In vivo evidence for the specific binding of human beta-endorphin to the lung and liver of the rat

Specific binding of human beta-endorphin (beta-EP) was demonstrated in the lung and liver of the rat in vivo by the following lines of evidence, using [125I-Tyr27]beta-EP as a radiolabeled tracer. First, the tissue-to-serum concentration ratios of the intact labeled peptide 15 min after intravenous administration were decreased significantly in the lung and liver by a simultaneous injection of unlabeled beta-EP (48.5 nmol/kg), whereas in the other tissues such a decrease was not observed. Second, serum concentrations of the preadministered labeled peptide were increased rapidly after an additional intravenous injection of unlabeled beta-EP via the femoral vein, but not via the carotid artery into the heart. Third, the immunoreactive labeled beta-EP (125I-beta-EP), which was purified on a Sephadex G-50 column and did not specifically bind to the rat brain membranes, did not accumulate in the lung and liver and was not displaced by unlabeled beta-EP in vivo, in contrast to [125I-Tyr27]beta-EP, the commercially available HPLC-purified labeled peptide. Fourth, an additional injection of dynorphin (1-13) or ethylketocyclazocine (kappa agonist) also increased the serum concentrations of preadministered [125I-Tyr27]beta-EP but injection of Ala2-D-Leu5-enkephalin (delta agonist) or naloxone (mu antagonist) did not, suggesting kappa-type binding sites in the lung.     

Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signaling

The mechanism by which ethanol induces beta-endorphin (beta-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of beta-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on beta-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of beta-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. beta-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-beta1 (TGF-beta1) protein. Ethanol and DDA increased TGF-beta1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-beta1 in these cells. TGF-beta1 increased apoptosis of beta-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-beta1 neutralizing antibody blocked the apoptotic action of ethanol on beta-EP neurons. Determination of TGF-beta1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated beta-EP neurons indicated that ethanol, TGF-beta1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases beta-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-beta1-linked apoptotic signaling.     

Changes in beta-endorphin and stress-induced analgesia in mice after exposure to forced walking stress.

In this study, we attempted to clarify the correlation between changes in the level of beta-endorphin (beta-EP) in the mouse brain and the stress-induced analgesia (SIA) after exposing animals to forced walking stress. The immunohistochemical distribution of beta-EP after stress was first analyzed quantitatively in mice and then more specifically using a microphotometry system with results showing that the fluorescence intensity of beta-EP in the peri-aqueductal gray matter (PAG) and arcuate nucleus of the medial basal hypothalamus (ARC) was increased 6 h after exposure to forced walking stress. Further, SIA was examined after exposing animals to the forced walking stress and the formalin test. At 6 h after forced walking stress, significant SIA was observed in the second phase (from 10 to 30 min after formalin injection) of the formalin-induced paw licking behavior, but not in the first phase (from 0 to 10 min after formalin injection). This SIA was antagonized by beta-EP-(1-27), an opioid epsilon receptor antagonist. In nonstressed mice, the injection of beta-EP produced a reduction in formalin-induced paw-licking in the second phase. A significant antinociceptive effect by beta-EP was well antagonized by beta-EP-(1-27). Thus, the present results suggest that the increase in beta-EP levels in PAG and/or ARC may be involved in SIA after exposure of mice to the forced walking stress.     

The calcium antagonist nimodipine increases beta-endorphin release from rat hypophysis through an action on adrenal glands. An "in vivo" and "in vitro" study

Intravenous injection of nimodipine (1, 10 and 100 micrograms/Kg) raised plasma ACTH and beta-endorphin (beta-EP) level and reduced pituitary beta-EP content, in the rat. These effects were sharp and short-lasting. Nimodipine (10(-8), 10(-7), 10(-6) M) did not change basal and hypothalamic extract stimulated beta-EP release from pituitary tissue in vitro. Basal release of corticosterone from adrenal glands, superfused in vitro with the calcium antagonist (10(-7) - 10(-6) M), was not modified. However, ACTH-induced release was strongly reduced. Since glucocorticoids feedback regulates biosynthesis and cleavage of pro-opiocortin, nimodipine, which reduces adrenal gland responsiveness to ACTH, might reflexly increase beta-EP release from hypophysis.     

Influence of age at drinking onset on the alcohol deprivation effect and stress-induced drinking in female rats

We have recently observed increased stress responsiveness with regard to alcohol consumption in male rats that consumed alcohol since their adolescent period. Thus, early age at drinking onset can induce enhanced stress-induced alcohol drinking in male rats. However, it is not known whether female rats respond in a similar way. Therefore, we compared the drinking behavior of two female Wistar rat groups--one that acquired alcohol consumption during adolescence (adolescent group) and the other that acquired their drinking during adulthood (adult group) in a model of long-term voluntary alcohol drinking with repeated deprivation and stress phases. Furthermore, we studied the influence of age at drinking onset on the efficacy of acamprosate treatment. Thirty-nine female Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as to 5% and 20% ethanol solutions during an observation period of 29 weeks. A deprivation phase of 14 days was introduced following 8 weeks of access to alcohol in order to measure the alcohol deprivation effect (ADE). After 15 and 25 weeks of alcohol access, all animals were subjected for 3 consecutive days of forced swim and electric foot-shock stress, respectively. After 29 weeks of access to alcohol all animals underwent a second deprivation phase and the subsequent ADE was measured either under acamprosate (200 mg/kg) or vehicle treatment. Drinking before the first deprivation phase was not different between animal groups. However, the expression of the first ADE was more pronounced in adult female rats and alcohol intake stayed increased for the remainder of the experiment in the adult group. Both repeated swim stress and foot-shock stress produced a more pronounced increase in ethanol consumption in the adolescent group compared to the adult group. Acamprosate reduced relapse-like drinking in the adult female rat group. However, it had no effect on the ADE in the adolescent group. In conclusion, female rats that initiate alcohol consumption during adolescence might be more susceptible to stress-induced alcohol consumption. Adolescent alcohol drinking might also result in a reduced response to acamprosate.     

Acetyl-l-carnitine restores the daily pattern of hypothalamic beta-endorphin in rats exposed to continuous light

With the aim of evaluating the effect of acetyl-l-carnitine (ALC) on the daily pattern of hypothalamic beta-endorphin (beta-EP), we studied the effect of chronic treatment with ALC on hypothalamic beta-EP contents after suppression of the dark-phase of the light-dark cycle in female rats. We evaluated the hypothalamic content of beta-EP immunoreactivity every 3 h for 24 h in: (1) female rats treated with ALC for 15 days; (2) female rats treated with ALC for 15 days and exposed to continuous light for 24 h. The concentration of beta-EP immunoreactivity in tissue extracts was measured by radioimmunoassay. The results demonstrate that concentrations of beta-EP immunoreactivity in the medial basal hypothalamus show a circadian rhythm, with beta-EP immunoreactivity levels being higher during the night than during the rest of the day. Exposure to continuous light for 24 h abolished the nocturnal increase in hypothalamic beta-EP immunoreactivity. Rats treated with ALC showed a daily pattern in the beta-EP content of the medial basal hypothalamus similar to that of control rats. These data emphasize the possible role of ALC in restoring or maintaining the endogenous rhythmicity of central beta-EP.     

Effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in Warsaw alcohol high-preferring rats

Rationale

Pharmacological treatment currently used for alcohol dependence is not sufficient for the all patients, and there is a crucial need to find more effective treatments. Recent studies indicate that topiramate is likely the most promising new medication for alcohol dependence. The rationale for topiramate as treatment for alcohol addiction is based on its multifaceted neurochemical activity that targets multiple neural pathways.

Objectives

This study aims to assess the effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in rats selectively bred for high alcohol preference.

Methods

Initially, Warsaw high preferring rats (N?=?50) were given a 24-h/day free choice between a 10 % (v/v) alcohol solution and water for three consecutive weeks. Subsequently, rats were administered with topiramate (40 or 80 mg/kg b.w.) or vehicle for 14 days and ethanol intake was measured daily. Subsequently, we examined the effects of topiramate on plasma beta-endorphin levels, while alcohol was available and when it was not available for an extended period time.

Results

We observed significantly increase in the levels of beta-endorphin in rats with free access to alcohol both in a topiramate- or vehicle-treated group. However, in topiramate-treated group, a voluntary consumption of alcohol diminished in comparison with the vehicle-treated rats.

Conclusion

The results from this study indicated that topiramate reduces voluntary alcohol intake and support our previous findings that the increase of beta-endorphin level is responsible at least partly for the effectiveness of drugs in treating the alcohol addiction.     

Lack of changes in beta-endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism--a pilot study

Clinical and animal studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may help to reduce alcohol intake but investigations led to conflicting results. A few studies indicated that serotonin (5-HT) may modulate the brain beta-endorphin level, which plays an important role in the development of alcohol craving. Our study examined the influence of fluoxetine on the endogenous opioid system. We investigated plasma levels of beta-endorphin in rats with either high alcohol preference (Warsaw High-Preferring; WHP) or low alcohol preference (Warsaw Low-Preferring; WLP) after repeated treatment with fluoxetine (5 mg/kg i.p. for 21 days). We examined the rats 24 hours after fluoxetine treatment in order to determine whether chronic fluoxetine produces a long-term change in the beta-endorphin levels. The animals received either a single dose of ethanol (2 g/kg) or an identical single dose of saline one hour before blood collection. While a few studies observed an increase in the level of beta-endorphin after a single fluoxetine injection, we did not observe any increase in beta-endorphin plasma levels after repeated fluoxetine treatment. We also did not observe any changes in beta-endorphin levels of rats treated with fluoxetine and injected with ethanol. A lack of increase of beta-endorphin levels may explain why fluoxetine has a limited value in the prevention of craving for alcohol.     

β—内腓肽抑制急性低氧暴露大鼠下丘脑促甲状腺素释放激素的释放

AIM: To study the influences of beta-endorphin (beta-EP) on the responses of thyrotropin-releasing hormone (TRH) in median eminence (ME) and paraventricular nucleus (PVN) of hypothalamus to acute hypoxia in conscious rats. METHODS: Brain TRH, serum T3 and T4 were measured by radioimmunoassay. The male Wistar rats were exposed in a simulated hypobaric chamber at 7000 m altitude (8.2 % O2) for 2 h. beta-EP was given by intraventricular injection (icv) before hypoxia. RESULTS: beta-EP (0.1 or 1 micromol/L, icv) elevated TRH levels of ME by 12 % (P <0.05) and 15 % (P < 0.05) in treated groups comparing with saline control group (4.8+/-0.3) microg/g protein, and enhanced TRH of PVN by 24 % (P <0.05) and 44 % (P < 0.01) in treated groups comparing with control group (180+/-21) ng/g protein during hypoxia. Meanwhile, serum T3 and T4 were significantly decreased (P < 0.05 or P < 0.01). Naloxone 10 micromol/L abolished the effects of beta-EP (0.1 micromol/L) on TRH in ME (P <0.01) and PVN (P < 0.01) as well as T3 and T4. Naloxone (10 micromol/L, icv) alone reduced contents of TRH in ME and PVN (P <0.05 or P <0.01), but increased the levels of serum T3 and T4 (P <0.01). CONCLUSION: beta-Endorphin was involved in the modulation of hypothalamic TRH release of rats during hypoxia, through an inhibitory mechanism of TRH release in ME and PVN of hypothalamus.     

Selective reduction by the 5-HT antagonist amperozide of alcohol preference induced in rats by systemic cyanamide.

This investigation was undertaken to determine the effect of a unique psychotropic agent on the volitional drinking of alcohol induced pharmacologically in the rat by an inhibitor of aldehyde dehydrogenase. Following administration of cyanamide in a dose of 10 mg/kg twice daily for 3 days, the pattern of drinking of ethyl alcohol was determined in each of 12 Sprague-Dawley rats by means of a standard preference test for 3-30% alcohol vs. water. Then, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7-15%. After a 4-day predrug test, either the saline control vehicle or the diphenylbutylpiperazinecarboxamide derivative, amperozide, was administered subcutaneously. The injections of amperozide were given b.i.d. at 1600 and 2200 h over 3 days in a dose of 0.5, 1.0, or 2.5 mg/kg. The intake of alcohol during the sequence of amperozide injections was significantly reduced in a dose-dependent manner in terms of both absolute g/kg and proportion of alcohol to water intake, whereas the saline control vehicle was without any effect on alcohol consumption. Although the highest dose of amperozide reduced the total intake of fluid due to the sharp decline in alcohol drinking, neither the consumption of food nor level of body weight was affected by any dose of the drug either during or after its administration. Because amperozide acts centrally on the synaptic activity of dopaminergic and serotonergic neurons in limbic system structures, it is envisaged that the drug ameliorates the aberrant drinking of alcohol by virtue of a direct effect on either one or both of these classes of neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: A caloric response?

The purpose of this study was to elucidate further the role of serotonin (5-HT) in the preference for ethyl alcohol induced in the Sprague-Dawley rat by lesions of the N. accumbens. Following a standard preference test for 3–30% alcohol, dopaminergic or serotonergic neurons in the N. accumbens of the rat were lesioned bilaterally by 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), respectively. After recovery postoperatively, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7% to 11%. Following a 4-day pretest, either the saline control vehicle or the 5-HT reuptake inhibitor, sertraline, was injected subcutaneously in a dose of either 3.0 or 10 mg/kg b.i.d. at 0800 and 2000 h over the next 3 days. Alcohol preference during the injection sequence and for 4 days thereafter was significantly reduced by sertraline in terms of both absolute g/kg and proportion of alcohol to water intakes. Saline was without effect on alcohol drinking. Comparisons of the drinking profiles of serotonergic versus dopaminergic lesioned rats revealed a dose dependent response to sertraline only in the 5,7-DHT lesioned animals. Although sertraline did not alter water drinking, the consumption of food declined significantly during and after its administration with a decline in body weight also observed at the higher dose. These results suggest that in addition to dopaminergic neurons in the N. accumbens, the synaptic activity of 5-HT in this structure contributes to the aberrant drinking of alcohol. However, this interpretation is tempered by the fact that caloric intake was suppressed concomitantly by the drug. Thus the presumed central action of sertraline may not be functionally specific to the reinforcing or other behavioral properties of alcohol.     

Treatment with cyclohexenonic long-chain fatty alcohol reverses diabetes-induced tracheal dysfunction in the rat

In this study, we tried to elucidate the effect of cyclohexenonic long-chain fatty alcohol (N-hexacosanol) on tracheal dysfunction in diabetic rats. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an intraperitoneal injection of 50 mg/kg streptozotocin. Non-diabetic control rats received an injection of citrate-phosphate buffer alone. Four weeks after the induction of diabetes, rats were randomly divided into 5 groups: age-matched non-diabetic control rats (group A); 4-week diabetic rats without N-hexacosanol treatment (group B); diabetic rats treated with vehicle (group C), and diabetic rats treated with N-hexacosanol at a dose of 2 or 8 mg/kg i.p. every day for the following 4 weeks (group D and group E, respectively; n = 6-8 animals in each group). Serum glucose and insulin levels were determined, as were the contractile responses induced by carbachol and 100 mmol/l KCl. The participation of M(2) and M(3) receptors was investigated in the trachea by real-time polymerase chain reaction (PCR), hematoxylin and eosin (HE) and immunohistochemical staining. Hypertrophy of airway smooth muscle was observed in diabetic rats, and was ameliorated by treatment with N-hexacosanol. Treatment with either 2 or 8 mg/kg N-hexacosanol did not alter diabetic rat status, i.e., body weight, serum glucose or serum insulin levels, but it significantly reversed the decrease in tracheal wall thickness and diabetes-induced hypercontractility in the rat trachea. In the immunohistochemical studies, muscarinic M(2) and M(3) receptors were expressed in the airway smooth muscle, the elastic fibers, the fibroblast and the surface of epithelium, and these expressions were not altered by either induction of diabetes or N-hexacosanol treatment. The expression of M(3) muscarinic receptor mRNAs in the trachea tended to be increased by the induction of diabetes and normalized when treated with N-hexacosanol. Our data indicate that N-hexacosanol could reverse diabetes-induced hypercontractility in the rat trachea.     

One injection of estradiol valerate induces dramatic changes in rats' intake of alcoholic beverages

A series of experiments investigated the effects of a single injection of estradiol valerate (EV) on female rats' consumption of alcoholic beverages. EV provides sustained release of estradiol. Just after an injection of EV, rats' intake of a palatable alcoholic beverage, which had been taken regularly before, is reduced dramatically. Subsequently, rats' intake of alcoholic beverage returns to baseline levels. With continued opportunity to drink, rats take more ethanol than controls. When EV was given 15 and 31 days before the first opportunity to drink an alcoholic beverage, female rats markedly enhanced their intake of ethanol. Once enhanced intakes emerged, they were observed with different kinds of alcoholic beverages and endured for months.     

Monoamine and metabolite levels in CNS regions of the P line of alcohol-preferring rats after acute and chronic ethanol treatment

Levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 8 brain regions of the P line of alcohol-preferring rats following: (a) an IP injection of 2.5 g ethanol/kg body wt; (b) 8 and 15 weeks of chronic free-choice drinking of 10% ethanol; (c) 15 weeks of chronic free-choice drinking of 10% ethanol and 24 hours of withdrawal; and (d) 7 weeks of forced administration of 5% ethanol in liquid diet. One hour after IP injection of 2.5 g ethanol/kg body wt, the levels of DOPAC and HVA increased 209-45% in the cerebral cortex (CTX) and striatum (STR). A 209% lower content of NE in the CTX of the ethanol group was the only other statistically significant difference observed. Chronic free-choice drinking of 10% ethanol for 8 weeks (6.5 +/- 0.4 g ethanol/kg/day) or 15 weeks (7.8 +/- 0.2 g ethanol/kg/day) and the chronic forced administration of ethanol in liquid diets (up to 13.2 +/- 0.2 g ethanol/kg/day) did not produce any consistent pattern of alterations in the levels of the monoamines or their metabolites in the 8 CNS regions. After 15 weeks of chronic free-choice drinking of 10% ethanol, withdrawal from alcohol also did not produce alterations in the content of the monoamines or their metabolites. These data indicate that acute administration of hypnotic doses of ethanol increases the metabolism of specific dopaminergic neurons in the CNS of the P rat, but monoamine levels and metabolism are not altered after chronic (7-15 weeks) alcohol consumption.     

Neonatal monosodium glutamate lesions alter neurosensitivity to ethanol in adult mice

A number of studies have indicated a relationship between brain peptide activity and sensitivity to the behavioral effects of ethanol. Specifically, it has been suggested that ethanol effects are mediated by changes in the endogenous opioid peptides derived from the proopiomelanocortin (POMC) precursor. Most cell bodies containing brain POMC-derived peptides are found in the arcuate nucleus of the hypothalamus. Neonatal administration of monosodium glutamate (MSG) has been reported to destroy cell bodies of the arcuate nucleus. We treated WSC strain mice on postnatal Day 4 with a single SC injection of 4 mg/g MSG or saline. When adult, MSG and control mice were challenged with an IP injection of ethanol and its effect on body temperature, open field activity, or duration of loss of righting reflex was assessed. Blood ethanol concentration (BEC) was measured and the hypothalamic content of beta-endorphin like immunoreactivity (beta-EP) was determined by radioimmunoassay. beta-EP was markedly reduced in both females and males by MSG treatment. MSG-treated animals of both sexes showed significantly less ethanol-induced hypothermia than controls. BEC was higher in MSG-treated animals of both sexes than in controls, so the differences were not due to ethanol pharmacokinetics. beta-EP was generally lower in males. Duration of righting reflex was prolonged in MSG treated animals, and the reduction in open field activity was potentiated. These latter effects may be in part attributable to the higher BECs achieved in lesioned animals. These data suggest that beta-EP cell bodies in the arcuate nucleus of the hypothalamus mediate neurosensitivity to some effects of ethanol in mice, but further experiments will be necessary to implicate beta-EP specifically.     

Effect of acute administration of ethanol on beta-endorphin plasma level in ethanol preferring and non-preferring rats chronically treated with naltrexone

An ample support can be found in professional literature for the hypothesis that the endogenous opioid system plays an important role in developing a craving for alcohol. It is well established that people with a genetic deficit of beta-endorphin are particularly susceptible to alcoholism. In our study, we looked into the beta-endorphin plasma level of animals with high- and low-risk of alcohol dependency after repeated treatment with naltrexone, the opioid antagonist known to be effective in the treatment of alcoholism. We used the Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats and treated them for 10 days with naltrexone in a dose of 2 mg/kg i.p. One hour before blood collection the rats were injected with a single dose of ethanol. A prolonged naltrexone treatment or a single application of ethanol resulted in the increase of the beta-endorphin plasma level. In the WLP rats repeated naltrexone treatment prevents the ethanol-induced increase in beta-endorphin plasma level. In the WHP rats the level of this peptide was similar to it while they were undergoing the naltrexone treatment or had received a single alcohol injection. This finding supports the proposition that the endogenous opioid system plays an important role in developing a craving for alcohol. It is likely that effectiveness of naltrexone in reducing craving for alcohol results from the attenuation of the rewarding properties of ethanol and restoring the beta-endorphin deficit in reward system.     

Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line

The development of tolerance to alcohol with chronic consumption is an important criterion for an animal model of alcoholism and may be an important component of the genetic predisposition to alcoholism. The aim of this study was to determine whether the selectively bred Warsaw High Preferring (WHP) line of alcohol-preferring rats would develop behavioral and metabolic tolerance during the free-choice drinking of ethanol. Chronic tolerance to ethanol-induced sedation was tested. The loss of righting reflex (LRR) paradigm was used to record sleep duration in WHP rats. Ethanol (EtOH)-naive WHP rats received a single intraperitoneal (i.p.) injection of 5.0 g ethanol/kg body weight (b.w.), and sleep duration was measured. Subsequently, rats had access to a 10% ethanol solution under a free-choice condition with water and food for 12 weeks. After 12 weeks of the free-choice intake of ethanol, the rats received another single i.p. injection of 5.0 g ethanol/kg b.w., and sleep duration was reassessed. The blood alcohol content (BAC) for each rat was determined after an i.p. injection of 5 g/kg of ethanol in naive rats and again after chronic alcohol drinking at the time of recovery of the righting reflex (RR). The results showed that the mean ethanol intake was 9.14 g/kg/24 h, and both sleep duration and BAC were decreased after chronic ethanol intake. In conclusion, WHP rats exposed to alcohol by free-choice drinking across 12 weeks exhibited increased alcohol elimination rates. Studies have demonstrated that WHP rats after chronic free-choice drinking (12 weeks) of alcohol develop metabolic tolerance. Behavioral tolerance to ethanol was demonstrated by reduced sleep duration, but this decrease in sleep duration was not significant.     

Angiogenesis: modulation with opioids.

1. The effect of beta-endorphin (beta-EP) and morphine sulfate (MS), in presence and absence of naloxone (NX), on chicken chorioallantoic membrane was studied as a function of blood vessel proliferation. 2. A 50% reduction in blood vessel proliferation occurred by 10 micrograms of beta-EP or by 5 micrograms of MS per egg compared to controls. 3. An individual dose, i.e. 5 micrograms of beta-EP, did not significantly inhibit blood vessel counts after initial 24 hr period of the drug application when given alone compared to inhibition occurring with combined use of NX. 4. NX (1 microgram) did not significantly reverse the angiostatic effects of MS (10 micrograms) or of beta-EP (5 micrograms). 5. The observed modulation of angiogenesis by opioids suggests involvement of beta-EP and MS in the proliferation of vascular endothelial cells. 6. This may be due to an effect of beta-EP and MS on cell-mediated immunity factors such as interferons, interleukins and prostaglandin E2.     

Behavioral and biochemical effects of intracerebrally injected alkaloids

Tetrahydroisoquinolines and beta-carbolines, substances which may form in the brain following the ingestion of alcohol, could be responsible for some of the behavioral effects of alcohol. When certain of these alkaloids are infused into the brain of the rat they induce an enhanced consumption of alcohol in a free-choice situation, both during infusion and for months after the cessation of infusion. In investigating the possible mechanism behind this permanent change in preference for alcohol, it does not appear that the post-synaptic side of the catecholamine neurons is involved. Likely candidates for future investigation include the pre-synaptic side of the catecholamine neurons and the serotonergic and opiate systems.     

Effect of third ventricular injection of beta-endorphin on the electrophysiological responses of some regions of endocrine hypothalamus

Multiunit activity (MUA) of arcuate nucleus and cortical EEG were recorded in the regularly cycling female rats on the day of proestrous under urethane anaesthesia. The MUA was compared before and after injection of beta-endorphin in third ventricle. In some animals MUA increased after 30-40 min and persisted for 3-4 hr, in others MUA got inhibited within 5-10 min of injection of beta-Endorphin and effect lasted for 5-6 hr. There was no change in frontoparietal EEG activity. In another group of animals medial pre-optic responses (MPO) to stimulation of medial amygdala were tested before and after ventricular infusion of beta-endorphin. Most of the facilitatory MPO responses got blocked. These observations suggest the involvement of opioid receptors in the mediation of neuroendocrine control of preovulatory events through the amygdalo-preoptico-medial basal hypothalamic axis. There seems to be heterogeneity of beta-endorphin receptors in the arcuate nucleus.