Differential involvement of GABA system in mediating behavioral and neurochemical effect of acupuncture in ethanol-withdrawn rats

In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague–Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72 h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1 min. The selective GABA_A antagonist bicuculline and the selective GABA_B antagonist SCH 50911 were injected intraperitoneally 20 min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABA_B receptor system in ethanol-withdrawn rats.     

大黄防治实验性胃粘膜损伤机理分析

本工作通过观察测定胃酸分泌,胃排空运动和胃壁粘液分泌的变化,初步探讨了中药大黄水浸煎剂对乙醇和消炎痛造成胃粘膜损伤的防治机理。结果表明:中药大黄可抑制胃排空速度,促进胃壁粘液分泌,并能预防乙醇和消炎痛造成的胃粘膜损伤,治疗乙醇造成的胃粘膜损伤。提示:中药大黄防治胃粘膜损伤机理与抑制胃酸分泌、抑制胃排空和促进胃壁粘液分泌有关。     

急性乙醇中毒大鼠学习记忆行为的改变与脑组织NO和nNOS含量变化

目的：通过观察急性乙醇中毒对大鼠学习记忆的影响并测定脑组织中一氧化氮（NO）与神经型一氧化氮合酶（nNOS）含量的变化，探讨乙醇中毒影响学习记忆的分子机制。方法:成年SD大鼠随机分为2组，模型组腹腔1次性注射乙醇2.5 g/kg［用生理盐水配成含20%乙醇(W/V)溶液］制备急性乙醇中毒大鼠模型；对照组注射等容量的生理盐水。Y-型迷宫检测大鼠学习记忆成绩、硝酸还原酶法检测鼠脑海马CA1、新纹状体中NO的含量、免疫组化方法检测鼠脑海马CA1、纹状体、小脑中nNOS的含量。结果:（1）模型组大鼠达到学会标准所需要的训练次数（34.33±13.04）明显大于对照组（27.50±8.79），P<0.05；（2）海马CA1区NO的含量在模型组为23.09±9.60，明显高于对照组（8.46±5.67）（P<0.01）；新纹状体（尾壳核）NO的含量在模型组（19.46±8.25）也明显高于对照组（8.22±4.46），P<0.01；（3）海马CA1区nNOS阳性神经元的数量在模型组为18.22±7.47，明显高于对照组（10.15±4.24）（P<0.05）；新纹状体（尾壳核）nNOS阳性神经元的数量在模型组（11.38±5.00）也明显高于对照组（6.15±3.69），P<0.05。结论:乙醇的神经毒性作用可能与脑组织中nNOS和 NO信号通路有关。     

Rat self administration of ethanol: Enhancement by darkness and exogenous melatonin

Using an FT 60 schedule, rats on 100% free feeding tested in the dark phase of a 12:12 light-dark cycle were trained to self-administer ethanol intravenously. The effect was dose-dependent with 20% ethanol being the preferred dose as measured by the number of infusions. Daily administration of 1.5 mg/kg melatonin significantly increased ethanol self-injection in the dark but not in the light. The time of day of testing and/or drug administration may be an important variable in studies on self-administration of drugs. Testing in the dark may eliminate the need for reducing body weight when inducing self-administration of ethanol.     

Adaptive changes in cerebral blood flow and oxygen consumption during ethanol intoxication in the rat

Cerebral blood flow (CBF) and oxygen consumption (CMRO₂) were measured during acute and long-term ethanol intoxication in the rat. The purpose was to investigate whether the adaptive changes (development of tolerance) occurring in the CNS during ethanol intoxication were associated with changes in CBF and/or CMRO₂. Consistent with other studies we found that acute severe ethanol intoxication (median blood alcohol concentration (BAC=5.4 mg/ml)) caused a significant decrease in CBF and CMRO₂. After 3–4 days of severe intoxication (BAC of 6.6 mg/ml) these physiological variables were less affected indicating that functional tolerance had developed: CMRO₂ and CBF during acute ethanol intoxication were 9.3 ml/100 g/min and 60 ml/100 g/min respectively; after the long term intoxication period these variables reached 11.2 ml/100 g/min and 78 ml/100 g/min respectively, i.e. values not significantly lower than those of the control group. After induction of hypercapnia (PaCO₂ about 80 mmHg) CBF increased by 360% in the control group; in the acutely intoxicated group CBF increased by only 127% and in the long term intoxicated group by 203 % indicating that the cerebrovascular CO₂-reactivity had also adapted to the ethanol intoxication. It is concluded that adaptive changes of the CNS to chronic ethanol intoxication comprise alterations in CMRO₂, CBF and cerebrovascular reactivity.     

Attenuation of ethanol tolerance by a novel stimulus

A Pavlovian conditioning model of tolerance emphasizes that an association between predrug cues and the systemic effects of the drug contributes to tolerance. On the basis of this model, established tolerance should be attenuated by external inhibition, i.e., by presentation of a novel, extraneous stimulus. This prediction was evaluated in the present experiment. Rats that were so tolerant to the hypothermic effect of ethanol that they evidenced no drug-induced decrease in temperature were presented with a bright strobe light following ethanol administration. The light precipitated a large decrease in temperature in these rats. These results provide further evidence that tolerance to the hypothermic effect of ethanol is, in part, mediated by learning.     

The effects of ethanol,estrogen, and hexachlorobenzene on the activities of hepatic δ-aminolevulinate synthetase, δ-aminolevulinate dehydratase,and uroporphyrinogen decarboxylase in male rats

To determine if clinically observed disorders in heme biosynthetic enzymes, known as sporadic porphyria cutanea tarda (PCT), could be reproduced in experimental animals, male Fischer rats were treated with ethanol, estrogen and hexachlorobenzene (HCB). A series of heme biosynthetic enzymes were assayed. In the rats given free access to 8% ethanol-drinking water for 15 weeks, -aminolevulinate (ALA) dehydratase was significantly reduced in erythrocytes. In the liver, ALA synthetase and uroporphyrinogen (UROgen) decarboxylase activities remained unchanged. In bone marrow cells, these activities did not change markedly. In the rats treated with estrogen (1 mg estrioltripropionate /rat/week, IM), no body weight gain was observed during the treatment for 15 weeks and urinary ALA excretion increased to 1.7 fold over normal level. In the liver, a significant increase was observed in the activity of ALA dehydratase, but other enzymes remained within the normal level. In bone marrow cells and erythrocytes, ALA dehydratase was also increased. ALA synthetase increased only in bone marrow cells to 2.1 times higher than the control level. In rats fed 0.3% HCB-diet for 8 weeks, urinary excretion of ALA, coproporphyrin and uroporphyrin increased to 2.4, 3.3 and 3.8 times higher than the controls, respectively. In the liver, an increase was observed in ALA synthetase, while a decrease was observed in ALA dehydratase and UROgen decarboxylase. In bone marrow cells and erythrocytes, ALA dehydratase was reduced and activities of other enzymes did not show any changes.These results indicate that alcohol, estrogen and HCB do not produce phenomena similar to those observed clinically in PCT.     

Effects of ethanol on murine aggression assessed by biting of an inanimate target

The effects of acutely administered ethanol (0, 0.5, 1.0 and 2.0 g/kg, IP) were studied in a tube-restraint/target biting model of aggressive responding using naive group-and individually-housed male Swiss mice. Behavioural measures were the latency to the first bite and the biting frequency. In saline-injected control animals, the levels of responding were significantly higher in group-housed than isolated mice. Animals given alcohol exhibited a dose-dependent suppression of biting frequency, and an increase in biting latency. Mice experienced in the tube-testing situation showed reduced baseline levels of biting, but alcohol produced similar effects to those in naive mice. There was no evidence of a biphasic action of alcohol.     

Distinctions among sedative,disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice

Three different domains of behavioral action of ethanol (ETOH) were examined in a battery of seven inbred strains and in the selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice. Sedative effects were examined with the loss of the righting reflex test at 3.8 g/kg. The variation among inbred strains was only half the size of the difference between LS and SS mice which were selectively bred for extremes in this phenotype; such a result is expected for phenotypes controlled polygenically. Blood ETOH levels at waking from the narcosis also showed a range of differences among the inbred strains that was less than the LS/SS difference. Ataxia was measured with the grid test, and the inbred strains fell into two groups, resembling the highly ataxic LS line, and the less ataxic SS line. Biphasic effects of ETOH on locomotor activity were strongly genotype dependent. Variation in degree of activation/disinhibition produced by doses up to 1.5 g/kg (IP) ranged from no activation, in the C57BL/6Abg strain, to a stimulation effect in the MOLD/RkAbg strain which was larger than that seen for SS mice. The patterns of strain differences for both ataxia and activation were highly different from the duration of loss of righting reflex measure, suggesting multiple independent genetically based sensitivities to ETOH.     

Free choice ethanol intake of laboratory rats under different social conditions

To study the effects of different kinds of social deprivation on voluntary ethanol (ETOH) intake male Wistar rats were housed by (a) individual caging, (b) contact caging (partial social deprivation), and (c) group caging (four individuals per cage). In the latter condition the individuals were separated once a week from each other for 24 h. The rats simultaneously received water 5%, 10% and 20% ETOH for a period of 14 weeks. Additional control animals received water. Isolated individuals drank significantly more alcohol than group-housed or contact-caged rats. After a few days they preferred the 20% solution. Circadian measures revealed a discontinuous intake of high doses (> 0.5 g/kg/h) during short time periods. Contact-caged rats consumed much less ETOH, but both the preference for 20% ETOH and the circadian course of intake were similar to those occurring after isolation. ETOH intake of group-housed individuals was low. These individuals preferred the 5% solution and continuously consumed small ETOH doses. During the period of short-term isolation they drank even more ETOH than long-term isolated individuals. In contrast to the latter, the enhancement of intake decreased after some weeks. It is suggested that the differences between the housing groups not only reflect different degrees of isolation stress, but may also be explained by a contribution of different reinforcing or aversive psychotropic effects of ETOH. Reduction of isolation stress is probably most important in the situation of short term separation, whereas dose-dependent reinforcement via social stimulation or sedation may affect the drug taking behavior under the other social conditions.