Sexual differentiation and the effects of alcohol on aggressive behavior in mice

Male and female mice are differentially sensitive to the effects of alcohol on aggressive behavior. We investigated the role of testosterone during sexual differentiation in determining sex differences in alcohol effects on aggression. On the day of birth male mice were castrated or sham-operated. Neonatal female mice were injected with 250 micrograms of testosterone propionate (TP) or the oil vehicle. At approximately 75 days of age the mice which had not been gonadectomized at birth were gonadectomized. Control males and androgenized female mice then received 7.5 mm Silastic capsules containing testosterone, SC. Aggressive behavior toward an intruder was assessed following administration of ethanol (0.1-3.0 g/kg) or water, PO. Neonatally sham-gonadectomized male mice had a significant increase in aggressive behavior following administration of 1.0 g/kg alcohol, with no significant suppression of aggression at 3.0 g/kg. Neonatally androgenized female mice showed neither the male-typical response to adult testosterone and alcohol, nor did they show the female-typical response. Neonatally gonadectomized males showed an alcohol dose response curve that was similar to that of androgenized females. Postnatal testosterone did not appear to completely determine the male- and female-typical responses to alcohol on aggression. The critical period for this sexually dimorphic response to alcohol and testosterone may be primarily prenatal.     

Resistance of androgen-mediated aggressive behavior in mice to flutamide,an antiandrogen

The effects of ethanol (0.4, 0.8, 1.6, and 2.4 g/kg p.o.) on behavior of aggressive, timid, and sociable male mice treated with the drug on paired interactions with non-aggressive males given water were investigated. Under control interactions, aggressive mice attacked their partners, timid mice showed defensive-escape activities though their partners were completely non-aggressive, and sociable mice intensively investigated their partners. A low dose of ethanol (0.4 g/kg) increased while higher doses (0.8 to 2.4 g/kg) reduced aggressive activities in aggressive mice. Ethanol (0.8 g/kg) also evoked aggressive behavior in non-aggressive timid mice but no dose of ethanol stimulated aggression in non-aggressive sociable mice. Ethanol altered timid defensive-escape activities only in the highest dose of 2.4 g/kg: this dose increased defences and escapes in aggressive males while it reduced defensive upright postures in timid mice. However, 2.4 g/kg of ethanol reduced also another upright movement (exploratory rearing) in timid mice. Sociable activities were not increased by any dose of ethanol tested. By contrast, 0.4 g/kg of ethanol reduced sniffing and following partners in sociable mice. Thus, ethanol exhibited relatively strong aggression-stimulating effects in aversively disposed subjects while the drug was not able to supress timid defensive escape behavior and to stimulate active non-aggressive contacts between strange male mice.     

Facilitation of copulatory performance in male rats by naloxone: Effects of hypophysectomy, 17 α-estradiol,and luteinizing hormone releasing hormone

Three experiments were performed to explore the mechanism whereby systemic administration of the opiate receptor antagonist, naloxone hydrochloride (20 mg/kg) causes reductions in the frequency of intromissions preceding ejaculation and latency to ejaculation in sexually experienced male rats. Administration of naloxone to male rats which were hypophysectomized in addition to being castrated and implanted SC with 30 mm silastic capsules containing testosterone caused such behavioral changes, suggesting that these behavioral effects of naloxone do not result from interference with the binding of endorphin of pituitary origin. Surprisingly, a significant facilitatory effect of naloxone on sexual performance was absent in castrated controls bearing 30 mm testosterone implants. Recent evidence suggests that 17α-hydroxylated estrogens, which may be produced in gonadally intact males, possess appreciable affinity for opioid receptors. However, daily administration of 17α-estradiol (50 μg) to castrated, testosterone-implanted males failed to make them as behaviorally responsive to naloxone as gonadally intact animals. Administration of LHRH (1 μg given SC 1.5 hr prior to testing) caused a significant reduction in ejaculation latency in gonadally intact males but not in castrated males bearing 30 mm testosterone implants. It is suggested that the facilitatory effect of naloxone on masculine sexual performance results, in part, from a drug-induced release of LHRH.     

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline

RATIONALE: In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. OBJECTIVES: To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. METHODS: Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. RESULTS: After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. CONCLUSIONS: Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.     

Lack of increased intermale fighting behavior in mice after low ethanol doses.

The effect of ethanol on intermale fighting behavior, measured mainly as the total fighting time, was studied using Swiss-Webster mice in 5-min encounters in a neutral arena (i.e., not the home cage). Ethanol treatment compared to control treatment had no statistically significant effect on fighting behavior when given to both equal-sized members of a pair of males socially isolated for a) 5 or 10 days at a dose of 0.4 g/kg IP; b) 4 weeks at 0.8 g/kg IP; and c) 38 weeks at 0.4 g/kg IP. Moreover, no significant effect was found when ethanol was given only to the expected dominant member of a pair, that is, to: a) a male isolated for 48 weeks confronting a younger and smaller group-housed male at 0.4 g/kg PO; and b) a male that had been pair housed with a female conspecific for 5 weeks confronting a group-housed male of equal age and weight at 0.4 g/kg IP. The results suggest that under these conditions ethanol does not lead to increased fighting behavior in Swiss-Webster male mice.     

Repeated alcohol: behavioral sensitization and alcohol-heightened aggression in mice

RATIONALE: Repeated administration of psychomotor stimulants or opiates can induce behavioral sensitization, typically detected as progressive and long-lasting increases in the motor-activating effects of these drugs. This phenomenon may be relevant to seizure susceptibility, drug self-administration, and sexual behavior. Repeated administration of alcohol can also induce behavioral sensitization and may have consequences on how alcohol affects aggressive behavior. OBJECTIVES: To (1) determine the enduring nature of locomotor sensitization to alcohol; (2) examine subsequent changes to morphine and amphetamine effects on locomotor behavior; and (3) test whether behavioral sensitization to alcohol or morphine is relevant to alcohol-heightened aggression. METHODS AND RESULTS: In the first experiment, male CFW mice were given ten injections of alcohol (2.4 g/kg/day), morphine (30.0 mg/kg/day), or saline. Video tracking confirmed locomotor sensitization--an approximate 200% increase in the motor-stimulating effects of these drugs. Challenges with 2.0 g/kg alcohol revealed that locomotor sensitization to alcohol persisted for at least 2 months. Alcohol-sensitized mice showed evidence of cross-tolerance to the sedative effects of morphine (5 mg/kg) but showed no evidence of cross-sensitization to the stimulant effects of 30.0 mg/kg morphine or 1.0 mg/kg amphetamine. In the second experiment, under conditions resulting in species-typical aggressive behavior against a male intruder, there were no differences in the aggressive behavior relative to saline control mice following alcohol or morphine sensitization. However, in the mice sensitized to alcohol, but not to morphine, there was a vertical shift in the dose-effect curve for moderate doses of alcohol (0.6-1.7 g/kg, p.o.). In addition, twice as many alcohol-sensitized mice consistently showed alcohol-heightened aggression when compared with the saline control mice (74% vs 37%, respectively). CONCLUSIONS: Repeated administration of alcohol can sensitize locomotor stimulation and may also render mice more vulnerable to increased aggression after alcohol. Moreover, the results suggest that at least some of the neuroadaptations caused by repeated administration of alcohol are relevant to alcohol-heightened aggression.     

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

Rationale

Higher doses of benzodiazepines and alcohol induce sedation and sleep; however, in low to moderate doses these drugs can increase aggressive behavior.

Objectives

To assess firstly the effects of ethanol, secondly the effects of flunitrazepam, a so-called club drug, and thirdly the effects of flunitrazepam plus alcohol on aggression in mice and rats.

Methods

Exhaustive behavioral records of confrontations between a male resident and a male intruder were obtained twice a week, using CF-1 mice and Wistar rats. The salient aggressive and non-aggressive elements in the resident's repertoire were analyzed. Initially, the effects of ethanol (1.0 g/kg), and secondly flunitrazepam (0; 0.01; 0.1; and 0.3 mg/kg) were determined in all mice and rats; subsequently, flunitrazepam or vehicle, given intraperitoneally (0; 0.01; 0.1; and 0.3 mg/kg) was administered plus ethanol 1.0 g/kg or vehicle via gavage.

Results

The most significant finding is the escalation of aggression after a moderate dose of ethanol, and a low dose of flunitrazepam. The largest increase in aggressive behavior occurred after combined flunitrazepam plus ethanol treatment in mice and rats.

Conclusions

Ethanol can heighten aggressive behavior and flunitrazepam further increases this effect in male mice and rats.     

Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT_1A receptors. The present experiments tested the hypothesis that activating 5-HT_1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT_1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1–0.3 mg/kg, IP) or flesinoxan (0.1–1.0 mg/kg, IP). The 5-HT_1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, IP) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, PO) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03–0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT_1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT_1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT_1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission. Received: 26 January 1998/Final version: 10 March 1998     

Ethanol-induced depression of aggression in mice antagonized by hyperbaric exposure

The present study investigated the effect of hyperbaric exposure on ethanol-induced depression of aggressive behavior measured by resident-intruder confrontations. Adult male CFW mice (residents) were paired with females and housed together for 26 days. Then, resident mice were intubated with either ethanol (2 g/kg) or water (20 ml/kg) and were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium oxygen (heliox) or 12 ATA heliox using a within-subjects counterbalanced design. Thirty minutes after intubation an intruder was introduced. Ethanol significantly decreased aggressive behaviors (attack latency, attack bites, sideways threats, tail rattles and pursuit) in 1 ATA-treated animals. Pressure completely antagonized the depression of aggression induced by ethanol. Ethanol alone and pressure alone did not significantly affect nonaggressive behaviors. There were no statistically significant differences between groups in blood ethanol concentrations 50 minutes after intubation. These results suggest that ethanol's effects on aggressive behavior result from the same membrane actions leading to loss of righting reflex, depression of locomotor activity, tolerance and dependence.     

Ethanol effects on aggression of rats selected for different levels of aggressiveness

Male rats confronting strange male intruders into their home cages were divided into nonaggressive, low-to-intermediate aggressive, and highly aggressive groups. In tests with low (0.3 and 0.6 g/kg) doses of ethanol the nonaggressive rats did not become aggressive; low-intermediate animals showed a significant increase in frequency and duration of attack behaviors; but highly aggressive rats displayed a slight (nonsignificant) decline. A higher ethanol dose (1.2 g/kg) consistently led to decreased aggression. This rate-dependency of the enhancement of aggression by low doses of ethanol is concordant with a view that the mechanism of this enhancement involves ethanol interference with some mechanism which normally acts to limit or inhibit attack.     

Toxicity and carcinogenicity of riddelliine in rats and mice

These investigations of riddelliine analyzed potential carcinogenesis and the utility of the female-rat/male-mouse design in bioassays and dose-response. Groups of 50 Fischer rats and B6C3F1 mice were gavage-administered riddelliine 5 days per week for 105 weeks. The dose levels for male rats were 0 or 1.0 mg/kg body weight; female rats 0, 0.01, 0.033, 0.1, 0.33, or 1.0 mg/kg; male mice 0, 0.1, 0.3, or 1.0, 3.0 mg/kg; and female mice 0 or 3.0 mg/kg. The dose groups were purposely designed to evaluate the dose-response relationship only in female rats and male mice. In rats, liver hemangiosarcoma, hepatocellular adenoma, and mononuclear cell leukemia were significantly increased in the 1.0 mg/kg male and female dose groups. Non-neoplastic lesions occurred in the liver and kidney of male and female rats. In mice, hemangiosarcomas increased significantly in the liver of males in the 3.0 mg/kg dose group. Alveolar/bronchiolar neoplasms in the 3.0 mg/kg dose group of female mice were significantly increased. Hepatocellular neoplasms were significantly decreased in the 1.0 mg/kg dose group of male and 3.0 mg/kg dose groups of male and female mice. Non-neoplastic lesions occurred in the liver and kidney of male and female, and lung and arteries of female mice. These studies demonstrate toxicity and carcinogenicity of riddelliine in rats and mice, and a dose-response relationship in female rats and male mice under the experimental conditions employed.     

Interaction between ethanol and caffeine in operant behavior of rats

The interaction between ethanol and caffeine on operant behavior was studied in 24 water-deprived male rats trained in a discrete trial spatial alternation schedule with water as reinforcer. One single drug dose-response experiment or one dose combination of ethanol and caffeine (including the associated control treatments) was run on 4 successive days in 1 week. The four treatments of 1 week were administered to each animal in a distinct order according to the 24 possible permutations. In the single drug weeks, ethanol (0.25, 0.5, 0.75 and 1.0 g/kg IP) or caffeine (5, 10, 20, and 40 mg/kg PO) were administered 15 min before the session. In four interaction experiments all combinations of two doses of ethanol (0.5 and 1.0 g/kg IP) and two doses of caffeine (25 and 50 mg/kg PO) were employed. Ethanol and caffeine alone showed both dose-dependently decreased choice accuracy and increased response latency and passiveness. In combination, caffeine normalized the ethanol-induced alterations in ITI response rate and pause length but potentiated the effects on choice accuracy, latency and number of pauses. The results are interpreted in terms of effects of these drugs on attentional and arousal processes, and the test procedure is proposed as a screening tool for the preclinical assessment of ethanol-drug interactions.     

Decrease in d-methamphetamine sensitivity in mice due to ethanol: apparent inhibitory and stimulatory effects of ethanol on d-methamphetamine-induced locomotor activity

The locomotor activity of mice was recorded after administration of d-methamphetamine-HCl (1.5, 2.5, 5.0 and 7.5 mg/kg body weight) and/or ethanol (0.8 and 1.6 g/kg body weight). Mice injected with lower doses of d-methamphetamine (1.5 or 2.5 mg/kg) showed a marked increase in locomotor activity, while in those with higher doses of d-methamphetamine (5.0 or 7.5 mg/kg), locomotor activity was not further enhanced, but slightly decreased. Administration of ethanol inhibited the stimulated locomotor activity caused by low doses of d-methamphetamine (1.5 or 2.5 mg/kg), while the stimulation of motility after higher doses of d-methamphetamine (5.0 or 7.5 mg/kg) was potentiated by administering ethanol. Although apparent inhibition and stimulation of d-methamphetamine-induced locomotor activity of mice due to ethanol was observed, it is suggested that mice administered ethanol showed the decreased sensitivity to d-methamphetamine by plotting total locomotor activity of mice against doses of d-methamphetamine administered. The half maximum effective dose of d-methamphetamine for locomotor activity was increased from 1.5 mg/kg to 3.0 mg/kg by concomitant administration of 1.6 g/kg ethanol.     

NMDA receptor antagonism: escalation of aggressive behavior in alcohol-drinking mice

Rationale

Memantine is a potential treatment for alcoholic patients, yet few studies investigate the effect of concurrent treatment with memantine and ethanol on aggression. We evaluated aggressive behavior following ethanol consumption and treatment with glutamatergic drugs to characterize interactions between these compounds.

Objective

This study aimed to use rodent models of aggression to examine interactions between glutamatergic compounds and ethanol.

Materials and methods

Once male CFW mice reliably self-administered 1 g/kg ethanol or water, they were assessed for aggression in resident–intruder confrontations. Alternatively, aggression was evaluated following a social-instigation procedure. Animals were then injected with memantine, ketamine, neramexane, MTEP, or LY379268 before aggressive confrontations. Effects of the pharmacological manipulations on salient aggressive and non-aggressive behaviors were analyzed.

Results

Moderate doses of memantine, neramexane, and MTEP interacted with ethanol to increase the frequency of attack bites while ketamine did not. The highest dose of LY379268, an mGluR_2/3 agonist, reduced both aggressive and non-aggressive behaviors after water and ethanol self-administration. Attack bites increased with social instigation and decreased with administration of high doses of MTEP and LY379268. Memantine and MTEP both reduced attack bite frequency in the instigation condition without reducing locomotor behavior.

Conclusions

Memantine and neramexane interacted with ethanol to heighten aggression. The binding characteristics of these compounds allow for ‘partial trapping’ by which some NMDARs are unblocked between depolarizations. We propose that this feature may contribute to the differential aggression-heightening interactions between these compounds and ethanol. MTEP also interacted with ethanol to escalate aggression, possibly through inhibition of mGluR₅ modulation of NMDARs.     

Failure of ethanol or pentobarbital to suppress fighting in the pit gamecock (Gallus gallus)

The pit gamecock (Gallus gallus) provides a model of strong trained aggression. A total of 16 aggressive pairs was treated with pentobarbital (40 or 60 mg/kg, intramuscularly), or ethanol (10–30 ml/kg of 33% v/v ethanol, by gastric intubation), or ethanol plus immobilization. Pairs of treated cocks were allowed to recover together in one cage. Fighting behavior occurred immediately upon recovery of the second cock of each pair. Thus, recovery from anesthesia in pairs failed to attenuate aggressive behavior in the gamecock, contrary to the marked attenuation previously observed in the male rabbit.     

Age- and sex-related differences in the acquisition and reinstatement of ethanol CPP in mice

Many people begin to experiment with alcohol during adolescence, an important developmental period during which sex differences in the effects of ethanol appear. In the present study we evaluated the effect of ethanol (0, 0.625, 1.25 or 2.5 g/kg) on the acquisition of a conditioned place preference (CPP) in early and late adolescent male and female mice. In addition, we assessed the capacity of ethanol to induce reinstatement of the CPP after its extinction. CPP was induced in early and late adolescent females with 2.5 g/kg, and in early adolescent males with 1.25 or 2.5 g/kg of ethanol. No CPP was observed in late adolescent males. Priming with ethanol reinstated the CPP induced by the highest dose in early adolescent male and early and late adolescent female mice. Our data suggest that early adolescents of both sex and late adolescent females are particularly vulnerable to the effects of ethanol.     

An evaluation of the locomotor stimulating action of ethanol in rats and mice

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanolinduced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.     

Long-term citalopram maintenance in mice: selective reduction of alcohol-heightened aggression

Background Selective serotonin reuptake inhibitors (SSRIs) alleviate many affective disturbances in human clinical populations and are used in animal models to study the influence of serotonin (5-HT) on aggressive behavior and impulsivity. Objective We hypothesized that long-term SSRI treatment may reduce aggressive behavior escalated by alcohol consumption in mice. Therefore, aggression was tested in male CFW mice to determine whether repeated citalopram (CIT) administration reduces alcohol-heightened aggression. Materials and methods Resident male mice self-administered alcohol by performing an operant response on a panel placed in their home cage that delivered a 6% alcohol solution. Mice repeatedly confronted an intruder 15 min after self-administration of either 1 g/kg alcohol (EtOH) or water (H₂O). Aggressive behaviors were higher in most mice when tests occurred after EtOH intake relative to H₂O. Once baseline aggression was established, animals were injected (i.p.) twice daily with 10 mg/kg CIT or saline (SAL) for 32 days. Every 4 days throughout the CIT treatment period, aggressive encounters occurred 6 h after CIT injections, with testing conditions alternating between EtOH and H₂O intake. Results Aggression was only modestly affected by CIT in the first 2 weeks of treatment. However, by day 17 of CIT treatment, alcohol-heightened aggressive behavior was abolished, while baseline aggression remained stable. These data lend support for the role of the 5-HT transporter in the control of alcohol-related aggressive behavior, and the time course of effects suggests that a change in density of 5HT_1A autoreceptors is necessary before antidepressant drugs produce beneficial outcomes.     

鹿茸益肾胶囊治疗肾阳虚证阳痿的药效学研究

目的：研究鹿茸益肾胶囊治疗肾阳虚证阳痿的药效学机制。方法：观察鹿茸益肾胶囊对去势雄性大鼠阴茎勃起潜伏期的影响,对去势雄性大鼠附性器官和垂体、肾上腺、胸腺、脾脏质量系数的影响,对去势雄性大鼠性腺内分泌激素血清含量的影响,对氢化可的松致阳虚模型小鼠的影响。结果：鹿茸益肾胶囊能够提高去势雄性大鼠阴茎对刺激的兴奋性,显著缩短勃起潜伏期,提高去势雄性大鼠附性器官的质量系数;提高去势雄性大鼠垂体、肾上腺质量系数;降低去势雄性大鼠胸腺、脾脏质量系数;显著升高大鼠血清睾酮（T）、皮质醇（F）含量、显著降低血清促黄体生成素（LH）、促卵泡刺激素（FSH）含量;显著改善阳虚小鼠的阳虚症状,增强生命力。结论：鹿茸益肾胶囊具有温阳益肾的作用,可用于治疗肾阳虚证阳痿、性功能减退。     

Effects of delta 9-THC and castration on behavior and plasma hormone levels in male mice

Gonadectomy resulted in a rapid increase in plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, but had no consistent effects on plasma prolactin (PRL) and growth hormone (GH) levels. In castrated males, oral administration of THC (50 mg/kg) significantly increased plasma LH levels within hours following surgery and again from 3 to several weeks post-castration, while THC treatment decreased LH levels between 1 day and 2 weeks postcastration. Administration of THC to 12-hour sham castrates significantly increased plasma LH levels. Plasma FSH, PRL and GH levels were either reduced or unchanged by THC. Administration of THC significantly reduced levels of gonadotropins, PRL and GH in intact males. In additional studies, we examined the influence of THC on the negative feedback response of the anterior pituitary to gonadal steroids. In testosterone propionate (TP)-treated castrated males, concomitant administration of THC increased plasma testosterone (T) and LH at 20 min, while plasma FSH levels were elevated after 60 min. In contrast, in intact TP-treated mice, concomitant THC exposure reduced plasma T levels except at 60 min, when plasma LH levels were significantly increased. Testosterone replacement failed to restore copulatory behavior in castrated mice given a single dose (50 mg/kg) of THC. In fact, acute THC administration to these TP-treated castrates resulted in marked sedation, which was not observed in intact mice given the same dose of THC in an earlier study. The present findings indicate that the effects of acute THC treatment on pituitary gonadotropin release is dependent upon the time after castration. Furthermore, THC administration can suppress copulatory behavior even in animals whose peripheral T levels have been maintained. Effects of THC on plasma androgen levels in animals injected with TP suggest that THC can alter the metabolism or target tissue response to gonadal steroids.