-spatial performance. Bratisl Lek Listy,2002.103(2):59-69
77van Honk, J., et al., Testosterone administration impairs cognitive empathyin women depending on second-to-fourth digit ratio. Proc Natl Acad Sci US A,2011.108(8):3448-3452
78Gomez-Gil, E., et al., Androgen treatment effects on memory infemale-to-male transsexuals. Psychoneuroendocrinology,2009.34(1):110-117
79Martin, D.M., N.R. Burns, and G. Wittert, Free testosterone levels,attentional control, and processing speed performance in aging men.Neuropsychology,2009.23(2):158-167
80Hogervorst, E., M. Combrinck, and A.D. Smith, Testosterone andgonadotropin levels in men with dementia. Neuro Endocrinol Lett,2003.24(3-4):203-208
81Schulz, K. and V. Korz, Hippocampal testosterone relates to referencememory performance and synaptic plasticity in male rats. Front BehavNeurosci,2010.4:187
82Naghdi, N., N. Nafisy, and N. Majlessi, The effects of intrahippocampaltestosterone and flutamide on spatial localization in the Morris water maze.Brain Res,2001.897(1-2):44-51
83Soreide, J.A., et al., Androgen receptors in operable breast cancer: relationto other steroid hormone receptors, correlations to prognostic factors andpredictive value for effect of adjuvant tamoxifen treatment. Eur J SurgOncol,1992.18(2):112-118
84Wilson, C.M. and M.J. McPhaul, A and B forms of the androgen receptorare present in human genital skin fibroblasts. Proc Natl Acad Sci U S A,1994.91(4):1234-1238
85Chang, C.S., J. Kokontis, and S.T. Liao, Molecular cloning of human andrat complementary DNA encoding androgen receptors. Science,1988.240(4850):324-326
86Kumar, R., B.H. Johnson, and E.B. Thompson, Overview of the structuralbasis for transcription regulation by nuclear hormone receptors. EssaysBiochem,2004.40:27-39
87Matias, P.M., et al., Structural evidence for ligand specificity in thebinding domain of the human androgen receptor. Implications forpathogenic gene mutations. J Biol Chem,2000.275(34):26164-26171
88Sack, J.S., et al., Crystallographic structures of the ligand-binding domainsof the androgen receptor and its T877A mutant complexed with the naturalagonist dihydrotestosterone. Proc Natl Acad Sci U S A,2001.98(9):4904-4909
89Kawashima, H., et al., A novel steroid receptor co-activator protein (SRAP)as an alternative form of steroid receptor RNA-activator gene: expressionin prostate cancer cells and enhancement of androgen receptor activity.Biochem J,2003.369(Pt1):163-171
90Cutress, M.L., et al., Structural basis for the nuclear import of the humanandrogen receptor. J Cell Sci,2008.121(Pt7):957-968
91Cato, A.C., D. Henderson, and H. Ponta, The hormone response elementof the mouse mammary tumour virus DNA mediates the progestin andandrogen induction of transcription in the proviral long terminal repeatregion. EMBO J,1987.6(2):363-368
92He, B., et al., Activation function2in the human androgen receptor ligandbinding domain mediates interdomain communication with theNH(2)-terminal domain. J Biol Chem,1999.274(52):37219-37225
93Loy, C.J., K.S. Sim, and E.L. Yong, Filamin-A fragment localizes to thenucleus to regulate androgen receptor and coactivator functions. Proc NatlAcad Sci U S A,2003.100(8):4562-4567
94Liao, G., et al., Regulation of androgen receptor activity by the nuclearreceptor corepressor SMRT. J Biol Chem,2003.278(7):5052-5061
95He, B., et al., Dependence of selective gene activation on the androgenreceptor NH2-and COOH-terminal interaction. J Biol Chem,2002.277(28):25631-25639
96Schaufele, F., et al., The structural basis of androgen receptor activation:intramolecular and intermolecular amino-carboxy interactions. Proc NatlAcad Sci U S A,2005.102(28):9802-9807
97Rahman, M.A., et al., Separation of zinc compounds by sequential metalvapor elution analysis with atomic absorption detection. Talanta,2004.64(4):989-992
98Lee, Y.F., et al., Convergence of two repressors through heterodimerformation of androgen receptor and testicular orphan receptor-4: a uniquesignaling pathway in the steroid receptor superfamily. Proc Natl Acad SciU S A,1999.96(26):14724-14729
99Zhou, Z.X., et al., A ligand-dependent bipartite nuclear targeting signal inthe human androgen receptor. Requirement for the DNA-binding domainand modulation by NH2-terminal and carboxyl-terminal sequences. J BiolChem,1994.269(18):13115-13123
100Cao, X., et al., Regulator of G-protein signaling2(RGS2) inhibitsandrogen-independent activation of androgen receptor in prostate cancercells. Oncogene,2006.25(26):3719-3734
101Manin, M., et al., Androgen receptor expression is regulated by thephosphoinositide3-kinase/Akt pathway in normal and tumoral epithelialcells. Biochem J,2002.366(Pt3):729-736
102Scheid, M.P. and J.R. Woodgett, PKB/AKT: functional insights fromgenetic models. Nat Rev Mol Cell Biol,2001.2(10):760-768
103Gioeli, D., et al., Androgen receptor phosphorylation. Regulation andidentification of the phosphorylation sites. J Biol Chem,2002.277(32):29304-29314
104Rochette-Egly, C., Nuclear receptors: integration of multiple signallingpathways through phosphorylation. Cell Signal,2003.15(4):355-366
105Kritzer, M.F., Selective colocalization of immunoreactivity forintracellular gonadal hormone receptors and tyrosine hydroxylase in theventral tegmental area, substantia nigra, and retrorubral fields in the rat. JComp Neurol,1997.379(2):247-260
106Powell, S.M., et al., Mechanisms of androgen receptor signalling viasteroid receptor coactivator-1in prostate. Endocr Relat Cancer,2004.11(1):117-130
107Klokk, T.I., et al., Ligand-specific dynamics of the androgen receptor at itsresponse element in living cells. Mol Cell Biol,2007.27(5):1823-1843
108Galineau, L., et al., Ontogeny of the dopamine and serotonin transportersin the rat brain: an autoradiographic study. Neuroscience Letters,2004.363(3):266-271
109Gaughan, L., et al., Regulation of androgen receptor and histonedeacetylase1by Mdm2-mediated ubiquitylation. Nucleic Acids Res,2005.33(1):13-26
110Lee, D.K. and C. Chang, Endocrine mechanisms of disease: Expressionand degradation of androgen receptor: mechanism and clinical implication.J Clin Endocrinol Metab,2003.88(9):4043-4054
111Foradori, C.D., M.J. Weiser, and R.J. Handa, Non-genomic actions ofandrogens. Front Neuroendocrinol,2008.29(2):169-181
112Baron, S., et al., Androgen receptor mediates non-genomic activation ofphosphatidylinositol3-OH kinase in androgen-sensitive epithelial cells. JBiol Chem,2004.279(15):14579-14586
113Bennett, N.C., et al., Molecular cell biology of androgen receptorsignalling. Int J Biochem Cell Biol,2010.42(6):813-827
114Okamoto, T., et al., Caveolins, a family of scaffolding proteins fororganizing "preassembled signaling complexes" at the plasma membrane.J Biol Chem,1998.273(10):5419-5422
115Finley, S.K. and M.F. Kritzer, Immunoreactivity for intracellular androgenreceptors in identified subpopulations of neurons, astrocytes andoligodendrocytes in primate prefrontal cortex. J Neurobiol,1999.40(4):446-457
116Balthazart, J., et al., Distribution of androgen receptor-immunoreactivecells in the quail forebrain and their relationship with aromataseimmunoreactivity. J Neurobiol,1998.35(3):323-340
117Wood, R.I. and S.W. Newman, Androgen receptor immunoreactivity in themale and female Syrian hamster brain. J Neurobiol,1999.39(3):359-370.
118Yi, P., et al., Peptidyl-prolyl isomerase1(Pin1) serves as a coactivator ofsteroid receptor by regulating the activity of phosphorylated steroidreceptor coactivator3(SRC-3/AIB1). Mol Cell Biol,2005.25(21):9687-9699
119Lumbroso, S., et al., Immunohistochemical localization andimmunoblotting of androgen receptor in spinal neurons of male andfemale rats. Eur J Endocrinol,1996.134(5):626-632
120Yu, W.H. and M.Y. McGinnis, Androgen receptor levels in cranial nervenuclei and tongue muscles in rats. J Neurosci,1986.6(5):1302-1307
121Drengler, S.M., R.J. Handa, and K.J. Jones, Regulation of androgenreceptor mRNA expression in hamster facial motoneurons: differentialeffects of non-aromatizable and aromatizable androgens. Brain Res MolBrain Res,1996.41(1-2):8-15
122Choate, J.V., O.D. Slayden, and J.A. Resko, Immunocytochemicallocalization of androgen receptors in brains of developing and adult malerhesus monkeys. Endocrine,1998.8(1):51-60
123Taneja, S.S., et al., Cell-specific regulation of androgen receptorphosphorylation in vivo. J Biol Chem,2005.280(49):40916-40924
124Yang, C.S., et al., Simian virus40small t antigen mediatesconformation-dependent transfer of protein phosphatase2A onto theandrogen receptor. Mol Cell Biol,2005.25(4):1298-12308
125Guo, Z., et al., Regulation of androgen receptor activity by tyrosinephosphorylation. Cancer Cell,2006.10(4):309-319
126Kraus, S., et al., Receptor for activated C kinase1(RACK1) and Srcregulate the tyrosine phosphorylation and function of the androgenreceptor. Cancer Res,2006.66(22):11047-11054
127Mellinghoff, I.K., et al., HER2/neu kinase-dependent modulation ofandrogen receptor function through effects on DNA binding and stability.Cancer Cell,2004.6(5):517-527
128Chen, S., et al., Androgen receptor serine81phosphorylation mediateschromatin binding and transcriptional activation. J Biol Chem,2012.287(11):8571-8583
129Gordon, V., et al., CDK9regulates AR promoter selectivity and cellgrowth through serine81phosphorylation. Mol Endocrinol,2010.24(12):2267-2280
130Palazzolo, I., et al., Akt blocks ligand binding and protects againstexpanded polyglutamine androgen receptor toxicity. Hum Mol Genet,2007.16(13):1593-1603
131Kasina, S. and J.A. Macoska, The CXCL12/CXCR4axis promotesligand-independent activation of the androgen receptor. Mol CellEndocrinol,2012.351(2):249-263
132Varisli, L., et al., Androgen regulated HN1leads proteosomal degradationof androgen receptor (AR) and negatively influences AR mediatedtransactivation in prostate cells. Mol Cell Endocrinol,2012.350(1):107-117
133Lin, H.K., et al., Akt suppresses androgen-induced apoptosis byphosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U SA,2001.98(13):7200-7205
134Linn, D.E., et al., Differential regulation of androgen receptor by PIM-1kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3ligases. J Biol Chem,2012.287(27):22959-22968
135Xu, K., et al., Regulation of androgen receptor transcriptional activity andspecificity by RNF6-induced ubiquitination. Cancer Cell,2009.15(4):270-282
136Bubulya, A., et al., c-Jun potentiates the functional interaction between theamino and carboxyl termini of the androgen receptor. J Biol Chem,2001.276(48):44704-44711
137Chi, Y., et al., Thr-370is responsible for CDK11(p58)autophosphorylation, dimerization, and kinase activity. J Biol Chem,2011.286(3):1748-1757
138Zong, H., et al., Cyclin D3/CDK11p58complex is involved in therepression of androgen receptor. Mol Cell Biol,2007.27(20):7125-7142
139Sulzer, D., Multiple hit hypotheses for dopamine neuron loss inParkinson's disease. Trends Neurosci,2007.30(5):244-250
140Jacobs, F.M., et al., Retinoic acid-dependent and-independentgene-regulatory pathways of Pitx3in meso-diencephalic dopaminergicneurons. Development,2011.138(23):5213-5222
141Smidt, M.P. and J.P. Burbach, How to make a mesodiencephalicdopaminergic neuron. Nat Rev Neurosci,2007.8(1):21-32
142Verney, C., et al., Postnatal sequential development of dopaminergic andenkephalinergic perineuronal formations in the lateral septal nucleus of therat correlated with local neuronal maturation. Anat Embryol (Berl),1987.176(4):463-475
143Ratzka, A., et al., Fibroblast growth factor2regulates dopaminergicneuron development in vivo. J Neurochem,2012.122(1):94-105
144Coulter, C.L., H.K. Happe, and L.C. Murrin, Postnatal development of thedopamine transporter: a quantitative autoradiographic study. Brain ResDev Brain Res,1996.92(2):172-181
145Meng, S.Z., et al., Developmental and age-related changes of dopaminetransporter, and dopamine D1and D2receptors in human basal ganglia.Brain Res,1999.843(1-2):136-144
146Fasano, C., et al., Dopamine facilitates dendritic spine formation bycultured striatal medium spiny neurons through both D1and D2dopaminereceptors. Neuropharmacology,2013.67:432-443
147Grey, C.L. and J.P. Chang, Differential modulation of ghrelin-induced GHand LH release by PACAP anddopamine in goldfish pituitary cells. GenComp Endocrinol,2013.191:215-224
148Hauber, W. and S. Lutz, Blockade of dopamine D2, but not of D1receptors in the rat globus pallidus induced Fos-like immunoreactivity inthe caudate-putamen, substantia nigra and entopeduncular nucleus.Neurosci Lett,1999.271(2):73-76
149Pirot, S., J. Glowinski, and A.M. Thierry, Mediodorsal thalamic evokedresponses in the rat prefrontal cortex: influence of the mesocortical DAsystem. Neuroreport,1996.7(8):1437-1441
150Houk JC, Davis JL, Beiser DG, et al. Models of Information Processing inthe Basal Ganglia. Cambridge, Mass: MIT Press;1995.271(2):73-76
151Grey, C.L. and J.P. Chang, Differential modulation of ghrelin-induced GHand LH release by PACAP and dopamine in goldfish pituitary cells. GenComp Endocrinol,2013.191:215-224
152Aimone, L.D. and G.F. Gebhart, Spinal monoamine mediation of
stimulation-produced antinociception from the lateral hypothalamus. Brain
Res,1987.403(2):290-300