长期饮酒对大鼠睾丸睾酮合成和雄激素结合蛋白mRNA表达的影响

目的探讨饮酒对大鼠睾丸组织睾酮合成和雄激素结合蛋白（ABP）mRNA表达的影响。方法雄性Wistar大鼠40只，按体重随机分为4组，每组10只，即对照组（蒸馏水5g·kg^-1·d^-1）；大剂量饮酒组（酒精量5g·kg^-1·d^-1）；中剂量饮酒组（酒精量2．5g·kg^-1·d^-1）；小剂量饮酒组（酒精量0．5g·kg^-1·d^-1），喂养时间5个月。ELISA测定睾酮含量，RT—PCR测定睾丸组织外周型苯二氮革受体（PBR）、PPARα和ABP mRNA水平。结果与对照组相比，（1）大剂量饮酒组大鼠睾丸组织睾酮含量下降31．13％（P〈0．05），中剂量饮酒组下降26．8％（P〈0．05），小剂量饮酒组下降14．2％（P〉0．05）；（2）各饮酒组PBR mRNA水平明显降低（均P〈0．05），PPARα mRNA水平也明显降低（均P〈0．05）；（3）各饮酒组ABP mRNA水平明显下降（均P〈0．05）。结论长期饮酒可显著降低大鼠睾酮合成，PBR和PPARα表达降低是其可能机制之一；长期饮酒还可抑制大鼠ABP表达，影响睾酮生物学效应的发挥。     

The effect of alcohol on testosterone concentrations in alcohol-preferring and non-preferring rat lines

BACKGROUND: Previous studies have reported associations between human alcohol drinking and testosterone levels. METHODS: In this study we investigated serum testosterone concentrations without and under the influence of alcohol in alcohol-preferring (AA) and nonpreferring (ANA) rat lines. Animals were tested in both mornings and afternoons and the alcohol doses were 0.75 and 1.50 g/kg. RESULTS: Higher basal serum testosterone levels were detected in the AA rats compared with the ANA rats in both mornings (152%, p = 0.028) and afternoons (75%, p = 0.035). The high alcohol dose decreased the testosterone concentrations of both the AA and the ANA rats (p = 0.001-0.01). The low dose, however, decreased testosterone concentrations only in the ANA line (line difference in the morning: p = 0.027; in the afternoon p = 0.000). CONCLUSION: The present results support previous indications of a positive association between testosterone and alcohol drinking. Furthermore, the present results, together with earlier reports on the AA and ANA rats, introduce the possibility of a connection between this association and the hypothalamic opiate system, which is also involved in the feedback regulation of testosterone synthesis.     

Chronic ethanol increases ganglioside sialidase activity in rat leukocytes, erythrocytes, and brain synaptosomes

In view of the chronic alcohol-mediated pathological changes in various sialic acid-deficient glycoconjugates and the potential importance of sialidase in the generation of these glycoconjugates in the blood compartment and in the brain, we have investigated the effects of chronic ethanol feeding for 8 weeks on ganglioside sialidase activities in rat blood and brain. Ganglioside sialidase activity in erythrocytes (whether expressed as units/mg of protein or units/ml of blood) was 1.37- to 1.40-fold higher (p < 0.01) in the ethanol-fed group than in the control group. On the other hand, the same ethanol treatment increased sialidase activity in the leukocyte soluble fraction by 2.50- to 2.60-fold (p < 0.01) and by 1.61- to 1.63-fold (p < 0.01) in the leukocyte particulate fraction, compared with the control group. More importantly, most of the blood compartment sialidase activity was localized in the leukocytes particulate fraction (80 to 86% of total blood activity). Similarly, chronic ethanol treatment increased brain synaptosomal sialidase activity (whether expressed as units/gram of brain or units/mg of protein) 2.16- to 2.43-fold (p < 0.01). In contrast, brain lysosomal sialidase was not significantly altered by ethanol treatment, even though the major proportion of the brain sialidase activity was localized in the lysosomes. The proportion of synaptosomal sialidase activity as the percentage of total brain sialidase activity increased markedly from 13% in the control group to 24% in the ethanol group. Thus, chronic ethanol-mediated increases in sialidase activity in the leukocytes and brain synaptosomes could account for alterations in the ganglioside status of the animal and consequent adverse effects of chronic ethanol on behavioral and pathological changes.     

Neuropeptide Y in the paraventricular nucleus of the hypothalamus increases ethanol intake in high- and low-alcohol-drinking rats

BACKGROUND: The behavioral effects of neuropeptide Y (NPY) attributed to its actions in the hypothalamus are complex and include effects on feeding, sedation, and the hypothalamic-pituitary-adrenal axis. NPY infused into the paraventricular nucleus (PVN) increases ethanol intake in unselected rats. High-alcohol-drinking (HAD1) and low-alcohol-drinking (LAD1) rats differ in basal NPY levels in the PVN, and HAD1, but not LAD1, rats exhibit decreases in ethanol intake after infusion of NPY into the ventricles. This study examined whether NPY infused into the PVN alters ethanol intake in HAD1 and LAD1 rats. METHODS: Female HAD1 (n = 14) and LAD1 (n = 18) rats were given 24-hr free-choice continuous access to 15% (v/v) ethanol and water for 6 weeks and then implanted bilaterally with cannulas aimed at the PVN. Two weeks later, rats received a series of microinfusions, each separated by 1 week, that included four doses of NPY (0.0, 0.25, 0.5, and 1.0 microg). Ethanol, water, and food were available ad libitum after infusions. All rats received a final microinfusion of 1.0 microg of NPY, after which ethanol and water, but no food, were made available for 2 hr. RESULTS: During the 2 hr after infusion, NPY yielded dose-dependent increases in both water and food consumption. With food concurrently available, the 0.25- and 1.0-microg doses of NPY did not alter baseline ethanol intake, whereas the 0.5-microg dose increased ethanol intake. Infusion of 1.0 microg of NPY in the absence of food yielded a decrease in water intake and an increase in ethanol intake relative to the same dose in the presence of food. Twenty-four hours after infusion, there were no effects of NPY on water and food intake, and increases in ethanol intake were no longer apparent. CONCLUSIONS: Increases in ethanol intake after infusion of NPY into the PVN may depend on NPY dose and whether food is concurrently available.     

The effects of short-term chronic ethanol intoxication and ethanol withdrawal on the molecular composition of the rat hippocampus by FT-IR spectroscopy

Background: The numerous adverse effects of ethanol abuse and ethanol withdrawal on biological systems are well documented. Conversely, the understanding of the molecular mechanisms underlying these pathological effects is still incomplete. This study was undertaken to investigate the effects of short‐term chronic ethanol administration and ethanol withdrawal on the molecular structure and function of hippocampal tissue, a brain region important for mnemonic processes and known to be highly susceptible to ethanol intoxication. Methods: Ethanol was administered to adult Wistar rats by intragastric intubation for 15 days with a stepwise increase in the daily dose from 6 to 12 g/kg body weight, with the highest dose delivered for the last 2 days only. The total daily dose of ethanol was divided into 3 equal portions administered 4 hours apart. Animals were sacrificed by decapitation at 4, 24, and 72 hours after the last ethanol administration to examine potential effects of ethanol intoxication and ethanol withdrawal. Ethanol‐related molecular changes were monitored by Fourier transform infrared (FT‐IR) spectroscopy. Results: Significant changes in the hippocampal content, structure, and function of lipids, proteins, and nucleic acids were recorded under ethanol intoxication. Seventy‐two hours after the cessation of ethanol administration, during the late phase of withdrawal, alterations in the macromolecules’ content and conformational changes in protein and nucleic acid structure ameliorated, while the changes in macromolecular ratios, lipid order, and dynamics aggravated. Conclusions: Our results suggest that 15 days of binge‐like drinking resulting in the high blood alcohol concentration (varying in the dose‐dependent manner between 253 and 606 mg/dl) produced a strong physical dependence manifested mainly by the changes in lipid profiles pointing toward withdrawal‐induced oxidative stress. These results show that ethanol withdrawal may cause equal to or even more severe brain damage than the ethanol itself, which should be considered when designing antialcohol therapies.     

Effects of ethanol and ethanol withdrawal on nociception in rats

The effect of acute and chronic administration of ethanol and ethanol withdrawal on a radiant heat tail-flick assay of nociception was examined in rats. Acute administration of ethanol (2.0 g/kg, i.p.) produced peak antinociception (68% of maximum) by 30 min, and effects were gone by 120 min. Cumulative doses of ethanol (0.5-2.0 g/kg, i.p.) produced dose-dependent increases in latencies to 49% of maximum. During chronic administration, a liquid diet containing ethanol (6.5%) was given for 10 days. Tail-flick latencies were measured on day 0 (baseline), day 2, 4, 6, 8, and 10 of chronic ethanol and at 3, 6, 12, and 36 hr after removal of ethanol. To test for behavioral tolerance, both between- and within-group designs were used. In both between- and within-group experiments, the antinociceptive effects of chronic ethanol peaked by day 4 of exposure to the liquid diet, and tolerance developed by day 10. When the liquid diet was removed, hyperalgesia was detected at 6 and 12 hr after withdrawal, and was gone by 36 hr after withdrawal. When cumulative doses of ethanol (0.5-2.0 g/kg) were administered starting 12 hr after withdrawal, ethanol (0.5 g/kg) fully reversed the hyperalgesia induced by ethanol withdrawal, even though this dose was without antinociceptive effect in the absence of withdrawal. Higher doses of ethanol during ethanol withdrawal did not increase tail-flick latencies over baseline. In summary: (1) ethanol produces antinociception when administered acutely or chronically; (2) tolerance to the antinociceptive effects develops during chronic administration; (3) ethanol withdrawal induced hyperalgesia, which was reversed by ethanol; and (4) repeated testing did not produce behavioral tolerance.     

Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats

BACKGROUND: Adolescents respond differently to alcohol than adults. Furthermore, binge drinking in young adolescents is becoming increasingly common. METHODS: To determine if the effects of binge drinking on brain damage are different in juveniles compared with adults, the effects of a 4 day binge ethanol treatment (e.g., 4 days of 4 times per day 15% ethanol intragastrically, approximately 9-10 g/kg/day ethanol) were investigated in adolescent-juvenile rats (JVN) 35 days old and compared with adult (ADT) rats 80 to 90 days old. Brain damage was measured by using the amino cupric silver stain of de Olmos et al. (1994). RESULTS: Significant brain damage was found in both groups. The olfactory bulbs were equally damaged in both groups; however, the associated frontal cortical olfactory regions were damaged only in JVN. The anterior portions of the piriform and perirhinal cortices also were damaged only in JVN rats. Quantitation of silver-stained frontal areas in binge ethanol-treated JVN rats ranged from 400% to 1,260% of control values. For example, in anterior perirhinal cortex, silver stain increased from 48 +/- 14 to 444 +/- 114 (mm2 x 10(3) argyrophilic area; p < 0.01) in JVN control and binge ethanol-treated animals, respectively. In contrast, posterior perirhinal cortex showed greater damage in adults, being 236 +/- 76 vs. 875 +/- 135 (mm2 x 10(3) argyrophilic area; p < 0.005) in JVN and ADT, respectively. CONCLUSIONS: The young-adolescent brain shows differential sensitivity to alcohol-induced brain damage compared with adults.     

Low-dose stimulatory effects of ethanol during adolescence in rat lines selectively bred for high alcohol intake

Abstract : Background: The low‐dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes. Methods: Subjects were adolescent (31–40 days of age) rats from the alcohol‐preferring (P) and ‐nonpreferring (NP) lines and from the high–alcohol‐drinking (HAD) and low–alcohol‐drinking (LAD) replicate lines. On day 1, all subjects (n= 8–10/line/gender/dose) received intraperitoneal saline injections and were placed in the activity monitor for 30 min. On day 2, subjects received intraperitoneal saline or 0.25, 0.50, 0.75, 1.0, or 1.5 g EtOH/kg. Results: The LMA of male and female P rats was increased with low doses (0.25–0.75 g/kg) and decreased at the highest dose (1.5 g/kg) of EtOH. Similar effects were observed with low doses of EtOH on the LMA of HAD‐1 and HAD‐2 rats. None of the EtOH doses stimulated LMA in the NP, LAD‐1, or LAD‐2 rats, although all of the low–alcohol‐intake lines of rats showed decreased LMA at the highest dose of EtOH. Only the P rats among the high–alcohol‐consuming lines of rats showed decreased LMA at the highest dose of EtOH. Conclusion: Selective breeding for high alcohol consumption seems to be associated with increased sensitivity to the low‐dose stimulating effects of EtOH and reduced sensitivity to the high‐dose motor‐impairing effects of ethanol. The expression of these phenotypes emerges during adolescence by the age of onset of alcohol‐drinking behavior.     

Alcohol withdrawal increases neuropeptide Y immunoreactivity in rat brain

BACKGROUND: Neuropeptide Y (NPY) is widely expressed in the brain and is known to affect consummatory behaviors including drinking alcohol as well as to play a role in seizures. We investigated the effects of a 4 day binge ethanol treatment model that is known to induce physical dependence and withdrawal seizures to determine the effects of ethanol dependence and withdrawal on NPY expression. METHODS: Male Sprague Dawley rats were treated with ethanol or control nutritionally complete diets by intragastric treatment three times per day for 2 or 4 days with an average daily dose of approximately 8 g/kg ethanol per day. Ethanol-fed rats treated for 4 days and then withdrawn for 24, 72, and 168 hr also were studied. Brains were perfused and sectioned for immunohistochemistry for NPY, phospho-cyclic adenosine monophosphate responsive element binding (pCREB), and other proteins. RESULTS: NPY immunoreactivity (NPY-IR) was found in several brain regions, with the hippocampus and cerebral cortex showing the most pronounced changes. NPY-IR was reduced by ethanol treatment in hippocampus and cortex, although at 72 hr of withdrawal there was a dramatic increase in NPY-IR in the hilus of the dentate gyrus and in CA3 and CA2 fields of hippocampus. Ethanol withdrawal seizures occurred around 12 to 24 hr of withdrawal, preceding the changes in NPY-IR at 72 hr. pCREB immunoreactivity (pCREB-IR) tended to decrease during ethanol treatment but showed a dramatic increase in dentate gyrus at 72 hr of withdrawal. Parvalbumin immunoreactivity indicated that some of the pCREB-IR and NPY-IR were within inhibitory interneuron basket cells of the hippocampal hilus. NPY-IR returned to control levels by 168 hr of withdrawal. CONCLUSIONS: These studies suggest that hippocampal NPY is reduced during the development of ethanol dependence. Ethanol withdrawal seizures precede a dramatic increase in hippocampal NPY-IR. Previous studies have suggested that NPY in the hippocampus reduces seizure activity and that NPY is induced by seizure activity. Thus, the increase in NPY-IR at 72 hr of withdrawal after binge ethanol treatment may be protective against prolonged withdrawal seizure activity.     

The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure

Background: Neuropeptide Y (NPY) has been implicated in the alcohol-drinking behaviors of rodents. This study investigated the possible involvement of NPY in the neuroadaptational mechanisms to chronic ethanol exposure and its withdrawal.
Methods: Male Sprague-Dawley rats were treated either with Lieber-DeCarli ethanol diet or control diet for 15 days, and ethanol-fed rats were withdrawn for 0 and 24 hr. The protein expression of NPY was determined in cortical, hippocampal, amygdaloid, striatal, and hypothalamic structures by using the gold-immunolabeling histochemical procedure.
Results: It was found that ethanol withdrawal, but not ethanol treatment, produced significant reductions in NPY protein levels in (1) layers IV and V of the frontal and parietal cortex, (2) layer II of the piriform cortex, (3) the central and medial nuclei of the amygdala, and (4) the paraventricular nucleus of the hypothalamus in rat brain. Chronic ethanol exposure and its withdrawal had no effect on the NPY protein levels in layers II, III, and VI of the frontal and parietal cortex or cingulate gyrus, in hippocampal (CA1, CA2, CA3, and dentate gyrus) and striatal (caudate putamen and globus pallidus) structures, or in the ventro-medial hypothalamus and basolateral amygdala. However, chronic ethanol exposure and its withdrawal produced significant reductions in NPY protein levels in the arcuate nucleus of the hypothalamus and in layers IV and V of the cingulate gyrus.
Conclusions: These results suggest that the decreased protein levels of NPY in the central and medial nuclei of the amygdala, as well as in the cortical and hypothalamic structures, during ethanol withdrawal may play an important role in the neuromechanisms of some ethanol withdrawal symptoms.     

Chronic ethanol consumption reduces delta-and mu-opioid receptor-stimulated G-protein coupling in rat brain

BACKGROUND: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol-preferring rats uncouples mu-ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the delta- and the mu-OR after chronic ethanol consumption in a nonpreferring rat strain. METHODS: We used radiohistochemical methods to study mu- and delta-OR-stimulated G-protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair-fed control rats. Sections of brain from pair-fed and ethanol-treated rats were incubated with guanylyl 5'-[gamma-[35S]-thio]-triphosphate ([35S]-GTPgammaS) in the absence and presence of d-Pen2,d-Pen5 enkephalin (DPDPE), a delta-OR agonist, or Tyr-d-Ala-Gly-N(me)Phe-Gly-ol-enkephalin (DAMGO), a mu-OR agonist. RESULTS: DPDPE significantly stimulated [35S]-GTPgammaS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair-fed controls. By contrast, DPDPE-stimulated [35S]-GTPgammaS binding was reduced significantly in those brain regions in the ethanol-consuming group. DAMGO stimulated [35S]-GTPgammaS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]-GTPgammaS binding was not different between the two diet groups.CONCLUSIONS These data are the first to demonstrate functional uncoupling of delta-ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both delta- and mu-ORs and subsequent effects may contribute to continued ethanol consumption.     

Chronic ethanol ingestion increases aortic endothelial nitric oxide synthase expression and nitric oxide production in the rat

Background:  Chronic alcohol consumption perturbs cellular function in a variety of organ systems. Previous studies have suggested that moderate alcohol consumption reduces vascular disease, whereas heavier alcohol consumption may worsen it. The mechanisms for these vascular effects of chronic alcohol ingestion continue to be defined and constitute the focus of this study.
Methods:  Male Sprague Dawley rats were fed an isocaloric, Lieber-Decarli liquid diet containing either ethanol (36% calories) or Maltose–Dextrin (substituted for ethanol) for 6 weeks. Telemetric blood pressure measurements were taken before and after ethanol feeding. After the rats were killed, the aortas were analyzed for endothelial nitric oxide (NO) synthase expression and NO production.
Results:  Chronic ethanol ingestion decreased mean arterial pressure and increased aortic NO production as demonstrated by direct ex vivo measurements using iron diethyldithio-carbamic acid as well as analysis of nitrosyl-hemoglobin (NO-Hb) levels. Consistent with these assays of vascular NO production, endothelium-dependent relaxation responses to acetycholine (Ach) were enhanced in ethanol-fed animals. Aortic endothelial nitric oxide synthase expression was also increased by chronic ethanol ingestion.
Conclusions:  These findings demonstrate that a regimen of chronic alcohol ingestion in the rat produced generally salutary effects in the systemic vasculature following a 6-week treatment regimen. These findings extend previous in vitro studies to demonstrate that alcohol has potent effects on vascular endothelial nitric oxide synthase expression, NO production, and vascular function. Consistent with previous reports, these findings confirm that alcohol-induced alterations in the production of reactive nitrogen species play an important role in the pathogenesis of alcohol-mediated tissue effects.     

Detection and localization of protein-acetaldehyde adducts in rat brain after chronic ethanol treatment

BACKGROUND: Ethanol is metabolized to acetaldehyde in the cell, which is potentially deleterious because it can react with cellular proteins and form protein-acetaldehyde adducts, which can interfere with normal cellular function. Because the primary site of ethanol action is the brain, the present study was carried out to determine whether protein-acetaldehyde adducts are formed in rat brain after chronic ethanol administration. METHODS: Rats were treated with ethanol for 1 year, and the formation of protein-acetaldehyde adducts was examined by immunoblot analysis and localized in brain by immunohistochemical analysis by using affinity purified antibody to acetaldehyde-hemocyanin adduct. RESULTS: In the brain of rats administered ethanol for up to 1 year, protein-acetaldehyde adducts were detectable by immunoblot analysis. In brain, mitochondria was the primary site of adduct formation, unlike the liver, where the major protein-acetaldehyde adduct has been detected in the cytosol. Immunohistochemical localization of protein-acetaldehyde adducts in chronic ethanol-treated rat brain demonstrated the selective presence of adducts in cortical neurons, granule cell layer of dentate gyrus, neurons in the midbrain, and granular cell layers of cerebellum. CONCLUSIONS: These results demonstrate the significant formation of protein-acetaldehyde adducts in rat brain after ethanol ingestion. The modification of mitochondrial proteins in brain by protein-acetaldehyde adduct formation is significant because mitochondrial dysfunction has been implicated in neurodegeneration.     

Impact of circulating testosterone on iodomelatonin binding sites in the male rat brain

The effects of castration and subsequent testosterone and estradiol treatment and of a single injection of ethylene-1,2-dimethanesulphonate (EDS) on the distribution of [2-¹²⁵I]iodomelatonin ([¹²⁵I]melatonin) binding sites in the male rat brain were investigated. Castration produced a marked testosterone-reversible decrease in [¹²⁵I]melatonin binding in the male rat brain, particularly in the hypothalamus and hippocampus. In contrast, [¹²⁵I]melatonin binding in the parietal cortex, medulla-pons and cerebellum was generally unaffected by castration. Estradiol did not reverse the effect of castration on [¹²⁵I]melatonin binding.

A single injection of EDS which causes the destruction of Leydig cells led to a marked decrease in [¹²⁵I]melatonin binding in the brain of the rats between 3 and 7 days after treatment. This decrease correlated with the decline in serum concentrations of testosterone. Specific [¹²⁵I]melatonin binding and serum concentrations of testosterone subsequently increased to control levels within 37 days after treatment in accord with the repopulation of the Leydig cells. The results clearly show that testosterone regulates the density of melatonin receptors in the hypothalamus and hippocampus of the male rat.     

Effect of gender and estrous cycle on the pharmacokinetics of ethanol in the rat brain

BACKGROUND: Aspects of ethanol pharmacokinetics in the blood, such as elimination, are known to vary by gender in the rat. Ethanol concentrations reaching the brain, which are relevant in affecting behavior, have not been measured rigorously by gender. This study used quantitative microdialysis to measure ethanol pharmacokinetics in the nucleus accumbens after a moderate dose of ethanol, comparing males with females and females across the estrous cycle. METHODS: We administered 1 g/kg ethanol intravenously or intragastrically to male and female rats. We measured ethanol concentrations in the nucleus accumbens by use of microdialysis with in vivo probe calibration and compared them with concentrations in jugular venous blood. RESULTS: After intravenous delivery, apparent ethanol elimination was approximately 15% faster in females than males from both brain and blood. After intragastric delivery, blood ethanol concentrations peaked faster in females than males by approximately 20 min, suggesting faster absorption or diffusion from the stomach. Likewise, accumbal ethanol concentrations peaked faster in females than males by approximately 25 min, indicating faster distribution to the brain. These pharmacokinetic parameters did not vary across the estrous cycle, nor were they influenced significantly by body water. CONCLUSIONS: This study provides the first quantitative measurement of ethanol concentrations and, thus, pharmacokinetics in the brain of awake rats. If ethanol distribution to the brain varies between genders, as these results suggest, then differences in the pharmacological response to ethanol can be expected, providing a rationale for studying the pharmacodynamics of ethanol in the brain of the self-administering rat.     

Alterations in central preproenkephalin mRNA expression after chronic free-choice ethanol consumption by fawn-hooded rats

BACKGROUND: Neurotransmission mediated via opioid and dopamine receptors is believed to be involved in the reinforcing and/or rewarding effects of ethanol consumption. We previously examined the effect of ethanol consumption (and naltrexone treatment, used clinically to treat alcoholism) on micro-opioid receptor density. We describe here the effect of free-choice ethanol consumption and naltrexone treatment on preproenkephalin, preprodynorphin, and dopamine D1 and D2 receptor mRNA expression in the central nervous system. METHODS: Fawn-hooded rats were given continual free-choice access to a 5% ethanol solution or water (4 weeks) followed by 2 weeks of water alone. At the end of this abstinence period, osmotic minipumps were implanted subcutaneously to deliver saline (n = 4) or naltrexone (n = 4; 8.4 mg/kg/day for 4 weeks). After recovery from surgery, the rats again were given access to 5% ethanol under the same free-choice conditions (4 weeks). A third group of age-matched controls drank only water during the behavioral trial. At the end of the behavioral trial, the rats were decapitated, and a quantitative examination of peptide precursor mRNAs was made by using in situ hybridization histochemistry. RESULTS: Naltrexone treatment significantly decreased preprodynorphin expression in the nucleus accumbens, but neither naltrexone treatment nor ethanol consumption significantly affected dopamine D1 and D2 receptor mRNA expression. In contrast, ethanol consumption increased preproenkephalin mRNA in the central and intercalated nuclei of the amygdala but decreased preproenkephalin mRNA in the nucleus accumbens and olfactory tubercle. The decreased level of preproenkephalin mRNA in the nucleus accumbens may reflect a neuroadaptive response to increased release of dopamine, whereas the increased level of preproenkephalin mRNA in the central nucleus of the amygdala may be associated with an anxiolytic effect of ethanol consumption. CONCLUSIONS: The data support the putative role of opioid peptides in the effects of ethanol and suggest that the nucleus accumbens and central nucleus of the amygdala are loci for the reinforcing effects of ethanol.     

睾酮与脑卒中

睾酮是人类最重要的内分泌激素之一,与人类许多重要的生理、病理生理调节过程有关。近年研究发现,睾酮与脑卒中许多危险因素有关。如睾酮可加剧高血压的发展,可促进高血压性肾损害;睾酮可通过影响脂质代谢参与动脉粥样硬化的形成;可导致胰岛素抵抗的发生发展;还可加重脑卒中后脑损伤;并可能与肺损伤的发生机制有关。本文对近年有关睾酮与脑卒中及脑卒中后器官损伤的研究进展作一综述。     

Operant self-administration of ethanol in Sardinian alcohol-preferring rats

BACKGROUND: "Work" for ethanol, that is, the ability of a laboratory animal to press a lever to gain access to ethanol, has been proposed as (a) a requirement for definition of an animal model of alcoholism and (b) a measure of ethanol-reinforcing properties. The present study evaluated oral self-administration of ethanol under an operant (lever pressing) procedure in selectively bred Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. METHODS: Rats from both lines were initiated to self-administer 10% ethanol, on a fixed ratio 1 schedule and in daily 30 min sessions, by using the Samson sucrose fading procedure. Subsequently, rats were exposed to increasing concentrations of ethanol up to 30% on a fixed ratio 4 schedule. Finally, the extinction responding for ethanol, defined as the maximal number of lever responses reached by each rat in the absence of ethanol reinforcement, was determined. RESULTS: The results indicated that sP rats acquired and maintained lever pressing for ethanol, self-administering mean amounts of ethanol in the range of 0.6 to 1.1 g/kg/session, which gave rise to mean blood ethanol levels in the 30 to 45 mg% range. Extinction responding for ethanol in sP rats averaged 73. In contrast, once sucrose was faded out, sNP rats displayed minimal levels of responding for ethanol, and extinction responding averaged 6. CONCLUSIONS: The results of the present study extend to the sP/sNP rat lines the finding that ethanol can be established as a reinforcer in selectively bred alcohol-preferring rats, whereas it has modest, if any, reinforcing properties in alcohol-nonpreferring rats.     

Differential effects of chronic ethanol administration and withdrawal on gamma-aminobutyric acid type A and NMDA receptor subunit proteins in male and female rat brain

BACKGROUND: Investigations have shown that chronic ethanol exposure results in selective alterations in levels of gamma-aminobutyric acid (GABA)A and NMDA receptor subunits. We previously reported significant sex differences in these chronic ethanol-induced adaptations. Because we have more recently found important sex differences in timing for the development of and recovery from ethanol dependence, we wanted to ascertain whether there were associations between overt expression of withdrawal and neuroadaptations at the level of GABAA and NMDA receptors. METHODS: Western blot analysis was used to assay protein levels for several GABAA and NMDA receptor subunits in rat cerebral cortex and hippocampus by using subunit-selective antibodies. Rats were fed 6% ethanol in a liquid diet with pair-fed controls. Feeding, harvesting of tissue, and Western blot experiments were all conducted while maintaining the paired design. Tissue was harvested after 3 days of ethanol exposure, 9 days of ethanol exposure, or 3 days of ethanol withdrawal after 14 days of liquid diet administration. RESULTS: We again found sex-, subunit-, and brain region-selective effects of ethanol administration and withdrawal for GABAA and NMDA receptors. There was a strong association between increased GABAA receptor alpha4 subunit levels and previously determined withdrawal-induced changes in seizure susceptibility, highlighted by the sex differences in ethanol exposure length required to cause withdrawal signs. In addition, results obtained after 9 days of ethanol administration were in general agreement with previous findings after 14 days of ethanol administration. CONCLUSIONS: These data further support the suggestion that alterations in subunit assembly of GABAA and NMDA receptors may have some mechanistic role in neuroadaptations underlying ethanol dependence and withdrawal. Furthermore, significant sex differences in these adaptations suggest that multiple types of adaptations may be elicited, depending on innate differences in the actions/effects of ethanol.