The effects of cocaine on basal and human chorionic gonadotropin-stimulated ovarian steroid hormones in female rhesus monkeys

Cocaine stimulates gonadotropin (luteinizing hormone) release from the anterior pituitary in humans and in rhesus monkeys, but its acute effects on ovarian steroid hormones are unknown. The acute effects of cocaine and placebo on estradiol and progesterone were studied in 13 drug-naive female rhesus monkeys during the mid-follicular (days 8-10) and the mid-luteal (days 21-23) phases of the menstrual cycle. Each monkey was her own control under cocaine and placebo conditions. Samples for ovarian steroid hormone analysis were collected before and at 15-min intervals for 300 min after cocaine or placebo administration. In follicular phase females, estradiol levels increased significantly within 15 min after cocaine (0.8 mg/kg i.v.) administration (P <.008) but did not change after placebo administration. Estradiol remained significantly above baseline for 45 min (P <.002-0.02). In contrast, in mid-luteal phase females, estradiol did not change after cocaine or placebo administration. Basal progesterone levels did not change after cocaine or placebo administration in either mid-follicular or mid-luteal phase females. After hCG (500 I.U. i.m.) was administered to mid-luteal phase females, cocaine (0.4 and 0.8 mg/kg i.v.) and placebo administration did not increase or decrease estradiol or progesterone. One implication of these findings is that cocaine-induced increases in follicular phase estradiol levels could disrupt folliculogenesis and contribute to the menstrual cycle abnormalities observed during chronic cocaine self-administration.     

Effects of cocaine on luteinizing hormone in women during the follicular and luteal phases of the menstrual cycle and in men

Cocaine stimulates luteinizing hormone (LH) release in rhesus monkeys and in men, but its effects on LH in women are unknown. Cocaine (0.2 and 0.4 mg/kg i.v.) was administered to groups of follicular and luteal phase women (N = 22) and to men (N = 12) to examine the influence of gender and menstrual cycle phase on cocaine and LH interactions. All subjects met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for cocaine abuse, and menstrual cycle phase was verified by estradiol and progesterone measures. Baseline LH levels were equivalent between groups. Peak cocaine levels did not differ significantly between men and women and averaged between 87 +/- 21 and 124 +/- 18 ng/ml after 0.2 mg/kg cocaine and between 227 +/- 22 and 287 +/- 21 ng/ml after 0.4 mg/kg cocaine. The lower dose of cocaine (0.2 mg/kg) significantly increased LH levels in men (P < 0.001) but not in women at either phase of the menstrual cycle. The higher dose of cocaine (0.4 mg/kg) stimulated significant increases in LH in men (P < 0.001) and in women at both phases of the menstrual cycle (P < 0.004-0.001). Although cocaine's effects on LH in women were dose-dependent, there were no significant differences as a function of menstrual cycle phase. LH remained significantly elevated longer in men (32 min) than in women (8 and 12 min). This gender difference in cocaine's potency in stimulating LH was unexpected.     

Effect of ovarian hormones and estrous cycle on stimulation of the hypothalamo-pituitary-adrenal axis by cocaine

Cocaine is known to exert sexually dimorphic HPA axis effects in rats and to disrupt estrous cyclicity and/or fertility in rats, nonhuman primates, and humans. The present studies investigated the reciprocal interactions between ovarian hormones and HPA axis responses to cocaine. Thirty minutes after injection, cocaine (15 mg/kg i.p.) increased serum ACTH and corticosterone more in cycling than ovariectomized females or male rats. ACTH and corticosterone were highest in proestrus when estradiol was elevated. Cocaine did not alter serum estradiol in females or testosterone in males but did stimulate progesterone secretion in both sexes. Cocaine-stimulated progesterone secretion was significantly greater in females than in males or ovariectomized females, and greater in proestrous than diestrous 1 rats. Cocaine stimulated corticosterone and progesterone secretion in sham-adrenalectomized, but not adrenalectomized rats, indicating that the adrenal gland and not the ovary is the source of cocaine-stimulated progesterone. Estrogen influenced cocaine-stimulated progesterone secretion more than corticosterone, suggesting different release mechanisms for the two steroids in the adrenal. These results suggest that adrenally derived progesterone could contribute to cocaine-induced physiological changes, including inhibited gonadotropin release.     

Effects of intravenous cocaine and cigarette smoking on luteinizing hormone,testosterone, and prolactin in men

Cocaine and nicotine have a number of similar behavioral and neurobiological effects. This study compared the acute effects of cocaine and cigarette smoking on luteinizing hormone (LH), testosterone (T), and prolactin. Twenty-four men who met American Psychiatric Association Diagnostic and Statistical Manual criteria for cocaine abuse or nicotine dependence were given intravenous cocaine (0.4 mg/kg) or placebo-cocaine, or smoked a low or high nicotine cigarette under controlled conditions. Placebo-cocaine or low nicotine cigarette smoking did not change LH, T, or prolactin. Peak plasma levels of 254 +/- 18 ng cocaine/ml and 22.6 +/- 3.4 ng nicotine/ml were measured at 8 and 14 min, respectively. LH increased significantly after both i.v. cocaine and high nicotine cigarette smoking (P < 0.01). These LH increases were significantly correlated with increases in cocaine and nicotine plasma levels (P < 0.001-0.003), and high nicotine cigarette smoking stimulated significantly greater increases in LH release than i.v. cocaine (P < 0.05). Testosterone levels did not change significantly after either cocaine or after high nicotine cigarette smoking. After i.v. cocaine, prolactin decreased significantly and remained below baseline levels throughout the sampling period (P < 0.05-0.01). After high nicotine cigarette smoking, prolactin increased to hyperpro-lactinemic levels within 6 min and remained significantly above baseline levels for 42 min (P < 0.05-0.03). The rapid increases in LH and reports of subjective "high" after both i.v. cocaine and high nicotine cigarette smoking illustrate the similarities between these drugs and suggest a possible contribution of LH to their abuse-related effects.     

Effects of luteinizing hormone-releasing hormone on plasma cocaine levels in rhesus monkeys

No effective pharmacotherapy for the treatment of cocaine abuse is currently available. In addition to pharmacological approaches, immunologic methods that use specific antibodies to bind cocaine in blood and prevent it from reaching the central nervous system are also being evaluated. There is considerable evidence that cocaine binds to the dopamine transporter, and there are structural similarities between the dopamine transporter and an anterior pituitary hormone, luteinizing hormone (LH). These structural similarities led us to hypothesize that LH may bind cocaine and decrease plasma levels of free cocaine. Synthetic LH-releasing hormone (LHRH) was used to stimulate LH release from pituitary gonadotropes before i.v. cocaine administration to male and female rhesus monkeys. The effects of placebo-LHRH and 15 and 30 micrograms/kg LHRH on levels of free cocaine in plasma after i.v. administration of 0.8 mg/kg cocaine were studied. LHRH (15 and 30 micrograms/kg) significantly increased LH secretion in both males (P <.01-.001) and females (P <.01-.05). Peak plasma cocaine levels were significantly lower after both doses of LHRH than after placebo-LHRH in males and in females (P <.05). There was an inverse relationship between peak plasma cocaine levels and LHRH-stimulated LH levels in males (P <. 01) but not in females. Pharmacokinetic analyses showed that the time to reach peak plasma cocaine levels, the elimination half-life, and the area under the plasma cocaine curve did not differ as a function of the LHRH dose compared with placebo LHRH. Moreover, there were no gender differences in any cocaine-related, pharmacokinetic parameter after placebo-LHRH administration. These data suggest the feasibility of reducing peak levels of free cocaine in plasma by stimulating secretion of LH. The functional consequences and underlying mechanisms of LHRH-induced decreases in peak plasma cocaine levels remain to be determined.     

Alcohol effects on luteinizing hormone-releasing hormone stimulated luteinizing hormone and follicle-stimulating hormone in ovariectomized female rhesus monkeys

The effects of acute alcohol administration on anterior pituitary function were studied in five ovariectomized female rhesus monkeys. Integrated plasma samples were collected for 80 min before and 120 min after nasogastric intubation of alcohol (2.5 or 3.5 g/kg) or isocaloric sucrose control solution. Then synthetic luteinizing hormone-releasing hormone (LHRH; 100 micrograms/i.v.) was administered and plasma samples were collected for an additional 180 min. After sucrose control administration, LHRH stimulated a significant increase in luteinizing hormone (LH) within 30 min (P less than .001) and follicle-stimulating hormone (FSH) within 60 min (P less than .01). After alcohol administration, LHRH stimulated LH and FSH also increased significantly (P less than .01) when blood alcohol levels averaged 242 (+/- 26) and 296 (+/- 20) mg/dl. Moreover, there was an alcohol dose-dependent increase in LHRH-stimulated LH (P less than .01, .001) in comparison to control conditions, even though prealcohol and presucrose LH levels were equivalent. LHRH-stimulated FSH was also higher after 3.5 g/kg of alcohol than after 2.5 g/kg of alcohol and sucrose control administration (P less than .001) but base-line FSH levels before 3.5 g/kg of alcohol were also higher than control (P less than .05) or 2.5 g/kg of alcohol (P less than .001). An alcohol related enhancement of LHRH-stimulated LH without concomitant suppression of FSH in ovariectomized females contrasts with data reported previously in normally cycling females studied under identical conditions. The absence of ovarian steroid and/or ovarian peptide negative feedback in ovariectomized females may have permitted the synergistic effect of alcohol and LHRH on LH.     

Acute effects of cocaine on prolactin and gonadotropins in female rhesus monkey during the follicular phase of the menstrual cycle

The acute effects of i.v. cocaine on basal levels of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone were examined in nine female rhesus monkeys during the early follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected at 10-min intervals for 40 min before and 110 min after administration of cocaine (0.4 and 0.8 mg/kg i.v.). Cocaine plasma levels averaged 105 +/- 19 and 157 +/- 23 ng/ml after low- and high-dose administration. PRL decreased significantly (P less than .01) after cocaine administration and reached a nadir within 60 to 70 min. Inasmuch as cocaine blocks dopamine reuptake, PRL suppression is consistent with dopaminergic inhibitory control of PRL release from the pituitary. However, cocaine's effects on PRL were biphasic in 10 of 18 studies. PRL increased within 90 to 110 min post-cocaine and sometimes exceeded base-line levels by over 100%. The duration of PRL suppression (80 min) and the time of onset of the subsequent rebound PRL increase corresponds to the estimated half-life of i.v. cocaine in monkey plasma. PRL suppression followed by a rebound elevation also is consistent with clinical reports of hyperprolactinemia in chronic cocaine abusers. LH increased significantly (P less than .01) within 20 min after cocaine administration and remained above base-line for 40 to 50 min. Follicle-stimulating hormone did not change significantly after cocaine administration. Cocaine's stimulation of LH is consistent with cocaine's alleged enhancement of sexual arousal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of ovarian hormones and estrous cycle on the behavioral response to cocaine in female rats

Both humans and experimental animals demonstrate gender differences in response to cocaine. However, the mechanisms underlying these differences remain unclear. The purpose of the present study was to determine whether ovarian steroid hormones play a role in the locomotor response to cocaine in rats. Initial assessments of locomotor activity measured using photobeam monitors verified the robust gender difference in response to cocaine in our experimental paradigm. Subsequently, cocaine (5.0, 7.5, and 10.0 mg/kg) was shown to increase total horizontal activity in a dose-dependent manner in independent groups of intact females; the 5.0 mg/kg dose was selected for use in additional studies to determine the effect of estrogen (E) and progesterone (P) on the response to cocaine. Mature female rats were ovariectomized (OVX) or OVX and implanted with hormone-filled (E or P) Silastic capsules. Three to 4 weeks later, automated and observational measures of behavior were recorded after the administration of 5 mg/kg cocaine. Hormone replacement with E or E + P (but not P alone) resulted in greater cocaine-evoked hyperactivity than was observed in OVX animals. On measurement in normally cycling rats, hyperactivity induced by 5 mg/kg cocaine was greater during proestrus and estrus than during diestrus 2. The results of this series of experiments demonstrate that E significantly influences the responsiveness of female rats to cocaine. The enhanced response to cocaine was demonstrated in the presence of pharmacologically administered E as well as correlated with the normal estrous cycle.     

Modulation of ovarian LH receptor and serum hormone levels in rats with hyperprolactinemia induced by administration of ovine prolactin or sulpiride

Hyperprolactinemia was experimentally produced in rats by administration of ovine prolactin (oPRL) and sulpiride, and tried to evaluate the effect of hyperprolactinemia on ovarian receptor for luteinizing hormone (LH) as well as that on serum gonadotropin and steroid hormone levels. Wistar-Imamichi strain mature female rats showing 4-day estrous cycles were treated with various doses of oPRL or sulpiride twice a day for 4 days from diestrus. They were killed on the fifth day. Binding of ovarian LH receptors was reduced by a small dose of oPRL (0.1 IU) or sulpiride (0.25 mg) and restored to normal by larger doses of oPRL. However, larger doses of sulpiride (50 or 100 mg) increased the receptor bindings beyond the control level (4.39 +/- 0.40 ng/mg homogenate protein). Serum prolactin levels decreased in rats treated with larger doses of oPRL, but increased with larger doses of sulpiride. Serum LH levels increased with both agents. Although the ovaries treated with either oPRL or sulpiride suggested the lack of ovulation, there were no significant changes of steroid hormones in oPRL groups. In contrast, sulpiride treatment resulted in a reduction of estradiol and an increase of progesterone secretion, suggesting the prolonged effect of the drug. Thus, prolactin appeared to act on the rat ovarian LH receptors in two different manners in hyperprolactinemia, depending on the amount of this hormone or a ratio of prolactin to LH.     

围绝经期肾阴虚证妇女经中医治疗前后血清性激素水平的变化

目的比较围绝经期肾阴虚证妇女经滋阴补肾法治疗前、后血清性激素水平的变化,探讨滋阴补肾疗法治疗肾阴虚证妇女更年期综合征与血清性激素水平变化的相关性。方法分别检测58例围绝经期肾阴虚证妇女治疗前、后空腹血清性激素6项指标[包括雌二醇(E2)、促卵泡刺激素(FSH)、促黄体生成素(LH)、垂体泌乳素(PRL)、孕酮(P)、睾酮(T)];比较患者治疗前、后更年期综合征症状改善和血清性激素的变化并探讨其相互间的关系。结果 58例围绝经期肾阴虚证妇女经滋阴补肾法治疗后血清E2明显上升(P<0.05),FSH明显下降(P<0.05);LH、PRL、P、T治疗前、后差异无统计学意义(P>0.05)。滋阴补肾法治疗总有效率达78%,治疗有效组血清E2、FSH治疗前、后变化明显(P<0.05),而无效组的各项指标治疗前、后无明显变化(P>0.05)。结论围绝经期肾阴虚证妇女经滋阴补肾法治疗后血清E2、FSH较治疗前变化明显,说明血清E2、FSH的变化可能与疗效密切相关。     

Alcohol effects on luteinizing hormone releasing hormone-stimulated anterior pituitary and gonadal hormones in women

Plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol (E2) and progesterone were measured in 24 normal, adult women before and after i.v. administration of 100 micrograms luteinizing hormone releasing hormone (LHRH; Factrel) and p.o. ingestion of an alcohol (0.694 g of alcohol per kg b.wt.) or placebo solution. Twelve subjects were studied during the early follicular phase of the menstrual cycle and 12 subjects were studied during the midluteal phase of the menstrual cycle. During each menstrual cycle phase, six subjects received placebo solution and six subjects received alcohol solution administered under double-blind conditions. Mean peak blood alcohol levels of 113 to 122 mg/dl were measured 45 to 60 min after initiation of alcohol intake. LHRH stimulated a significant increase in LH after both alcohol (P less than .0001) and placebo (P less than .0001) administration, and this LH increase was equivalent during the follicular and the luteal phases of the menstrual cycle. LHRH also stimulated a significant increase in FSH levels after both alcohol and placebo intake during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in LHRH-stimulated FSH between the alcohol and placebo conditions. Plasma prolactin levels also increased significantly after LHRH administration during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in prolactin response to LHRH administration between the alcohol or placebo conditions during the follicular and luteal phases of the menstrual cycle. Plasma E2 levels did not increase significantly after LHRH administration and placebo alcohol during the follicular phase of the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

阿尔茨海默病患者性激素水平变化及其意义

背景女性阿尔茨海默病(Alzheimer disease,AD)的患病率较男性明显增高,雌激素替代治疗可预防和/或延缓AD的发生,因此推测AD的发病与雌激素缺乏有一定的关系.目的探讨AD患者血清性激素,特别是雌激素水平的变化及其意义.设计11病例-对照研究.地点和对象实验地点为西安交通大学第一医院神经内科.所有研究对象均来源于西安地区老年期痴呆患病率调查人群中确诊的AD患者和健康老年人.AD组27例,平均年龄(71.9±10.8)岁,男9例,女18例.对照组严格按照11配对的原则,选择与AD患者同性别,年龄相差小于3岁、同等文化程度、同一居住地,没有认知损害和精神症状的27例健康老人作为对照.干预两组均在清晨空腹800～900采集静脉血3 mL,用放射免疫法测定性激素.主要观察指标血清性激素水平(包括血清促卵泡生成素、促黄体生成素、泌乳素、孕酮、睾酮和雌二醇).血清雌二醇水平与AD患者痴呆的严重程度及简明精神状态检查表(MMSE)分值的相关性.结果血清促卵泡生成素、促黄体生成素、泌乳素、孕酮、睾酮水平在两组间比较差异没有显著性意义(P＞0.05);AD组血清雌二醇水平[(119.54±44.15)μg/L]比对照组[(154.55±63.62)μg/L]明显低(t=2.756,P＜0.05);血清雌二醇水平与AD患者痴呆的严重程度呈正相关(r=0.412,P=0.013);在AD组,血清雌二醇水平与MMSE分值呈正相关(r=0.59,P=0.25),但无统计学意义的相关关系.结论雌激素水平降低可能是AD发病的危险因素之一.     

Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment.

An ethanol oral self administration paradigm showed the existence of gender differences in alcohol preference in rats: whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. Neonatal estrogenization of females, which effectively confers a male phenotype on a genetically female brain, resulted in patterns of drinking that were similar to those displayed by intact male rats, indicating that gender differences in alcohol drinking patterns may be, at least partially, accounted for by sexual differentiation of the brain. To test whether gonadal steroids also exert activational effects on ethanol-seeking behavior, we also examined the effects of gonadectomy alone, or in combination with gonadal steroid replacement therapy. Castration did not significantly alter ethanol consumption in males, although treatment of castrated rats with dihydrotestosterone resulted in a significant inhibition of this parameter. As compared with the situation in intact female rats, ethanol ingestion was significantly reduced in ovariectomized female rats receiving estradiol (E2) and in ovariectomized female rats receiving combined E2 and progesterone replacement therapy. However, neither ovariectomy nor progesterone replacement in ovariectomized rats resulted in ethanol drinking patterns that were different compared to those observed in intact female controls. Thus, dihydrotestosterone and E2, respectively, appear to exert modulatory influences on the male and female rats' preference for ethanol, but further investigations are necessary to determine to what extent these effects result from activational actions on the brain.     

Alcohol effects on naloxone-stimulated luteinizing hormone, follicle-stimulating hormone and prolactin plasma levels in female rhesus monkeys

Alcohol's effects on hypothalamic function were examined under conditions of opioid antagonist stimulation. The effects of naloxone (0.5 mg/kg i.v.) on anterior pituitary hormone plasma levels after alcohol (2.5 and 3.5 g/kg) or sucrose control administration were studied in 10 normal female monkeys (Macaca mulatta) during the luteal phase of the menstrual cycle. Naloxone was administered 60 or 90 min after nasogastric alcohol administration when blood alcohol levels were above 120 and 140 mg/dl. The rate of naloxone infusion (i.v. bolus or slowly over 10 min) and basal levels of progesterone were critical determinants of the anterior pituitary response to opioid antagonist stimulation. Bolus administration of naloxone did not stimulate luteinizing hormone (LH) or follicle-stimulating hormone (FSH) under control or alcohol conditions. Slow naloxone infusion significantly stimulated LH (P less than .01-.05), but not FSH, in monkeys with high basal progesterone levels (14.1-15.8 ng/ml) under both control and alcohol conditions. Naloxone stimulation of LH was equivalent under control and 2.5 g/kg alcohol conditions (60 and 53% above base line). The LH response to naloxone was enhanced after administration of 3.5 g/kg alcohol and increased to 151% above base line (P less than .01) in monkeys with high progesterone levels. In monkeys with low progesterone levels (3.6-4.6 ng/ml), slow naloxone infusion did not stimulate LH or FSH after sucrose control or 3.5 g/kg alcohol administration, but LH increased (P less than .05) after 2.5 g/kg alcohol administration. A slow infusion of naloxone suppressed PRL levels significantly below base line after sucrose and alcohol administration in monkeys with high (P less than .01-.0002) and low progesterone levels (P less than .0001). Naloxone suppression of PRL was equivalent after alcohol and sucrose control administration. Alcohol alone did not suppress PRL levels significantly. We conclude that acute alcohol administration, with peak blood alcohol levels above 240 and 300 mg/dl, does not attenuate hypothalamic and pituitary responsivity to naloxone stimulation.     

Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys.

Cocaine is a nonselective monoamine reuptake inhibitor that is widely abused. Useful pharmacotherapies for cocaine dependence may include substitution medications that produce cocaine-like effects but have a slower onset and longer duration of action. Accordingly, the present study examined the effects of the long-acting, nonselective monoamine reuptake inhibitor indatraline in assays of cocaine discrimination and cocaine self-administration that have been used to evaluate other candidate treatment medications. In rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline, indatraline (0.1-1.0 mg/kg) produced a dose- and time-dependent substitution for cocaine. The effects of 1.0 mg/kg indatraline peaked after 30 min and lasted up to 24 h. In monkeys trained to self-administer 0.032 mg/kg/injection cocaine and food pellets during alternating daily sessions of cocaine and food availability, indatraline (0.0032-0.032 mg/kg/injection) maintained lower rates of responding than cocaine. Repeated treatments with indatraline (0.1-0.56 mg/kg/day) for 7 days produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses (0.0032-0.1 mg/kg/injection), and the highest dose of indatraline (0.56 mg/kg/day) nearly eliminated cocaine-maintained responding. However, doses of indatraline that decreased cocaine self-administration also usually decreased rates of food-maintained responding and produced behavioral stereotypies and trends toward weight loss and mild anemia. These findings suggest that although indatraline may decrease cocaine-taking behavior in rhesus monkeys, it also produces undesirable side effects that may limit its clinical utility in the treatment of cocaine dependence.     

Buprenorphine and naltrexone effects on cocaine self-administration by rhesus monkeys

The effects of daily treatment with buprenorphine (0.237-0.70 mg/kg/day), naltrexone (0.32-3.20 mg/kg/day) and saline on cocaine self-administration were compared in rhesus monkeys. Cocaine (0.05 or 0.10 mg/kg/injection) and food (1-g banana pellets) self-administration were maintained on a fixed-ratio 4 (variable ratio 16:S) schedule of reinforcement. Buprenorphine, naltrexone or an equal volume saline control solution were infused slowly over 1 hr through one lumen of a double lumen i.v. catheter at the same time each day. Saline and each dose of buprenorphine (0.237, 0.40 and 0.70 mg/kg/day) or naltrexone (0.32 and 3.20 mg/kg/day) were studied for 60 sessions over 15 consecutive days. Buprenorphine significantly suppressed cocaine self-administration (P less than .001-.0001) in comparison to saline in all monkeys. Cocaine self-administration decreased by 49 to 95% in five of six monkeys on the 1st day of buprenorphine administration (0.237 and 0.40 mg/kg/day) and remained suppressed by an average of 72 to 93% during buprenorphine treatment. After abrupt termination of buprenorphine treatment (0.237 and 0.70 mg/kg/day), cocaine self-administration remained suppressed for an average of 16 +/- 4.4 and 28 +/- 6.6 days, respectively. Buprenorphine (0.237 and 0.40 mg/kg/day) initially suppressed food self-administration in some monkeys (P less than .01), but tolerance developed to buprenorphine's effects on food-maintained responding whereas cocaine self-administration remained significantly suppressed. During treatment with 0.70 mg/kg/day of buprenorphine, food self-administration returned to or significantly exceeded (P less than .01) base-line levels in three animals. Daily patterns of food self-administration were not disrupted by buprenorphine treatment. Naltrexone (0.32 mg/kg/day) initially suppressed cocaine self-administration by an average of 28% over 15 days (P less than .0009). During high-dose naltrexone treatment (3.20 mg/kg/day), cocaine-maintained responding was suppressed by 25% over 15 days (P less than .01). Cocaine-maintained responding was not significantly changed by naltrexone in one of the five subjects. Food self-administration decreased by 24% (P less than .05) after 5 days of 0.32 mg/kg of naltrexone administration, then exceeded baseline levels during 3.20 mg/kg of naltrexone administration. These data suggest that buprenorphine decreases cocaine's reinforcing properties more effectively than naltrexone across the dose-range studied. Buprenorphine may be an effective pharmacotherapy for treatment of cocaine abuse as well as dual abuse of cocaine plus heroin.     

Opioid antinociception in ovariectomized monkeys: comparison with antinociception in males and effects of estradiol replacement.

Baseline nociception and opioid antinociception were compared in male and ovariectomized female rhesus monkeys. Females were studied without estradiol replacement or during treatment with estradiol benzoate at doses (0.002 and 0.01 mg/kg/day) designed to mimic 17beta-estradiol blood levels observed during different phases of the menstrual cycle and during pregnancy. Baseline sensitivity to thermal stimuli (42-54 degrees C) was similar in male and ovariectomized female monkeys. The antinociceptive effects of the mu-opioid agonists fentanyl, morphine, butorphanol, and nalbuphine were examined at 50 and 54 degrees C. There were no sex-related differences in the antinociceptive effects of the high-efficacy mu agonist fentanyl; however, the lower-efficacy mu agonists morphine, butorphanol, and nalbuphine produced greater antinociceptive effects in males than in untreated ovariectomized females. Because butorphanol and nalbuphine have low selectivity for mu versus kappa receptors and may produce kappa-agonist effects under some conditions, the high-efficacy, kappa-selective agonist U50,488 was also studied. U50,488 also produced greater antinociceptive effects in males. Treatment with estradiol benzoate tended to enhance opioid antinociception in the ovariectomized females; however, this effect was significant only for butorphanol and U50,488 during treatment with the highest dose of estradiol benzoate. These findings suggest that opioid agonists usually produce greater antinociception in male monkeys than in females, and the magnitude of these sex-related differences may be inversely related to efficacy at mu receptors or selectivity for mu versus kappa receptors. Estradiol appears to have little effect on mu-agonist antinociception in primates but may enhance the antinociceptive effects of kappa agonists.     

男性甲状腺功能亢进及低下患者血清性激素测定分析

目的：分析男性甲状腺功能亢进（甲亢）和甲状腺功能减退（甲减）患者性激素水平的变化及其临床意义。方法选择2013年1～6月来该院诊治并确诊为甲亢及甲减的男性患者,分为甲亢组及甲减组,另选健康志愿者为对照组,采用化学发光方法分别在治疗前及病情缓解分别检测性激素的水平。结果治疗前甲亢组及甲减组的血清促卵泡刺激激素（FS H ）、促黄体生成激素（L H ）水平与对照组比较差异无统计学意义（ P＞0．05）;治疗前甲亢组及甲减组的血清垂体泌乳素（PRL ）、雌二醇（E2）和睾酮（T）水平与对照组比较差异有统计学意义（P＜0．05）。治疗后甲亢组的血清E2水平与对照组比较差异有统计学意义（P＜0．05）。甲亢组血清PRL、E2及T水平治疗前后比较差异有统计学意义（P＜0．05）;甲减组血清PRL、E2及T水平治疗前后比较差异有统计学意义（ P＜0．05）。结论甲状腺激素水平对血清FS H、L H水平影响不明显,主要通过影响性激素PRL、E2及T水平变化,影响性功能等。     

Dynorphin effects on plasma concentrations of anterior pituitary hormones in the nonhuman primate

The role of dynorphin-(1-13) and dynorphin-(1-10)-amide in the neuroendocrine control of primate anterior pituitary hormones was studied in nonrestrained, ovariectomized rhesus monkeys. The effects of these opioids on plasma concentrations of prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and thyrotropin (TSH), and interactions with naloxone are reported here. Intravenous administration of dynorphin-(1-13), 30 to 120 micrograms/kg, significantly increased plasma PRL levels 3- to 4-fold. These PRL increases occurred within 5 min and levels remained elevated for at least 60 min. Administration of naloxone (1.0 mg/kg i.v.) antagonized the rise in PRL levels. Dynorphin-(1-13) had no significant effect on plasma LH, FSH or TSH levels. Dynorphin-(1-10)-amide (30-120 micrograms/kg) increased plasma PRL levels 2- to 4-fold at 5 to 40 min after administration. Plasma LH levels were significantly depressed 100 to 120 min postdrug. Dynorphin-(1-10)-amide produced no change in plasma FSH or TSH levels. These results indicate that dynorphin is involved in the modulation of PRL and perhaps LH secretion, although not affecting TSH or FSH release.     

Sex steroid hormone regulation of follicle-stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat.

Follicle-stimulating hormone (FSH) beta, luteinizing hormone (LH) beta, and alpha subunit messenger RNA (mRNA) levels were examined in rats after castration and sex-steroid replacement. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta complementary DNA (cDNA). Rat FSH beta mRNA is 1.7 kilobase in size. After ovariectomy, female FSH beta mRNA levels increased fourfold, whereas those of LH beta and alpha increased twenty- and eightfold, respectively. With estradiol, all subunits returned toward normal levels. Male LH beta and alpha mRNA levels rose eight- and fourfold, respectively, 40 d postcastration, but FSH beta mRNA levels increased minimally. After 7 d of testosterone propionate, LH beta and alpha mRNAs declined to normal levels, whereas FSH beta mRNA increased slightly. We conclude that in female rats FSH beta is negatively regulated by gonadal steroids, but to a lesser extent than LH beta or alpha mRNAs, and there is a differential regulation of FSH beta mRNA levels in males as compared with females at the time points examined.