Acamprosate and diazepam differentially modulate alcohol-induced behavioural and cortical alterations in rats following chronic inhalation of ethanol vapour.

The effects of Acamprosate (the calcium salt of an acetylated form of homotaurine) and the benzodiazepine-receptor agonist Diazepam, were investigated on the alcohol-induced behavioural preference towards alcohol following chronic alcoholization by inhalation. We also examined the effects of Acamprosate and Diazepam on the blood alcohol level (BAL) and on the cortical microvascular network. Acamprosate (50, 100, 200 and 400 mg/kg daily per os during the alcoholization period) did not significantly reduce either BAL or alcohol-induced cortical hypervascularization. Increasing dosages of Acamprosate (i.e. 50, 100, and 200 mg/kg/day), however, progressively reduced preference for alcohol as expressed in a free choice beverage procedure, whereas 400 mg/kg/day of Acamprosate immediately stopped this behaviour. Acamprosate (50 mg/kg/day) also reduced the spontaneous activity of rats during the withdrawal syndrome. By contrast, Diazepam (5 mg/kg) induced inversion in the animals' choice (i.e. increased water consumption versus decreased alcohol intake) during the same experimental procedure, and potentiated the alcohol-induced hypermotility of the animals during the withdrawal syndrome without altering cortical hypervascularization. Taken together, our data provide evidence that both substances exert dose-dependent effects on preference towards alcohol, but display opposite profiles on spontaneous motor activity during the withdrawal phase without any modification of brain microvascularization or blood alcohol levels.     

SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats.

This study investigated the effect of the new CB1 cannabinoid receptor antagonist, SR147778, on ethanol preference in chronically alcoholized Wistar rats. In study 1, SR147778, at doses of 0.3, 1, or 10 mg/kg/day (mg/kg/d) intraperitonealy (ip), was administered during chronic pulmonary ethanol intoxication for 30 days. The rats were then exposed to a two-bottle choice (ethanol 10% v/v vs. water) for at least 30 days. Neither 0.3 nor 1 mg/kg/d had any effect on ethanol preference. In contrast, the high dose induced a significant transient increase in ethanol intake between days 6 and 10. In study 2, SR147778, at doses of 0.3, 1, or 10 mg/kg/d ip, was administered during the free-choice period after chronic alcoholization. Both ethanol preference and intake were significantly reduced only for 1 and 10 mg/kg/d. These results reinforce the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol. When these results are compared with those obtained with SR141716 (Rimonabant) on ethanol preference, we observed that (1) coadministration of 10 mg/kg/d SR147778 during chronic alcoholization induced a shorter transient increase of ethanol intake than Rimonabant and (2) SR147778 treatment during the free-choice period at doses of 1 and 10 mg/kg/d decreased ethanol intake more dramatically than SR141716 which, furthermore, continued for the duration of the free choice.     

Threshold to N-methyl-D-aspartate-induced seizures in mice undergoing chronic nutritional magnesium deprivation is lowered in a way partly responsive to acute magnesium and antioxidant administrations

Magnesium deficiency may be induced by a diet impoverished in magnesium. This nutritional deficit promotes chronic inflammatory and oxidative stresses, hyperexcitability and, in mice, susceptibility to audiogenic seizures. Potentiation by low-magnesium concentrations of the opening of N-methyl-D-aspartate (NMDA) receptor/calcium channel in in vitro and ex vivo studies, and responsiveness to magnesium of in vivo brain injury states are now well established. By contrast, little or no specific attention has been, however, paid to the in vivo NMDA receptor function/excitability in magnesium deficiency. The present work reports for the first time that, in mice undergoing chronic nutritional deprivation in magnesium (35 v. 930 parts per million for 27 d in OF1 mice), NMDA-induced seizure threshold is significantly decreased (38 % of normal values). The attenuation in the drop of NMDA seizure threshold (percentage of reversal) was 58 and 20 % upon acute intraperitoneal administrations of magnesium chloride hexahydrate (28 mg magnesium/kg) and the antioxidant ebselen (20 mg/kg), respectively. In nutritionally magnesium-deprived animals, audiogenic seizures are completely prevented by these compound doses. Taken as a whole, our data emphasise that chronic magnesium deprivation in mice is a nutritional in vivo model for a lowered NMDA receptor activation threshold. This nutritional model responds remarkably to acute magnesium supply and moderately to acute antioxidant administration.     

Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic alcohol administration combined with repeated re-exposures and withdrawals

AIMS: The cannabinoid CB1 receptor antagonist, SR141716A, differentially affects the ethanol preference of chronically alcoholized rats when administered during cycles of ethanol exposure and withdrawal. In this study, ethanol preference was investigated in chronically alcoholized rats that underwent regular withdrawal periods during which the brain cannabinoid CB(1) receptor antagonist, SR141716A, was administered. METHODS: The cannabinoid receptor antagonist SR141716A, 3 or 10 mg/kg/day, was administered i.p. to Wistar rats at the conclusion of a 4-week period of chronic alcoholization, as they commenced a cycle of alcohol withdrawal for 10 days followed by a period of 10 days chronic ethanol exposure. In a second set of experiments, an additional cycle of ethanol withdrawal and re-exposure was given. Preference for ethanol versus water started at the end of the first or second chronic ethanol re-exposure for a period of at least 30 days. RESULTS: In rats pretreated with the higher dose of SR141716A, ethanol preference during free choice was significantly increased after two ethanol re-exposures. In contrast, pretreatment with the lower SR141716A dose induced no significant change in ethanol intake during the free choice followed by either one or two ethanol re-exposures. CONCLUSIONS: SR141716A, 10 mg/kg/day dose, induced a significant increase in ethanol preference which was dependent on both the number of ethanol withdrawals and chronic ethanol re-exposures, while 3 mg/kg/day had no significant effect on ethanol preference.     

NMDA receptor antagonists inhibit ethanol-produced locomotor stimulation in NMRI mice.

The effects of competitive and noncompetitive NMDA receptor antagonists on locomotor stimulation produced by low doses of ethanol were studied in NMRI mice. Both competitive (CGP 39551) and noncompetitive (MK-801) NMDA receptor antagonists inhibited ethanol-produced behavioral stimulation in doses which by themselves had no effects on the locomotor activity. In additional experiments, where the muscle relaxant actions of ethanol and the NMDA receptor antagonists were studied, it was found that the "inhibitory" effects of the NMDA receptor antagonists in the locomotor activity test situation most likely were due to a potentiation of the sedative effects of ethanol and/or the antagonists. The implications of the current observations with regard to previously reported results concerning interactions between ethanol and NMDA receptor antagonists and with regard to a possible therapeutic advantage of using competitive NMDA receptor antagonists in the management of the human alcohol abstinence syndrome are discussed.     

ADRENALECTOMY PROTECTS ETHANOL-WITHDRAWN RATS FROM HARMINE-INDUCED TREMOR

Abstract-A growing number of studies have implicated the hypothalamic-pituitary-adrenal(HPA) axis in acute and chronic alcoholization and in ethanolwithdrawal. In order to study the ethanol/HPA axis interactionduring alcohol withdrawal, we performed experiments using adrenalectomized(ADX) male rats alcoholized by a chronic pulmonary alcoholizationprocedure. Eight hours after the 3 weeks of the alcoholizationprocedure, the rats were evaluated for a tremor activity Inorder to reduce the great variability of the withdrawal tremors,we estimated the supersensitivity of the withdrawn rats to thetremorogenic compound harmine. We also studied the effect ofa hydrocortisone treatment given in the drinking bottle duringthe alcoholization procedure on the harmine-induccd tremorsof ADX and sham rats. Alcohol withdrawal resulted in increasedtremor response to 10 mg/kg harmine, and a protective effectof adrenalectomy on this effect was observed. Hydrocortisoneadministration to ADX or sham rats did not affect the tremorprofile of the alcohol withdrawn rats.     

The GABA(B) receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats

AIMS: The present study investigated the effect of the gamma-aminobutyric acid (GABA)(B) receptor agonists, baclofen and CGP 44532, on the acquisition of alcohol drinking behaviour in selectively bred Sardinian alcohol-preferring (sP) rats. METHODS: Baclofen [0, 1 and 3 mg/kg, intraperitoneally (i.p.)] and CGP 44532 (0, 0.1, 0.3 and 1 mg/kg, i.p.) were administered immediately before alcohol presentation to alcohol-naive sP rats. Alcohol was offered under the two-bottle free-choice regimen with unlimited access for 24 h/day. Drug treatment was repeated once daily for 10 consecutive days. RESULTS: Baclofen and CGP 44532, dose-dependently and with comparable efficacy, suppressed alcohol intake; compensatory increases in water intake left total fluid intakes virtually unchanged. CONCLUSIONS: These results demonstrate that baclofen and CGP 44532 prevent the acquisition of alcohol drinking behaviour in sP rats, and suggest the involvement of the GABA(B) receptor in the mechanisms underlying the disclosure and experience of the reinforcing properties of alcohol in this rat line.     

Effects of chronic alcohol treatment on acoustic startle reactivity during withdrawal and subsequent alcohol intake in high and low alcohol drinking rats

AIMS: The purpose of the present study is to determine whether the inverse genetic association between alcohol withdrawal magnitude and genetic propensity for alcohol drinking that we have previously identified in alcohol-naive rats given alcohol acutely, would also be seen following chronic alcohol exposure. The effect of forced, chronic alcohol treatment on subsequent voluntary alcohol drinking was also examined. METHODS: Male rats from the high alcohol drinking (HAD2) and low alcohol drinking (LAD2) lines received two intragastric (IG) infusions of alcohol (3.0 g/kg BW; 25% v/v) or an equal volume of water, separated by 5 h, every day for 20 consecutive days (chronic alcohol treatment). Acoustic startle reactivity was assessed at 10, 14, and 18 h after the second infusion on days 1, 5, 10, 15, and 20. After acoustic startle testing was completed, all rats received two IG infusions of 3.0 g alcohol/kg BW, separated by 5 h, and blood alcohol content was assessed at 10, 14, and 18 h after the second alcohol infusion. All rats were then given a 24 h free-choice between alcohol and water for 8 weeks. RESULTS: Startle magnitude to a 120 dB tone was suppressed during alcohol withdrawal in both alcohol-treated HAD2 and LAD2 rats after 5, 10, and 15 days of alcohol treatment. Forced, chronic alcohol treatment produced metabolic tolerance in both the HAD2 and LAD2 lines and significantly suppressed subsequent voluntary alcohol intake in rats of the HAD2 line. CONCLUSIONS: Reduced acoustic startle reactivity during alcohol withdrawal in both HAD2 and LAD2 rats is consistent with our previous findings in the HAD2 but not the LAD2 line and may reflect reduced CNS excitability during withdrawal from forced alcohol exposure. Forced alcohol exposure robustly retarded the expression of a genetic predisposition toward alcohol drinking in rats selectively bred for high alcohol intake.     

Ethanol induces higher BEC in CB1 cannabinoid receptor knockout mice while decreasing ethanol preference

AIMS: Previous studies have shown that CB(1) cannabinoid receptors are involved in the behavioural effects induced by chronic ethanol administration in Wistar rats by using SR 141716, a CB(1) cannabinoid receptor antagonist. These studies have now been extended to investigate the effect of acute and chronic alcoholization on blood ethanol concentration (BEC) and ethanol preference in CB(1) knockout (-/-) mice. METHODS: BEC was monitored for a period of 8 h in both CB(1)(-/-) male mice and CB(1) male wild-type (+/+) mice, which had received an acute i.p. injection of ethanol in 1, 3 or 5 g/kg doses. Ethanol preference was assayed in both groups of male mice in non-forced ethanol administration and forced chronic pulmonary alcohol administration for 14 and 39 days, respectively. RESULTS: After an acute intraperitoneal ethanol injection of 5 g/kg, CB(1)(-/-) mice showed a significant higher BEC during the ethanol elimination stage than the CB(1)(+/+) mice. However, those in the 1 and 3 g/kg groups showed no significant difference. A 2-3 fold increase in BEC was observed in CB(1)(-/-) mice on days 10 and 11 after commencement of forced chronic pulmonary alcoholization in comparison with CB(1)(+/+) mice, although comparable BEC values were assayed in both groups on day 12. In addition, these CB(1)(-/-) mice showed a significantly lower preference for ethanol than CB(1)(+/+) mice. CONCLUSIONS: The studies on CB(1)(-/-) and CB(1)(+/+) mice have clearly confirmed the involvement of CB(1) receptor on ethanol induced behavioural effects and also revealed that CB(1) receptors may be implicated in ethanol absorption/distribution, particularly after administration of high ethanol doses.     

TOLERANCE AND DEPENDENCE IN HIGH ALCOHOL SENSITIVITY (HAS) AND LOW ALCOHOL SENSITIVITY (LAS) RATS AFTER CHRONIC ALCOHOL INTOXICATION BY INHALATION

In rats selected for their differences in sleep time followingacute administration of ethanol (high or low alcohol sensitivity:HAS or LAS), alcohol chronic tolerance and behavioural dependencewere determined. Tolerance was assessed by calculating the intervalbetween the loss and regain of the righting reflex followingan acute administration of ethanol (4 g/kg body wt), after intoxicationby inhalation of ethanol vapour for 3 weeks. The impoetanceof behavioural dependence was estimated by measuring the ethanolintake in a free-choice situation water/ethanol (10% v/v), afterintoxication by inhalation for 4 weeks. The two HAS and LASlines did n show any behavioural dependence, while they developeda significant tolerance to the hypnotic effect of ethanol, whichwas more marked for the LAS line.     

Topiramate (Topamax) reduces conditioned abstinence behaviours and handling-induced convulsions (HIC) after chronic administration of alcohol in Swiss-Webster mice

Topiramate has emerged as one of the promising drugs for the treatment of alcoholism and alcohol addiction. Recent studies have shown that topiramate reduces harmful drinking and initiates abstinence in humans, but little is known as to why this drug is effective. AIMS: In the present study, we examined the effects of topiramate in reducing convulsions during alcohol withdrawal using a procedure called the handling-induced convulsion (HIC) test in male Swiss-Webster mice. In addition, we examined the ability of topiramate to reduce alcohol conditioned and anxiety related behaviours during conditioned abstinence using the elevated plus maze (EPM) test. METHODS: HICs were examined 10 h after the 3rd daily alcohol (2.5 g/kg; 20% w/v)+4 methylpyrazole (4MP) (9 mg/kg) intraperitoneal (i.p.) injection with topiramate (0, 10 or 20 mg/kg ip) administered 30 min before testing. In the EPM, alcohol (1.75 g/kg; 20%, i.p.) or saline was administered daily for 9 days and subjects were immediately placed on the maze. Anxiety related behaviours included the amount of time spent and number of entries in the open or closed arms and grooming bouts, and conditioned behaviours including the stretched-attend posture were examined 24 h after the last day of alcohol injection. RESULTS: Topiramate (10 and 20 mg/kg) significantly reduced HIC scores (P<0.05) compared to the alcohol/saline group. In the EPM, topiramate (20 mg/kg) reduced the stretched-attend postures (P<0.001) compared to the alcohol/saline group. CONCLUSION: These findings suggest that topiramate reduces HICs during alcohol withdrawal and alcohol-conditioned behaviours during conditioned abstinence in Swiss-Webster mice.     

Reduction of alcohol intake by the positive allosteric modulator of the GABAB receptor, rac-BHFF,in alcohol-preferring rats

Previous research has demonstrated that treatment with the positive allosteric modulator (PAM) of the GABA_B receptor (GABA_B PAM), rac-BHFF, suppressed lever-responding for alcohol and amount of self-administered alcohol in Sardinian alcohol-preferring (sP) rats. The present study was designed to extend the investigation on the anti-alcohol effects of rac-BHFF to alcohol drinking behavior. To this end, sP rats were exposed to the homecage, 2-bottle “alcohol (10%, v/v) vs water” choice regimen, with unlimited access for 24 h/day. rac-BHFF was administered once daily and for 7 consecutive days at the doses of 0, 50, 100, and 200 mg/kg (i.g.). Treatment with rac-BHFF resulted in an immediate, stable, and dose-related reduction in daily alcohol intake; the overall magnitude of reduction in alcohol intake averaged approximately 25%, 40%, and 65% in 50, 100, and 200 mg/kg rac-BHFF-treated rat groups, respectively. An increase in daily water intake fully compensated the reduction in alcohol intake, so that daily total fluid intake was unaffected by treatment with rac-BHFF. Daily food intake tended to be reduced only by the highest dose of rac-BHFF. These results complement closely with previous data indicating that (a) rac-BHFF suppressed operant, oral alcohol self-administration in sP rats and (b) the prototypic GABA_B PAMs, CGP7930 and GS39783, reduced alcohol drinking in sP rats. However, while the reducing effect of CGP7930 and GS39783 on the daily alcohol intake tended to vanish after the first 2–3 days of treatment, the reducing effect of rac-BHFF on daily alcohol intake remained unchanged over the entire 7-day treatment period. These data strengthen the hypothesis that GABA_B PAMs may represent a step forward in the search for GABA_B receptor ligands with therapeutic potential for alcoholism.     

Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician

AIMS: To test whether the dose-dependent motivation-suppressing effect of baclofen in animals could be transposed to humans, and suppress craving and sustain abstinence. METHODS: Neurologists safely use up to 300 mg/day (10 times the dosage currently used for alcohol dependence) of high-dose oral baclofen, to control spasticity, in order to avoid invasive therapy. I am a physician with alcohol dependence and comorbid anxiety. I self-prescribed high-dose baclofen, starting at 30 mg/day, with 20 mg increments every third day and an (optional) additional 20-40 mg/day for cravings. RESULTS: Cravings became easier to combat. After reaching the craving-suppression dose of 270 mg/day (3.6 mg/kg) after 5 weeks, I became and have remained free of alcohol dependence symptoms effortlessly for the ninth consecutive month. Anxiety is well controlled. Somnolence disappeared with a dosage reduction to 120 mg/day, now used for the eighth consecutive month. CONCLUSIONS: High-dose baclofen induced complete and prolonged suppression of symptoms and consequences of alcohol dependence, and relieved anxiety. This model, integrating cure and well-being, should be tested in randomized trials, under medical surveillance. It offers a new concept: medication-induced, dose-dependent, complete and prolonged suppression of substance-dependence symptoms with alleviation of comorbid anxiety.     

Balance of magnesium and iron and their content in tissues and body fluids of rats after supplementation with magnesium carbonate

Effect of magnesium on iron and magnesium metabolism in rats were investigated. 96 male Wistar rats were divided into four groups received 2.5; 5.0 and 10.0 mg magnesium daily per kg of body weight--dissolved in 2%--solution of arabic gum (tests groups) or clear 2%--solution of arabic gum (test group) for 4 weeks and the next 4 weeks without supplements. Iron concentrations increased in the brain and kidney of the experimental rats, but decreased in the spleen, intestine and liver (2 and 4 weeks only) also in the heart and femur (only 8 week). Percentage of iron retention decreased during the whole experiment. Magnesium concentrations increased in the spleen, liver and intestine of rats. It was shown that at 8 weeks of experiment the magnesium level of heart and femur decreased (only groups received 2.5 mg and 5.0 mg Mg/kg b.w./24 h), but in group received 10.0 mg Mg/kg b.w./24 h increased for all experiment. The apparent retention of magnesium increased in start of the experiment. This results show that oral magnesium supplementation disturbs metabolism of these elements, especially balance of iron.     

Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in mice: tolerance and cross-tolerance.

Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.     

Pharmaco-EEG-based assessment of interaction between ethanol and levetiracetam.

Recent research suggests a potential role for a new generation of anticonvulsant drugs, including levetiracetam, in the treatment of alcohol dependence. Some elements of the central mechanism of action that levetiracetam has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. In this study, we have used a pharmaco-electroencephalographic (EEG) method to examine the interaction of ethanol with levetiracetam. The influence of levetiracetam on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Levetiracetam was administered p.o. as a single dose (50mg/kg or 200mg/kg) or repeatedly at a dose of 100mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of levetiracetam. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 Hz and 30-45 Hz). Changes in the EEG recordings after levetiracetam alone were more significant when the drug was given in repeated doses. Combined administration of ethanol and levetiracetam (200mg/kg) resulted in a markedly synergistic effect in the frontal cortex and the midbrain reticular formation. The drug decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.     

Effects of 5-HT(3) receptor antagonists on daily alcohol intake under acquisition, maintenance, and relapse conditions in alcohol-preferring (P) rats.

Previous research indicated that 5-HT(3) antagonists can reduce ethanol drinking in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT(3) antagonists MDL 72222 (MDL) or ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisition, maintenance, and following a period of deprivation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL (1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 10 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT(3) antagonist. To examine the effects of a 5-HT(3) antagonist on relapse of ethanol drinking, another group of P rats was allowed access to ethanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to ethanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 mg/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60-80%) and during maintenance drinking (35-70%) in P rats pretreated with saline during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of either MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with 1 mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) or ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observed on the first day of reinstatement. Overall, the results suggest that 5-HT(3) receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treatment with 5-HT(3) antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat.     

硫酸镁联合硝苯地平治疗新生儿持续性肺动脉高压临床观察

目的观察硫酸镁联合硝苯地平治疗新生儿持续肺动脉高压(PPHN)的临床效果。方法对收治并确诊的31例PPHN患儿在呼吸支持的基础上采用硫酸镁联合硝苯地平治疗,硫酸镁首剂为200mg/kg,30min内微量泵静脉注入,继之维持量20～50mg/(kg.h)持续微量泵静脉注入,维持4个小时后改用硝苯地平1mg/(kg.次)口服,6～8小时应用一次。治疗期间监测血压、经皮血氧饱和度、血气分析、血钙、血镁和肺动脉压。结果硫酸镁联合硝苯地平治疗后,血氧饱和度、血氧分压、pH值与用药前比较明显改善,肺动脉压下降,差异显著。结论硫酸镁联合硝苯地平治疗新生儿持续肺动脉高压疗效确切,适合基层医院使用。     

ALCOHOL AND DRUG DEPENDENCE: AREAS OF CHANGE OR UNCERTAINTY

Developing areas are reviewed whose resolution will promoteunderstanding of basic issues or the solution of controversies.Points that are discussed include the neuronal actions of dependenceproducing substances (especially on neural membranes, GABA andcalmodulin), and contrary claims for acetaldehyde as a causeor a protection against alcohol misuse. Therapeutic implicationsare proposed for the high frequency of cerebral impairment amongproblem drinkers; the routine provision of drugs to cover alcoholwithdrawal is questioned; growing attacks on methadone maintenanceas a suitable treatment of opioid dependence are discussed.Suggestions for safe drinking levels are outlined, with particularregard to hypertension, cirrhosis, pancreatitis and foetal alcoholeffects.     

Acute and Chronic Alcohol–Cocaine Interactions in Rats

The widespread combined use of alcohol and cocaine across the United States underscores the importance of understanding how the actions of those two agents interact upon important physiological regulatory processes. In an experiment exploring acute ethanol–cocaine interactions, 16 rats were given 2.0 g/kg (IP) doses of ethanol at time zero. Two hours later, half of the rats were given cocaine (20 mg/kg, IP), while the other half were given injections of saline. The group given cocaine displayed a prolongation of the hypothermia condition induced by ethanol injection. In a chronic experiment, three groups of rats (n = 6–8) were exposed for an 11-day period to daily IP injections of 10 mg/kg cocaine, 20 mg/kg of cocaine, or saline. On day 12 these groups did not differ in their response to loss of the righting reflex induced by a 3.0 g/kg dose of ethanol. However, recovery from ethanol hypothermia was more rapid in the rats exposed to chronic cocaine. In summary, these initial studies provide evidence for exacerbation of the acute hypothermic effects of ethanol when a cocaine challenge is given 2 h after ethanol. In contrast, ethanol hypothermia was observed to be reduced when tested on day 12 after an 11-day chronic regimen of cocaine. Other dosage regimens and response measures need to be tested to understand the full scope of acute and chronic cocaine–ethanol interactions and the possible health consequences.