酒精依赖和戒断时大鼠伏隔核、杏仁核区内神经甾体水平的变化

目的:采用♂大鼠酒精依赖模型,观察酒精依赖及戒断对大鼠伏隔核、杏仁核中不同神经甾体水平的影响。方法:通过大鼠自由饮含6%的乙醇溶液,连续42d使大鼠形成酒精依赖,并撤除酒精使其自然戒断。断头取脑分离取出伏隔核、杏仁核脑区。使用液液萃取和固相萃取两步法提取脑组织中的孕烯醇酮(PREG)、脱氢表雄酮(DHEA)、别孕烯醇酮(AP)、脱氢表雄酮硫酸酯(DHEAS)、孕烯醇酮硫酸酯(PREGS),以高效液相色谱-质谱联用法测定神经甾体含量。结果:与对照组相比,酒精依赖大鼠伏隔核DHEA,PREG,AP,DHEAS,PREGS的水平显著降低(P<0.05),杏仁核AP,PREGS的水平显著降低(P<0.05);酒精戒断6h大鼠伏隔核DHEA,DHEAS,PREGS的水平显著降低(P<0.05),杏仁核PREGS的水平显著降低(P<0.05);酒精戒断24h大鼠杏仁核DHEA的水平显著上升(P<0.05),伏隔核、杏仁核DHEAS、PREGS的水平显著下降(P<0.01)。结论:酒精依赖形成和戒断对伏隔核、杏仁核中的神经甾体水平有不同的影响,具有区域特异性。     

吗啡依赖大鼠纹状体内神经甾体水平的变化

目的:探讨吗啡躯体依赖、精神依赖和戒断对♂大鼠纹状体内神经甾体水平的影响。方法:高效液相色谱-质谱法测定大鼠纹状体和血浆中脱氢表雄酮(DHEA)及其硫酸酯(DHEAS)、孕烯醇酮(PREG)及其硫酸酯(PREGS)和别孕烯醇酮(AP)的含量。结果:(1)与纳洛酮对照组比较,纳洛酮催促吗啡戒断大鼠的纹状体内PREG的含量显著升高(P<0.01);血浆中PREG、AP、DHEAS和PREGS的含量显著升高(P<0.01),而DHEA的含量显著降低(P<0.01);(2)与生理盐水对照组比较,吗啡精神依赖大鼠的纹状体内DHEA和PREG的含量显著升高(P<0.01),血浆中DHEA的水平显著降低(P<0.01)。结论:慢性吗啡处理可影响大鼠纹状体内某些神经甾体的水平,表明神经甾体可能参与吗啡依赖的形成。     

谷氨酸和γ-氨基丁酸对原代培养星形胶质细胞神经甾体合成释放的影响

目的研究氨基酸类神经递质对原代培养大鼠大脑皮质星形胶质细胞神经甾体合成释放的影响。方法采用原代培养的大鼠大脑皮质星形胶质细胞,分别加入不同浓度的谷氨酸和γ-氨基丁酸处理48h;采用固相萃取结合高效液相色谱质-谱联用分析方法提取分离和测定细胞培养液中游离型(脱氢表雄酮,DHEA;孕烯醇酮,PREG;别孕烯醇酮,AP)及结合型神经甾体(脱氢表雄酮硫酸酯,DHEAS;孕烯醇酮硫酸酯,PREGS)。结果与生理盐水对照组比较,谷氨酸处理使PREG和PREGS水平明显下降,DHEAS水平明显升高;γ-氨基丁酸处理使PREG水平明显降低,AP水平增加。结论谷氨酸和γ-氨基丁酸两种神经递质对原代培养的星形胶质细胞PREG合成释放均呈抑制作用;谷氨酸对DHE-AS、γ-氨基丁酸对AP的合成释放分别呈现明显促进作用;高剂量的谷氨酸还可以抑制PRGES的合成和释放。     

吗啡依赖对大鼠不同脑区内神经甾体水平的影响

目的建立大鼠条件性位置偏爱(CPP)模型，探讨吗啡精神依赖对大鼠脑内神经甾体水平的影响。方法 大鼠连续10 d腹腔注射吗啡5 mg·kg^-1，诱导CPP形成。高效液相色谱-质谱法测定大鼠伏隔核、杏仁核、下丘脑和血浆中脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯及孕烯醇酮硫酸酯的含量。结果经10 d吗啡训练后，吗啡组大鼠在伴药侧的停留时间显著长于对照组，吗啡诱导的大鼠CPP形成。与对照组相比，吗啡组大鼠下丘脑内孕烯醇酮明显降低，伏隔核和血浆中的脱氢表雄酮明显降低。结论吗啡诱导CPP形成，吗啡处理影响大鼠脑内某些神经甾体的水平，表明内源性神经甾体可能参与吗啡依赖的形成。     

吗啡依赖和复吸时大鼠脑内神经甾体水平的变化

目的探讨吗啡精神依赖和复吸对大鼠脑内神经甾体水平的影响。方法采用条件性位置偏爱(CPP)实验,吗啡诱导大鼠CPP形成,足底电击应激诱发CPP重建,高效液相色谱-质谱法测定大鼠额叶皮质、海马及血浆中孕烯醇酮(PREG)及其硫酸酯(PREGS)、别孕烯醇酮(AP)、脱氢表雄酮(DHEA)及其硫酸酯(DHEAS)的含量。结果5 mg.kg-1吗啡训练10 d诱导大鼠产生了稳定的CPP,间歇足底电击有效诱发CPP的重建。与对照组比较,吗啡CPP形成时,大鼠额叶皮质内DHEA、PREG水平升高(P<0.05),海马内DHEA水平降低(P<0.05);与吗啡消退组比较,足底电击诱发CPP重现时,大鼠额叶皮质内PREG水平降低(P<0.01),而海马内PREG水平升高(P<0.05)。结论大鼠额叶皮质和海马内神经甾体水平的变化可能与吗啡依赖和复吸有关。     

The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5beta-tetrahydrodeoxycorticosterone (5beta-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl-D-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5beta-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5beta-THDOC), or antagonistic way (PS, DHEAS), the GABA(A) receptor complex functions. Some of them (5beta-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.     

吗啡对原代培养大鼠皮质神经元神经甾体水平的影响

目的探讨吗啡慢性处理对大鼠大脑皮质神经元合成释放神经甾体水平的影响及其机制。方法建立原代培养大鼠大脑皮质神经元吗啡依赖样模型,固相萃取结合高效液相色谱-质谱联用法测定细胞培养液中神经甾体水平;免疫印迹法检测神经元中p-CREB水平。结果与盐水对照组相比,吗啡(1μmol.L-1)处理使PREG和DS的水平降低(P<0.01);μ-受体激动剂DAMGO使PREG、DS和PS水平下降,AP水平增高;与吗啡单独处理组相比,μ-阿片受体拮抗剂CTAP与吗啡联合处理使PREG增加(P<0.01)。与盐水对照组相比,吗啡或DAMGO慢性处理均可增加神经元内p-CREB的水平(P<0.01);与吗啡处理组相比,CTAP抑制吗啡诱导的p-CREB的增加。结论μ-阿片受体参与了介导吗啡慢性处理对皮质神经元神经甾体合成释放的影响;神经元内p-CREB水平的变化反映了吗啡引起的神经元适应性改变,提示神经甾体水平的变化可能与吗啡依赖有关。     

吗啡急性给药对大鼠伏隔核中神经甾体水平的影响

目的:观察吗啡急性给药后大鼠伏隔核中神经甾体水平的变化.方法:给3组大鼠腹腔分别注射0.5、5和20 mg/kg的盐酸吗啡,分别于给药后0.5和2 h将大鼠断头处死,分离伏隔核.经液-液萃取和固相萃取法提取脱氢表雄酮、孕烯醇酮和别孕烯醇酮,并采用高效液相色谱-质谱系统检测其含量.结果:与对照组比较,0.5 mg/kg剂量的吗啡使大鼠伏隔核中脱氢表雄酮水平显著降低,而5 mg/kg剂量的吗啡则使脱氢表雄酮水平显著升高;20 mg/kg剂量的吗啡使大鼠血浆中的别孕烯醇酮水平显著升高.结论:大鼠伏隔核中的脱氢表雄酮可能在吗啡急性给药的效应中发挥重要作用.     

Effects of sigma(1) receptor agonist SA4503 and neuroactive steroids on performance in a radial arm maze task in rats

This study examined the effects of sigma(1) receptor agonist SA4503 and neuroactive steroids dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate (PREGS) and progesterone (PROG) on spatial working and reference memory in a radial arm maze task in rats. The insertion of a 6-min delay between the 2nd and 3rd choices caused a specific decline in working memory, but had no effect on reference memory. This decline in working memory was improved by SA4503, but not by DHEAS, PREGS or PROG. A non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine significantly impaired both working and reference memory in the presence or absence of a delay. The dizocilpine-induced impairments in the presence of a 6-min delay were ameliorated by SA4503, DHEAS and PREGS, whereas PROG had no effect. The beneficial effects of SA4503, DHEAS and PREGS were antagonized by treatment with sigma(1) receptor antagonist N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-ethylamine hydrochloride (NE-100). Furthermore, PROG attenuated the ameliorating effects of SA4503, DHEAS and PREGS on dizocilpine-induced memory deficits. These results suggest that sigma(1) receptors play a significant role in short-term working memory. Furthermore, it is suggested that DHEAS and PREGS ameliorate dizocilpine-induced memory impairments by acting as sigma(1) receptor agonists, while PROG antagonizes their effects by acting as a sigma(1) receptor antagonist.     

Subunit-specific modulation of glycine receptors by neurosteroids

The effects of pregnene and androstane steroids were studied on recombinant human glycine receptors (GlyRs) by whole-cell voltage-clamp electrophysiology. The 3beta-sulphates of pregnenolone (PREGS) and dehydroepiandrosterone (DHEAS) inhibited GlyR currents with K(I) values of 2-20 microM for different (alpha(1), alpha(2), alpha(4) and beta) GlyR subunits. PREGS resulted in a parallel shift of the response curve of glycine for alpha(1) GlyRs. The inhibitory potencies of DHEAS relative to PREGS were decreased in transition from embryonic alpha(2) towards adult alpha(1)beta GlyRs. A decreased potency of DHEAS for alpha(4) versus alpha(2) GlyRs represents the first pharmacological difference reported between these subunits. A negative charge at C3 is required for GlyR antagonism but androsterone sulphate epimers at C3 inhibited without stereoselectivity. Some point mutations of alpha(1) GlyRs with characteristic functional consequences did not significantly affect the inhibitory potency of PREGS. Progesterone selectively inhibited alpha(2) GlyRs, while PREG and its acetic ester potentiated alpha(1) GlyRs. Coexpression of the alpha subunits with the beta subunit eliminated the enhancing effects of PREG and attenuated the inhibitory potencies of the neurosteroids. Based on these data we propose that neurosteroids might modulate perinatal GlyR activity and thereby influence neuronal development.     

Neurosteroids ameliorate conditioned fear stress: an association with sigma receptors.

Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; 10-50 mg/kg, s.c.), and by a putative sigma(1) receptor agonist, (+)-N-allylnormetazocine ((+)-SKF-10,047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 10-50 mg/kg, s.c. ) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and (+)-SKF-10,047 (6 mg/kg, s.c.) were reversed by NE-100 (5 mg/kg, i.p.), a sigma(1) receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with (+)-SKF-10,047 (3 mg/kg) at doses that do not affect the conditioned fear stress response by themselves, motor suppression was significantly attenuated. In mice showing the conditioned fear stress response, the serum concentration of DHEAS was lower than that in non-shocked mice. These results suggest that the attenuating effects of DHEAS and PREGS on the conditioned fear stress response are mediated via sigma(1) receptors and that PROG has a sigma(1) receptor antagonistic property. Further, the endogenous DHEAS may be involved in the expression of conditioned fear stress response in mice.     

Aβ_(25-35)对大鼠大脑皮质神经元神经甾体水平的影响

目的研究Aβ25-35对大鼠大脑皮质神经元合成神经甾体的影响。方法采用Aβ25-35(1μmol·L-1)处理原代培养的大鼠大脑皮质神经元,固相萃取结合高效液相色谱-质谱联用法测定细胞培养液中神经甾体的浓度,四甲基偶氮唑(MTT)法检测细胞活性。结果与对照组相比,Aβ25-35处理后神经元存活率降低约50%(P<0.01),胆固醇处理组神经元存活率未见改变(P>0.05),但Aβ+胆固醇组的神经元存活率明显高于Aβ处理组(P<0.01)。与胆固醇组相比,Aβ25-35处理后神经甾体PREG水平略有降低(P>0.05),PROG水平明显下降(P<0.01),AP水平明显增高(P<0.01)。结论神经甾体PREG-PROG-AP代谢通路在Aβ25-35引起的大鼠大脑皮质神经元损伤时发生明显改变,并能部分地对抗Aβ的神经毒性作用。     

Subjective effects and changes in steroid hormone concentrations in humans following acute consumption of alcohol

Background: GABA_A receptors are an important site of action of endogenous neurosteroids and an important mediator of several behavioral effects of alcohol. This study examined the effects of alcohol on plasma steroid hormone concentrations on the hypothesis that the endocrine effects mediate some of the subjective effects of alcohol. Methods: Thirty-two healthy subjects (17 men) with no history of a substance use disorder participated in this human laboratory study. All subjects consumed three standard drinks of grain alcohol. Subjective measures and blood samples for steroid concentrations were collected at baseline and 40 min after alcohol consumption. Results: Alcohol increased self-reported stimulation, alcohol liking, and desire for more alcohol. Alcohol also increased pregnenolone (PREG) and dehydroepiandrosterone (DHEA) concentrations, while it decreased progesterone (PROG) and allopregnanolone (ALLO) concentrations, as well as ALLO/PREG and PROG/PREG ratios. In men, the change in PREG concentration was significantly correlated with alcohol liking, while the alcohol-induced change in ALLO concentration correlated significantly with both alcohol liking and desire for more alcohol. Discussion: These findings provide preliminary support for the hypothesis that endogenous neurosteroids mediate some of the subjective effects of alcohol. Efforts to replicate these findings should aim to specify more clearly the nature and time course of the effects.     

Continuous de novo synthesis of neurosteroids is required for normal synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus

Both in vivo and in vitro studies have shown that neurosteroids promote learning and memory by modulating synaptic functions in the hippocampus. However, we do not know to what degree endogenously synthesized neurosteroids contribute to the hippocampal synaptic functions. Cytochrome P450scc is the enzyme that converts cholesterol to pregnenolone (PREG), which is required for the biosynthesis of all other neurosteroids. To investigate the physiological roles of endogenous neurosteroids in synaptic functions, we electrophysiologically examined the effects of aminoglutethimide (AG), a selective inhibitor of P450scc, on the synaptic transmission and plasticity in the dentate gyrus of rat hippocampal slices. The application of AG (100 μM) decreased the slope of the field excitatory postsynaptic potentials (fEPSPs) in granule cells by 20-30% in 20 min through the modulation of postsynaptic AMPA receptors, while it did not affect the presynaptic properties, including the paired-pulse ratio and the probability of glutamate release from presynaptic terminals. The AG-induced depression was nearly completely rescued by exogenously applied 500 nM PREG or by 1 nM dehydroepiandrosterone sulfate (DHEAS), one of the neurosteroids synthesized from PREG, suggesting that the AG-induced depression was caused by the loss of DHEAS. AG also reduced NMDA receptor activity, and suppressed high-frequency stimulation (HFS)-induced long-term potentiation (LTP). These findings provide novel evidence that the endogenous neurosteroids locally synthesized in the brain are required to maintain the normal excitatory synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus.     

高效液相色谱-质谱联用测定大鼠不同脑区的游离型神经甾体

目的建立大鼠不同脑区3种游离型神经甾体的测定方法。方法甾体分两步萃取，首先用乙酸乙酯-正己烷(90∶10)提取甾体，然后经固相萃取纯化。游离型甾体进行衍生化后应用高效液相色谱-质谱分离测定，选择甲基睾丸酮作为内标。结果去氢表雄酮的线性范围为0.030-2.00 μg·L^-1，孕烯醇酮和别孕烯醇酮的线性范围为0.025-2.00 μg·L^-1。正常雄性Sprague-Dawley (SD)大鼠不同脑区甾体去氢表雄酮(DHEA)，孕烯醇酮(PREG)和别孕烯醇酮(AP)的含量分别为额叶皮质(0.70±0.23)，(4.8±1.9)，(1.1±0.6) ng·g^-1，海马(0.57±0.28)，(6±3)，(0.5±0.3) ng·g^-1，杏仁核(1.5±1.0)，(9±5)，(1.4±0.9) ng·g^-1，纹状体(0.52±0.14)，(7.7±2.8)，(0.5±0.6) ng·g^-1，伏隔核(2.9±1.6)，(18±9)，(1.6±1.3) ng·g^-1，垂体(4.0±2.0)，(27±12)，(0.8±0.5) ng·g^-1，下丘脑(1.7±1.2)，(16±10)，(0.8±0.7) ng·g^-1。结论3种神经甾体都有良好的线性关系和准确度，本方法可满足大鼠不同脑区内游离型甾体的分离测定。     

The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels

In the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane on: (i) neurosteroid and monoamine levels in the brain, and (ii) the antidepressant activity of steroids and antidepressants in the forced swimming test (FST). 3β-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehydroepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, γ-aminobutyric acid (GABA) and serotonin (5-HT), with consequences on mood and depression. We previously reported that trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocorticotropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamus-pituitary-adrenal (HPA) axis activation. We here observed that adrenalectomy/castration blocked the trilostane effect, outlining the importance of peripheral steroid levels. Trilostane (25 mg/kg) decreased hippocampus PROG contents and paradoxically increased circulating PROG levels. It also increased PREG levels in the hippocampus and frontal cortex. In the FST, a co-treatment with trilostane facilitated DHEAS (5-20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10-40 mg/kg), PROG (10-40 mg/kg) or allopregnanolone (ALLO, 1-8 mg/kg). Trilostane (25 mg/kg) treatment significantly increased 5-HT and (-)-norepinephrine (NE) turnovers in the hippocampus, an effect likely related to its antidepressant action. In co-administration studies, trilostane further decreased immobility following fluoxetine (30-60 mg/kg), sertraline (20-40 mg/kg) and imipramine (20-40 mg/kg), but not desipramine (20-40 mg/kg), treatments. A significant additive effect was observed for the selective 5-HT reuptake inhibitors (SSRI) at their highest dose. This study confirmed that a systemic administration of trilostane directly affected peripheral and brain levels in neuroactive steroids and monoamine turnover, resulting in antidepressant activity. The drug could be proposed as a co-treatment with SSRI. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes

Rationale The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3α,5α THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory.Objective To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems.Methods We carried out keyword searches in “Medline” to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents.Results Peripheral and central administrations of PREGS, DHEAS, and 3α,5α THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions.Conclusions The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.     

吗啡依赖对大鼠伏隔核神经甾体和氨基酸递质的影响

目的　利用大鼠吗啡依赖模型,观察吗啡依赖及戒断对大鼠伏隔核中神经甾体和氨基酸类神经递质水平影响。方法　腹腔注射递增剂量的盐酸吗啡使雄性SD大鼠形成吗啡依赖,并用纳洛酮催促戒断。分离吗啡依赖和戒断大鼠的伏隔核。经液液萃取和固相萃取法提取脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯和孕烯醇酮硫酸酯,并采用高效液相色谱质谱系统检测其含量。采用柱前衍生-电化学检测-高效液相色谱法测定甘氨酸、谷氨酸和γ氨基丁酸的含量。结果　与对照组相比,纳洛酮催促戒断时,吗啡依赖大鼠伏隔核脱氢表雄酮硫酸酯的水平下降(P<0 .05),孕烯醇酮(P<0 .01 )和谷氨酸(P<0 .05 )水平均升高。结论　吗啡戒断时大鼠伏隔核的谷氨酸系统处于兴奋状态,伏隔核中的内源性神经甾体在吗啡依赖和戒断的形成中发挥作用。     

Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects.

BACKGROUND AND OBJECTIVE: Contradictory and confusing reports on serum dehydroepiandrosterone (DHEA) levels in schizophrenia led us to compare the serum concentration of its precursor, pregnenolone (PREG), between medicated schizophrenia patients and healthy subjects. The neurosteroid levels were monitored for two months and the relationship of these neurosteroids with schizophrenic symptomatology, emotional distress, and anxiety was examined. METHOD: We determined blood levels of PREG, and DHEA in 15 schizophrenia patients and 12 healthy controls at four time points: at the start of the study, after 2, 4 and 8 weeks. Analysis of covariance and canonical correlations across four time points were applied. RESULTS: Controlling for age, serum concentrations of PREG were lower, while the DHEA level and the molar ratio values of DHEA/PREG were higher in schizophrenia patients compared to healthy controls. Both levels of PREG and DHEA and their molar ratio did not change significantly during the study's period either among schizophrenia patients or healthy controls. The blood levels of PREG appear to be associated with trait-anxiety scores in the schizophrenia patients, while associations of clinical symptoms with two neurosteroids did not reach a significant level when the confounding effect of emotional distress, and anxiety scores was controlled. CONCLUSION: Low serum pregnenolone concentrations in schizophrenia appear to be associated with trait-anxiety scores independent of symptoms. Further research into the role of pregnenolone in schizophrenia is warranted.     

The involvement of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) in blocking the therapeutic effect of electroconvulsive shocks in an animal model of depression.

Depressed patients with resistance to electroconvulsive treatment (ECT) had high basal serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS). To clarify the role of DHEA/S in the ECT resistance, Flinder Sensitive Line (FSL) rats, which are a genetic animal model of depression, were injected i.p. with 2 mg/kg DHEA daily for 13 days to overload their serum and brain DHEA/S levels. Thereafter, rats were exposed to electroconvulsive shock (ECS), which is analogue to ECT in humans. Both ECS and DHEA displayed an antidepressive-like effect, as assessed by immobility time in forced swim test. However, combined DHEA and ECS treatment abolished these antidepressive-like effects. In addition, the levels of neurosteroids, corticosterone and adrenocorticotropin in selected brain regions were evaluated and compared to serum levels. The present study supports our assumption that high basal levels of DHEA/S play a role in the resistance to ECS and maybe ECT in humans.