海洛因依赖及戒断后雄性大鼠性腺轴组织病理学研究

规律腹腔注射海洛因建立♂大白鼠海洛因身体依赖模型（ｎ＝５），戒断后制成戒断模型（ｎ＝１０），并设对照组，对依赖组和戒断组大鼠的大脑、下丘脑、垂体、肾上腺、睾丸和附睾组织做光镜和电镜观察，结果发现依赖组的大脑皮质，下丘脑，垂体，睾丸和附睾均有明显的组织病理改变及超微结构改变，且短期戒断后这些改变仍持续存在。该文对海洛因依赖引起中枢神经系统及下丘脑－垂体－睾丸轴组织产生病理改变的机理作了探讨。     

海洛因及吗啡对恒河猴β-内啡肽、促肾上腺皮质激素、皮质醇、睾酮的影响海洛因及吗啡对恒河猴β-内啡肽、促肾上腺皮质激素、皮质醇、睾酮的影响

本文用放射免疫法对海洛因、吗啡依赖性恒河猴依赖形成前、后及戒断过程中,血中β－内啡肽（β－ＥＰ）、促肾上腺皮质激素（ＡＣＴＨ）、皮质醇、睾酮的浓度进行测定,以比较海洛因及吗啡对恒河猴下丘脑－垂体－肾上腺及性腺组织的影响是否一致。结果表明：（１）海洛因对β－ＥＰ的抑制强度大于吗啡;（２）海洛因对下丘脑－垂体－肾上腺轴（ＨＰＡ轴）的损害程度比吗啡重;（３）海洛因组睾酮分泌的受抑程度大于吗啡组。因此,海洛因对下丘脑－垂体－肾上腺及性腺轴的损伤程度比吗啡严重。     

海洛因及吗啡对恒河猴β—内啡肽,促肾上腺皮质激素,皮质醇 …

本文用放射免疫法海洛因,吗啡依赖性恒河猴依赖形成前,后及戒断过程中,血中β－内啡肽,保肾上腺皮质激素,皮质醇,睾酮的逍度进行测定,以比较洛洛因及吗啡对恒河猴下丘脑－垂体－肾上腺及性腺组织的影响是否一致;结果透明：（１）海洛因对β－ＥＰ的抑制强度大于吗啡;（２）海洛因对下丘脑－垂体－肾上腺的损害程度比吗啡重;（３）海洛因组睾酮分泌的受抑程度大于吗啡组。     

慢性阿片类耐受、戒断状态下下丘脑—垂体—性腺轴改变及温阳益气活血复方作用的临床与实验研究

目的：研究机体下丘脑-垂体-睾丸轴在阿片类耐受、戒断过程中的变化,探讨温阳益气活血复方抗戒断症状的作用机理;方法：建立慢性Mor依赖大鼠模型,设立正常组、自然戒断组和复方治疗组,对各组大鼠的睾丸、附睾组织进行光镜观察;运用放免法检测成瘾患者和大鼠血清FSH、LH、T、PRL等的变化;结果,发现耐受和戒断组大鼠的睾丸,附睾出现退行性改变,血清LH、T明显降低,PRL显著升高;成瘾患者血清性激素水平明显紊乱,温阳益气活血复方能逆转成瘾大鼠睾丸、附睾退行性改变,恢复机体紊乱的性激素水平;结论：阿片类依赖确能引起机体睾丸轴的机能和实质性改变,出现“贤阳虚损”未老先衰的退行性变化,且此变化在戒断后的一段时间内仍不能复常,温阳益所活血复方可逆转这种改变。     

男性海洛因依赖者戒断后的性腺功能改变

测定某强制戒毒所戒断９１ｄ±ｓ５．６ｄ的３１名男性海洛因依赖者的性激素水平，并做精液常规和生化分析，同吸毒组和正常对照组作比较，结果表明戒断治疗三个月的男性海洛因依赖者下丘脑－垂体－性腺轴的分泌调节功能紊乱已基本恢复，睾丸生精功能亦基本恢复，但附属性腺功能尚未恢复，表现在精液总量和精子活率仍低，精浆微量元素Ｚｎ、Ｃｕ、Ｃａ、Ｆｅ的改变尚未恢复，仅精浆果糖浓度同正常对照差异无显著性（Ｐ＞０．０５）。     

海洛因与吗啡依赖恒河猴的病理组织学研究

目的··：比较海洛因与吗啡恒河猴依赖模型。方法··：利用光镜对恒河猴海洛因及吗啡依赖形成过程中垂体、睾丸、肾上腺等器官组织进行病理形态观察。结果··：在注射海洛因３个月内,垂体从无明显病变转为个别嗜酸性细胞坏死到部分嗜酸性和嗜碱性细胞坏死;下丘脑从无明显病变转为少数神经细胞坏死;肾上腺从无明显病变转为个别束状带细胞水肿到大多数束状带细胞水肿;睾丸从无明显病变转为个别曲细精管萎缩,见成熟精子和间质细胞到大部分曲细精管萎缩到全部曲细精管萎缩,无成熟精子和间质细胞,且自然戒断３个月时垂体、睾丸的病变未得到恢复。注射吗啡３个月时,垂体仅有个别嫌色细胞水肿;下丘脑结构基本正常;睾丸仅为部分曲细精管萎缩,有成熟精子;肾上腺个别束状带细胞水肿,且自然戒断３个月时病变已恢复。结论··：海洛因依赖猴造成垂体、睾丸、肾上腺等组织器官损伤的程度比吗啡依赖猴的更重;在恒河猴海洛因依赖形成过程中,随注射时间延长,组织损伤程度加重。     

海洛因成瘾对下丘脑神经内分泌激素系统的影响

为探索海洛因依赖对人体下丘脑神经内分泌系统影响,本实验应用放射免疫法,检测了７０名海洛因依赖者脱瘾治疗前三轴变化即下丘脑－垂体－肾上腺轴（ＨＰＡ）、下丘脑－垂体－甲状腺轴（ＨＰＴ）、下丘脑－垂体－性腺轴（ＨＰＡＡ）共１２种内分泌激素水平的变化,并与６２例健康者作对照,结果显示：ＨＰＡ活性增强,ＨＰＴ、ＨＰＡＡ激素水平下降,其原因是与阿片类毒品抑制海洛因依赖者内源性阿片类物质生成和下丘脑神经元电兴奋,导致神经介质,内分泌系统调节失衡有关,这对探索成瘾戒断、复吸与新的戒毒方法研究都有十分重要意义     

复方中药制剂康赛德对海洛因依赖恒河猴脏器病变的疗效观察

目的··:探讨海洛因依赖恒河猴经用复方中药康赛德治疗后垂体、肾上腺、睾丸等脏器组织结构的恢复情况。方法··:利用光镜对海洛因依赖恒河猴在用康赛德治疗3个月后各脏器的病理学改变进行观察。结果·· :肝细胞变性在自然戒断组为3例 (3/3) ,而康赛德治疗组仅1例 (1/3)。肾上腺的病理改变在自然戒断组和治疗组均为2例 (2/3) ,不过前者病变程度较重 ,大部分皮质束状带细胞水肿 ;而后者仅为个别皮质束状带细胞水肿。睾丸病变在自然戒断组和治疗组也均为2例 (2/3) ,前者曲精细管全部萎缩 ,细胞层次减少 ,无精子形成 ,也未见间质细胞 ,间质内纤维组织增生 ;后者病变程度较轻 ,曲精细管仅是部分萎缩 ,部分管腔内有少数精子 ,可见间质细胞 ,间质内纤维组织轻度增生。附睾及垂体的病理改变在治疗组也较轻。结论··:康赛德治疗 ,可使肾上腺、睾丸、垂体等组织结构和功能尽快地得到恢复     

东莨菪碱对海洛因依赖者血清中性激素和甲状腺激素的影响

本文采用放射免疫分析法,对20例正常男性对照者和40例男性海洛因依赖者及东莨菪碱治疗10天后血清中睾酮（T）、雌二醇（E2）、促黄体生成素（LH）、促卵泡生存素（FSH）、三碘甲状腺原氨酸（T3）、甲状腺素（T4）的含量进行了测定。结果显示：海洛因依赖组与正常对照组比较,LH、FSH含量升高,T含量较低,E2含量无显著性差异,T3、T4含量升高。东莨菪碱治疗组与海洛因依赖组比较,LH含量较低,FSH含量无显著性差异,T、E2含量升高,T3、T4含量降低。结果表明：海洛因可致机体下丘脑－垂体－性腺轴和下丘脑－垂体－甲状腺功能的紊乱;东莨菪碱具有调节海洛因依赖者下丘脑－垂体－性腺轴和下丘脑－垂体－甲状腺轴功能紊乱的作用。     

东莨菪碱对海洛因依赖者血清中性激素和甲状腺激素的影响

本文采用放射免疫分析法,对20例男性正常对照者和40例男性海洛因依赖者及东莨菪碱治疗10天后血清中睾酮（T）、雌二醇（E2）、促黄体生成素（LH）、促卵泡生成素（FSH）、三碘甲状腺氨酸（T3）、甲状腺素（T4）的含量进行了测定。结果显示：海洛因依赖组与正常对照组比较,LH、FSH含量升高,T含量降低,E含量无显著性差异,T3、T4含量升高。东莨菪碱治疗组与海洛因依赖组比较,LH含量降低,FSH无显著性差异,T、E2含量升高,T3、T4含量降低。结果表明：海洛因可致机体吓丘脑－垂体、性腺轴和下丘脑－垂体－甲状腺轴功能的紊乱;东莨菪碱具有调节洛海因依赖者下丘脑－垂体－性腺轴和下丘脑－垂体－甲状腺轴功能紊乱的作用。     

Gender impacts behavioral and neurochemical adaptations in ethanol-dependent rats

Previous investigations have found gender differences in the effects of chronic ethanol exposure on ethanol withdrawal behaviors as well as GABA(A) receptor gene expression. The present investigation extended these studies with additional behavioral and neurochemical measures of ethanol dependence and withdrawal. No significant gender differences in the elevated plus-maze assessment of ethanol withdrawal anxiety behaviors were found. However, the neuroactive steroid, 3alpha,5alpha-THP, increased exploratory behavior in ethanol withdrawn female, but not male, rats. GABA(A) receptor binding assays showed potent competition of [35S]TBPS binding by 3alpha,5alpha-THP. Control females displayed a decreased affinity for 3alpha,5alpha-THP compared to control males, as evidenced by a nearly 30% increase in the IC50 value. There was no significant effect of ethanol withdrawal on 3alpha,5alpha-THP modulation of [35S]TBPS binding. However, gender differences were observed in the effects of chronic ethanol exposure on GABA(A) receptor subunit peptide levels in the hypothalamus. Female rats had a significant increase in peptide levels for the alpha2 and alpha3 but not alpha4 subunit, whereas male rats displayed a significant increase in alpha4 and alpha3 but not alpha2 subunits compared to pair-fed control levels. Chronic ethanol-induced alterations in gene expression in the hypothalamus did not coincide with previous findings in the cerebral cortex. In particular, male rats showed an increase in alpha1 subunit peptide levels in the hypothalamus, whereas significant decreases in this subunit have been observed in the cerebral cortex. Both female and male rats showed significant increases in the alpha3 subunit in the hypothalamus but not the cerebral cortex. Taken together, these studies provide additional support for gender-selective effects of chronic ethanol-elicited adaptations at the molecular level.     

Gender-selective effects of ethanol dependence on NMDA receptor subunit expression in cerebral cortex, hippocampus and hypothalamus

Previous investigations have shown subunit-selective alterations in NMDA receptors in ethanol dependent male rats. In the present study, we found pronounced gender differences in the effects of ethanol dependence on NMDA receptor subunit expression in all brain regions investigated. Ethanol dependent female rats exhibited increased NR1 subunit levels in cerebral cortex and hypothalamus, whereas males displayed increased NR1 levels only in hippocampus. NR2A subunit levels were significantly increased only in hippocampus from ethanol dependent male rats, whereas NR2B subunit levels significantly increased in cerebral cortex of both female and male rats. These findings suggest that gender influences neuroadaptations elicited by ethanol dependence at the level of NMDA receptor subunit expression.     

Changes in testicular and serum hormone concentrations in the male rat following treatment with m-dinitrobenzene

m-Dinitrobenzene (m-DNB)-induced testicular atrophy has been attributed to a direct effect upon the germinal epithelium. However, such degenerative changes in the germinal epithelium should induce shifts in the testicular hormonal milieu, which would in turn alter the hypothalamic-pituitary gonadal axis in general. This study evaluated the endocrine status of male rats (killed 3 hr, 24 hr, 1 week, and 2 weeks) following a single oral dose of m-DNB (32 mg m-DNB/kg). Serum and pituitary leuteinizing hormone, follicle-stimulating hormone (FSH), and protactin and hypothalamic gonadotropin-releasing hormone (GnRH) concentrations were determined. Testosterone and androgen-binding protein concentrations in serum, interstitial fluid, seminiferous tubule fluid, and caput epididymis were also determined. In vitro basal and hCG-stimulated testosterone release was determined in the decapsulated testis. Results of the present study indicate that pituitary hormone concentrations and hypothalamic GnRH were unaffected after a single oral dose of m-DNB. Serum FSH was elevated at 2 weeks. There was a transient decrease in serum testosterone at 24 hr, which returned to control values at 1 and 2 weeks. Interstitial fluid, seminiferous tubule fluid, and caput epididymal testosterone concentrations were increased at 1 and 2 weeks. Basal testosterone release in vitro was increased at 2 weeks, while hCG-stimulated testosterone release was increased at 1 and 2 weeks. Androgen-binding protein concentrations in serum and interstitial fluid were increased at 1 and 2 weeks. Androgen-binding protein was increased at 24 hr and 1 week in seminiferous tubule fluid, but returned to control concentrations by 2 weeks. However, the total tubular content of androgen-binding protein was dramatically decreased at 2 weeks. Androgen-binding protein in the caput epididymis was unaltered following m-DNB treatment. These data demonstrate that m-DNB exerts a direct effect on the testes and not through alterations in hypothalamic and pituitary control of gonadal function.     

Effects of chronic antidepressant and benzodiazepine treatment on corticotropin-releasing-factor receptors in rat brain and pituitary

We examined the effects of chronic treatment with antidepressants (imipramine or desipramine) or benzodiazepines (diazepam, alprazolam, or adinazolam) on modulation of corticotropin-releasing-factor (CRF) receptors in discrete areas of rat brain and in anterior pituitary. As previously reported, we found that chronic antidepressant treatment downregulated 5-HT2 serotonin and beta-adrenergic receptors in cerebral cortex. Although there was a trend toward increased CRF binding in brain stem, striatum, cerebellum, hypothalamus, and frontal cerebral cortex following antidepressant treatment, the changes were only statistically significant in brain stem in imipramine-treated rats. In addition, no significant changes were seen in CRF binding in other brain regions including parietal/temporal cerebral cortex, olfactory bulb, hippocampus, and anterior pituitary. Following chronic benzodiazepine treatment CRF receptor binding was significantly decreased in the frontal cerebral cortex and hippocampus; although there was a trend for CRF receptors to be decreased in other brain areas and increased in anterior pituitary, the changes were not statistically significant.     

The response to acoustic stimulation and the changes in brain amine levels after repeated administration of beta-phenylethylamine in rats

Reverse tolerance to stereotyped behavior was induced after repeated administration of beta-phenylethylamine (PEA) (50 mg/kg, i.p., daily for 10 days) in rats. The reverse tolerance was maintained for at least 4 weeks after the last administration. We studied the effects of acoustic stimulation on locomotor activity 2 days and 4 weeks after withdrawal from PEA and measured the changes in brain monoamine levels 4 weeks after the withdrawal. Locomotor activity during acoustic stimulation was increased in the saline treated group, and this response was unaffected after repeated PEA treatment. Four weeks after withdrawal, significant increases in noradrenaline levels in the cerebral cortex and decreases in 5-hydroxytryptamine levels in the hypothalamus were found. The effects of acoustic stimulation on locomotor activity and the changes in brain monoamine levels were different from those of methamphetamine treatment obtained in our previous study. In conclusion, it may be suggested that the response to acoustic stimulation after repeated PEA administration in rats cannot be a model for abnormal responsiveness to environmental stimulation that is observed in chronic paranoid schizophrenics.     

Effects of chronic ethanol administration and ethanol withdrawal on cyclic guanosine 3',5'-monophosphate (cGMP) levels in the rat brain

The main objective of the present study is to investigate the possible effects of chronic ethanol consumption and ethanol withdrawal on cyclic guanosine 3', 5'-monophosphate (cGMP) levels in cerebral cortex, striatum, hippocampus and hypothalamus of rat brain. Ethanol was given to female Wistar rats (225-270g) by a liquid diet for 21 days. cGMP levels were measured in respective brain regions using an EIA kit at 7th, 14th and 21st days of ethanol ingestion and at 6th and 24th h of ethanol withdrawal. cGMP levels in cortex, striatum and hippocampus but not hypothalamus were found significantly increased at 14th and 21st days of ethanol consumption. The most prominent increase was observed in striatal tissues (approximately 350%). cGMP levels of striatum and hippocampus were still remaining significantly high at 6th h of ethanol withdrawal. Blood ethanol levels were found as 115.60, 50.0 and 7.0mg/dl just before and after 6 and 24h of ethanol withdrawal, respectively and audiogenic seizures also occurred at 6th h of ethanol withdrawal with an incidence of 75% in individual parallel groups. Our results suggest that changes of cGMP levels in cerebral cortex, striatum and hippocampus might participate in the mechanism of ethanol dependence and withdrawal in rats.     

Effects of neonatal exposure to a high-dose p-tert-octylphenol on the male reproductive tract in rats

Time-course alterations in morphological changes of the reproductive tract including spermatogenesis as well as pituitary and gonadal hormones, reproductive ability, and the size of the sexually dimorphic nucleus of the preoptic area (SDN-POA) were investigated in male rats neonatally exposed to 100 mg/kg p-tert-octylphenol (OP) subcutaneously. OP treatment affected hormone levels of follicle stimulating hormone (FSH) and testosterone, reproductive organ weights and sperm counts. Slightly depressed FSH levels at prepuberty and prolonged suppression of testosterone till 7 weeks of age were observed as two hormonal alterations. The lasting reduction in testosterone appeared to be associated with growth inhibition of male reproductive organs such as the testis, prostate and epididymis, these demonstrating low organ weights compared with those of age-matched controls till 7 weeks of age. The FSH concentrations after puberty showed a rise to values equal to or higher than those of the control group, suggesting recovery of maturation of the reproductive tract. No morphological abnormalities, even with morphometric stage analysis of spermatogenesis, were detected in the male reproductive tract throughout the study. Size of the SDN-POA and reproductive ability was comparable to those in controls. At the termination (18 weeks of age), however, a reduction in the sperm count in the epididymis of OP-treated animals demonstrated a possibility that the male reproductive system might be still affected by neonatal exposure to OP. The results observed demonstrate that neonatal exposure to a high-dose OP exerts estrogenic action directly or indirectly, resulting in slight but prolonged impairment of the male reproductive tract. The suppression of FSH caused by modulation of the hypothalamus-pituitary control system may be the trigger for the impairment, while the possibility of direct estrogenic action of OP is not ruled out. Our results also indicate that more sensitive endpoints should be established to detect the effects of neonatal exposure to estrogens or estrogenic compounds on the male reproductive tract.     

Actylcholine output from the cerebral cortex,choline uptake and muscarinic receptors in morphine-dependent,freely-moving rats

Spontaneous acetylcholine (ACh) output from the cerebral cortex, choline high affinity uptake and [³H]-QNB binding to muscarinic receptors in the cerebral cortex and caudate nucleus in freely moving rats made morphine-dependent by morphine pellet subcutaneous implantation were investigated before and during naloxone-induced withdrawal syndrome. The frequency and intensity of the withdrawal signs were also assessed.No significant change in ACh output was found in tolerant rats when compared with that of placebopellet implanted rats. During naloxone-induced withdrawal syndrome a 60% increase in ACh output occurred.In rats made dependent after a large septal lesion or treated for ten days with calcium gluconate (10 mg/kg i.m.) no increase in ACh output was found during the withdrawal syndrome. The intensity of some of its signs was also reduced.During the withdrawal syndrome a marked increase in choline high affinity uptake in the cerebral cortex and caudate nucleus was detected.The affinity of muscarinic receptors (K_D) for [³H]-QNB was significantly increased in the cerebral cortex and caudate nucleus of morphine-dependent rats before naloxone administration. It returned to normal during the withdrawal syndrome. In the caudate nucleus the number of binding sites (B_max) was decreased before and after the withdrawal syndrome.These findings emphasize the role of cholinergic mechanisms in opiate addiction.