Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress

Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (IV) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, SC) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg; 12 h apart; IP) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50–200 mg/ kg; IP) had no consistent effects on IV heroin self-administration (50–100 μg/kg per infusion) and, in experiment 3, that acamprosate (100–200 mg/ kg, IP) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, SC) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users. Received: 4 November 1997/Final version: 25 January 1998     

Blockade of pre-and post-synaptic 5-HT1A receptors does not modify the effect of fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats

Selective serotonin reuptake inhibitors (SSRIs) or serotonin precursors inhibit ethanol and food intake by increasing the synaptic availability of 5-HT in the central nervous system. However, these agents can also increase 5-HT levels at somatodendritic 5-HT_1A autoreceptors, with negative effects on serotonergic transmission. (+)WAY100135 [N-ter-butyl 3-4-(2-methoxy-phenyl) piperazin-1-yl-2-phenylpropa-namide dihydrochloride] is a selective antagonist both at pre-and post-synaptic 5-HT_1A receptors. The present study investigated the effect on ethanol and food intake of (+)WAY100135, given alone or coadministered with the SSRI fluoxetine or the 5-HT precursor 5-hydroxytryptophan (5-HTP) in genetically selected alcohol-preferring rats. Blockade of presynaptic 5-HT_1A receptors after injection of (+)WAY100135, 0.1 or 1 μg/rat, into the dorsal raphe did not significantly modify ethanol, food or total fluid intake. The same doses of (+)WAY100135 did not modify the inhibition of ethanol and food intake induced by intraperitoneal (IP) injection of fluoxetine, 5 mg/kg. Subcutaneous (SC) administration of (+)WAY100135 (1 or 10 mg/kg) did not affect the 3-h, or the overnight intake of ethanol, food or total fluids. Given together with IP fluoxetine (5 mg/kg) or SC 5-HTP (100 mg/kg plus carbidopa, 12.5 mg/kg), the same SC doses of (+)WAY100135 did not modify their inhibitory effect on ethanol and food consumption. Present findings suggest that blockade either of pre-or of pre-and postsynaptic 5-HT_1A receptors does not potentiate the inhibitory effect of fluoxetine or 5-HTP on ethanol and food intake. Received: 2 November 1996/Final version: 23 April 1997     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Possible mechanism of action for the attenuation of ethanol intake induced by ritanserin in rats

The 5-HT₂ receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT₃ receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC. Received: 22 March 1996/Final version: 10 July 1996     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; IG) from ethanol (2.0 g/kg; IG) from water (4.7 ml; IG) using food reinforcement. Substitution tests were conducted following administration of the GABA_A positive modulators allopregnanolone (5.6–30.0 mg/kg; IP), diazepam (0.3–10.0 mg/kg; IP) and pentobarbital (1.0–21.0 mg/kg; IP), the non-competitive NMDA antagonist phencyclidine (0.3–10.0 mg/kg; IP), the 5-HT₁ agonists TFMPP (0.3–5.6 mg/kg; IP) and RU 24969 (0.3–3.0 mg/kg; IP), and isopropanol (0.10–1.25 g/kg; IP). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA_A- and 5-HT₁-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol. Received: 18 November 1997 / Final version: 10 February 1998     

Diurnal variation in plasma ethanol levels of TO and CBA mice on chronic ethanol drinking or ethanol liquid diet schedules

Diurnal variation in blood and plasma ethanol levels (BACs) has been observed in animals undergoing chronic ethanol treatment, but the information available is insufficient to determine whether the different patterns seen are due to differences in ethanol administration schedules or to strain of the animal. In this study, we have compared plasma ethanol levels in males of two mouse strains with no innate preference for ethanol, TO and CBA, during two commonly employed chronic ethanol treatment schedules. Ethanol was administered in solution as sole drink (CED) (10% or 20% w/v ethanol) for 4 weeks, or in liquid diet form (ELD), (3.5% w/v ethanol for 2 days, then 7% for 5 days). Mice were housed eight per cage on a 12-h light cycle (0900–2100 hours). Plasma ethanol concentration was monitored over the 24-h period. Activity of liver alcohol dehydrogenase (ADH) was measured between 0900 and 1100 hours. CBA mice showed greater variability in body weights than TO mice, which weighed more throughout the period of study and had significantly higher total energy intakes. TO mice consumed more ELD than CBA mice. Following an initial 2-day period of 3.5% ELD, both strains decreased their diet intake when ethanol content of the diet was increased to 7% w/v, which resulted in weight loss. Mice on the CED schedules decreased their fluid intake with increasing concentration of ethanol in the drinking solution. Highest daily ethanol intakes were observed in mice on ELD (19.1 ± 1.7 and 22.2 ± 0.6 g/kg body weight in CBA and TO mice, respectively). Marked diurnal variation in plasma ethanol levels was observed, which was dependent on the treatment schedule, strain and method of ethanol administration. Highest levels were found in mice on the ELD schedule (104.8 ± 7.7 mM in CBA mice, 113.5 ± 14.5 mM in TO mice), peaking at 1900 and at 0900 hours in CBA and TO mice, respectively. Lower plasma ethanol concentrations were reached in mice on the CED schedules, peaking at midnight (34.6 ± 8.1 mM and 35.4 ± 8.8 mM in CBA and TO mice on 20% CED, respectively, and 3.7 ± 1.2 mM and 6.6 ± 2.1 mM in CBA and TO mice on 10% CED). Naive CBA mice had slightly higher liver ADH activity as compared to their TO counterparts. No effect of 10% CED on liver ADH activity was found in either mouse strain. In conclusion, we have confirmed the importance of monitoring plasma ethanol levels during chronic treatment, as there is marked diurnal variation, dependent on the light/dark cycle. Factors such as strain of the animal and the method of delivery of ethanol are also important, whereas liver ADH plays a minor role. Monitoring the daily ethanol consumption is insufficient to predict the resulting plasma levels of the drug. Received: 19 May 1997 / Final version: 15 December 1997     

The reduction in alcohol intake in rats by isoproterenol is attenuated by indomethacin but not enalapril: relationship to blood glucose levels

 Many adrenergic agonists including isoproterenol, a β _{1,  2}-adrenergic agonist, reduce alcohol consumption, but the mechanism of this effect is not known. Adrenergic agonists have a variety of effects, among which are their ability to raise both angiotensin (ANG) II activity and plasma glucose levels. Previous research has shown that ANG II and enhanced glucose levels are accompanied by reductions in alcohol intake. Therefore, the following experiments assessed the roles of each of these factors in the suppression of alcohol intake by isoproterenol. Male Wistar rats were trained to drink a quantity of 6% (w/v) alcohol using the limited access procedure, which offers a daily 40-min access to alcohol and water. In experiment 1, isoproterenol or vehicle was administered SC just prior to alcohol availability, and only the group receiving isoproterenol showed a marked reduction in alcohol intake. Following this, the groups were pretreated IP with either vehicle or ascending doses of the prostaglandin synthetase inhibitor, indomethacin (2, 4 mg/kg), followed by either isoproterenol or vehicle. Control groups received either two vehicle injections or vehicle and indomethacin. Indomethacin alone did not affect alcohol intake at any of the doses tested but did dose-dependently attenuate the reduction in alcohol intake produced by isoproterenol. In experiment 2, isoproterenol was administered just prior to alcohol availability and when the suppression of alcohol intake stabilized, ascending doses of the angiotensin converting enzyme inhibitor, enalapril (1, 20, 40 mg/kg), were given IP 1 h prior to the isoproterenol. Enalapril altered water intake but had no effect on the isoproterenol-induced reduction in alcohol intake. These results show that the inhibition of alcohol drinking by isoproterenol varies more closely with altered glucose levels than with increased ANG II synthesis. They also demonstrate that downstream consequences of a drug may play a role in its effect on alcohol intake. Received: 19 June 1997 / Final version: 11 November 1997     

The reduction in alcohol intake by the 5-HT1A agonist 8-OH DPAT and its attenuation by the α2 adrenergic antagonist idazoxan correlates with blood glucose levels

 Serotonergic agents in general and the 5-HT_1A agonist 8-OH DPAT in particular, reduce alcohol intake in rats and primates but the mechanism of this effect is not known. Previous studies have shown a correlation between alcohol consumption and the propensity to consume sweet substances. Indeed, certain biochemical events accompanying glucose utilization have been proposed as satiety signals in the control of feeding. Since 8-OH DPAT produces hyperglycemia, we tested the hypothesis that its effect on alcohol intake may be partly mediated through an increase blood glucose. Male Wistar rats were trained to drink a bout of 6% (w/v) alcohol using the limited access procedure which offers a daily 40-min access to alcohol and water. On consecutive test trial days separated by intervening non-drug days, the amount of alcohol consumed (1 g/kg on intervening days) was measured following the administration of 8-OH DPAT (150 μg/kg 10 min prior to drinking) alone or in combination with the prior (20 min) injection of idazoxan (2 mg/kg), an alpha-2 adrenoceptor antagonist with hypoglycemic properties. Idazoxan attenuated the hyperglycemic effect of 8-OH DPAT and completely reversed 8-OH DPAT’s inhibitory effect on alcohol intake. Idazoxan alone produced a mild hypoglycemia and stimulated alcohol intake. These results support a role for glucoregulatory processes in serotonergically-mediated changes in alcohol consumption. Received: 22 November 1996 / Final version: 25 March 1997     

Electrophysiological indices of acute effects of ethanol on involuntary attention shifting

Dose-related effects of ethanol (placebo, 0.30, and 0.60 g/kg) on behavioral and event-related brain potential (ERP) indices of involuntary attention shifting of audition were investigated. ERPs were recorded from 11 healthy social drinkers during a forced-choice reaction-time (RT) task. Subjects were presented with 100 and 200 ms tones (P = 0.50 for each) with a constant inter-stimulus interval (ISI) of 1 s. The task was to press either of two buttons, depending on the tone duration. The majority of the tones (“standards”) were of 700 Hz (P = 0.82). Occasionally, however, the frequency of the tones changed, deviating either slightly (750 Hz), moderately (900 Hz), or widely (1200 Hz; P = 0.06 for each) from the standard frequency. In accordance with previous findings, the task-irrelevant frequency deviations prolonged the RT. This RT prolongation was attenuated by alcohol with the 0.3 g/kg dose, thus suggesting less distraction by irrelevant stimulus deviations under the influence of ethanol. Furthermore, the P3a, reflecting involuntary attention shifting, was suppressed by alcohol even with the 0.3 g/kg dose. These findings demonstrate a detrimental effect of alcohol on involuntary attention shifting, evident with doses considerably smaller than previously described, and still juridically acceptable in road traffic in most countries. Received: 19 December 1997/Final version: 26 May 1998     

Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats

Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals. Received: 3 April 1998/Final version: 7 September 1998     

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

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

Glutamate uptake in mice bred for ethanol withdrawal severity

Rationale: Withdrawal seizure-prone and withdrawal seizure-resistant mice were selectively bred to exhibit differences in handling-induced convulsion severity during ethanol withdrawal. The glutamatergic system has been implicated in seizure activity as well as ethanol withdrawal symptoms. Objective: This study assessed L-[³H]glutamate uptake into hippocampal synaptosomes prepared from withdrawal seizure-prone and- resistant mice. Methods:Glutamate uptake was characterized following repeated handling-induced convulsions, during acute intoxication, and during peak withdrawal following chronic ethanol exposure. Results: Hippocampal synaptosomal L-[³H]glutamate uptake did not differ between convulsion- and ethanol-naive withdrawal seizure-prone and- resistant mice. Furthermore, exposure to convulsions or to a hypnotic dose of ethanol (4 g/kg) did not alter L-[³H]glutamate uptake. However, withdrawal from 72 h of ethanol exposure significantly increased L-[³H]glutamate uptake in both mouse lines as compared to their respective ethanol-naive controls. Conclusions:These data suggest that glutamate uptake is influenced by chronic ethanol exposure similarly in both withdrawal seizure-prone and- resistant mice. The observed increases in glutamate uptake during withdrawal may be associated with compensatory mechanisms triggered by chronic intoxication and are independent of the selected differences for withdrawal severity. Received: 23 July 1998/Final version: 21 October 1998     

Further studies on the role of noradrenergic mechanisms in ethanol withdrawal syndrome in rats

Ethanol dependence was induced in rats by intragastric administration of ethanol. Clonidine (0.1 mg/kg ip) suppressed withdrawal reaction while yohimbine (2.5 mg/kg ip) produced an opposite effect. Propranolol (2.0 mg/kg ip) reduced withdrawal convulsions but not locomotor hyperactivity while prazosin (1.0 mg/kg ip) attenuated only the latter symptom. Electrolytic lesions in the ventral noradrenergic bundle slightly increased locomotor activity in ethanol-dependent rats but failed to change the convulsions. Our result indicates that drugs acting upon alpha and beta adrenoceptors are able to reduce the severity of certain withdrawal reactions in ethanol-dependent rats.     

Do GABAB receptors have a role in causing behavioural hyperexcitability,both during ethanol withdrawal and in naive mice?

The effects of the GABA_B agonist baclofen and the GABA_B antagonist CGP35348 were examined on the behavioural hyperexcitability which is seen on cessation of chronic ethanol treatment. When baclofen was given to mice of the TO strain after withdrawal from ethanol inhalation, there was evidence of increased hyperexcitability with one dose, 2.5 mg/kg, but no significant change was seen with other doses, 1.25 and 10 mg/kg. When given after withdrawal from a liquid diet containing ethanol, baclofen, 10 mg/kg, produced a large, but short lasting, increase in the ratings of hyperexcitability during the withdrawal period. This effect was significantly decreased when the antagonist CGP35348, 300 mg/kg, was given with baclofen 10 mg/kg. When the antagonist was given alone at 300 mg/kg it significantly decreased the hyperexcitability during ethanol withdrawal. Increases in the ratings of hyperexcitability were seen when baclofen was given to control mice, which had not received ethanol, and these effects were significant, so the effects during ethanol withdrawal were not confined to that syndrome. CGP35348 decreased the behavioural ratings in control animals, and blocked the effects of baclofen 10 mg/kg. When the effects of the compounds on spontaneous locomotor activity in control mice were measured, this parameter was decreased both by baclofen and by CGP35348, at does which were effective in altering the handling-induced behaviour.     

Acute tolerance to the ataxic effects of ethanol in short-sleep (SS) and long-sleep (LS) mice

 The objective of this series of studies was to examine the relationship between alcohol sensitivity and the development of very rapid acute tolerance to alcohol in mice. In order to measure acute tolerance to alcohol, a behavioral test was developed using a rotorod. In the first study, mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute hypnotic effects of ethanol were used, as well as mice from the base population (heterogenous stock, HS). Mice were trained to run on the rotorod at a speed of 14 rpm to a criterion of 200 s, in four daily training sessions. On the test day, baseline measurements of rotorod performance were taken and mice were injected IP with alcohol in doses from 0 to 2.5 g/kg. Animals were tested at 1-min intervals for the first 5 min following injection, then at 5-min intervals for a total of 30 min. The results demonstrated that SS and HS mice developed tolerance within 10 min following the alcohol injections. LS mice did develop some acute tolerance, but at a much slower rate than the SS or HS mice. In the second study, the effects of intoxicated practice on the rates of acute tolerance development were examined in the SS, HS and LS mice at a dose of 2.0 g/kg alcohol. A total of ten groups of each strain were given a different number of practice trials (ranging from one to ten) on the rotorod prior to a final test session at 30 min post-injection. The results provide evidence that SS and HS mice are capable of developing acute tolerance independent of practice. That is, the group of animals injected at 0 time and tested ten times up to 30 min were no better at the 30-min time point than the group injected at 0 time and tested only once at 30 min. On the other hand, the LS mice showed a modest practice effect, developing additional tolerance to the ataxic effects of alcohol with increasing intoxicated practice. Overall, these studies demonstrated that mice can develop acute tolerance within minutes following alcohol exposure, and that this ability is correlated with the initial sensitivity to alcohol. Received: 12 July 1997 / Final version: 26 August 1997     

Double-blind study of cyamemazine and diazepam in the alcohol withdrawal syndrome

OBJECTIVE: Cyamemazine is an original phenothiazine derivative which showed similar efficacy and tolerability to lorazepam during ethanol withdrawal in mice. This study investigated cyamemazine for its efficacy and tolerability in alcohol-dependent patients electing an alcohol withdrawal procedure, in comparison with diazepam. METHOD: A multicenter, randomized, double-blind study in 89 alcohol-dependent patients (CIWA-Ar score between 10 and 30), electing an alcohol withdrawal procedure, was used to find effective doses of cyamemazine and to compare it with diazepam for efficacy and tolerability. On day 1 (D(1)), cyamemazine or diazepam (50 mg and 10 mg capsule, respectively) were administered at hourly intervals to reduce CIWA-Ar = 5, up to a maximum of eight administrations. Starting from D(2), the compounds were given twice a day in progressively decreasing doses during a maximum period of 13 days (D(end)). RESULTS: At h(8) (8 h after the first treatment of D(1)), therapeutic success (CIWA-Ar score 相似文献   

Effect of the combined administration of ethanol and acamprosate on rabbit EEG

Central effect of ethyl alcohol and acamprosate is based on similar mechanisms. It is mainly connected with their effect on GABAergic, glutamatergic, serotonergic and opioid transmission. Thus, the question arises whether acamprosate administered together with alcohol increases acute central effects of ethanol. We have studied the effect of joint administration of acamprosate with ethanol in rabbits on EEG results from: frontal cortex, hippocampus and midbrain reticular formation. Acamprosate was applied into the stomach at a single dose of 400 mg kg(-1) or repeated doses of 200 mg kg(-1)/day (for 14 days). Ethanol at the dose of 0.8 g kg(-1) was administered iv 120 min after a single dose of acamprosate, or 4 h after the last dose of the drug. Ethanol caused an increase in the slow frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the fastest frequencies (13-30 and 30-45 Hz). Acamprosate administered jointly with ethanol increased the effect of ethanol on EEG recording; the amount of the fastest frequencies was decreased. When administered as repeated doses, it enhanced alcohol-related changes in EEG, both within slow and fast frequencies. Consumption of ethanol during acamprosate treatment may lead to intensification of central effects of ethanol.     

Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits

Rationale Prenatal exposure to alcohol can disrupt brain development, leading to a variety of behavioral alterations, including learning deficits. We have postulated that some central nervous system damage may be due to N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity that occurs during ethanol withdrawal. Consistent with this hypothesis, we previously demonstrated that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal attenuates ethanol-related learning deficits using an animal model of fetal alcohol effects. However, MK-801 binds to the phencyclidine site, which affects all NMDA receptor subtypes and can cause adverse side effects and toxicity. Eliprodil is a more selective NMDA receptor antagonist that acts at the polyamine modulatory site of NMDA receptors.Objectives The purpose of this study was to determine if administration of eliprodil during ethanol withdrawal would reduce the severity of learning deficits associated with developmental alcohol exposure.Methods Male rat pups were randomly assigned to ethanol-exposed or control treatments. On postnatal day (PD) 6, during a period of brain development similar to that of the mid-third trimester in humans, subjects were exposed to 6.0 g/kg ethanol or isocaloric maltose solutions via oral gavage. Twenty-four hours after the end of the ethanol treatment, during ethanol withdrawal, all subjects received an intraperitoneal injection of one of three doses of eliprodil (5, 10, or 25 mg/kg) or vehicle. On PD 40, all subjects were tested on a serial spatial discrimination reversal learning task.Results Ethanol-exposed subjects treated with vehicle committed a significantly greater number of errors compared to controls. Administration of eliprodil during ethanol withdrawal significantly decreased the number of errors in the ethanol-exposed groups, but had no significant effect on the performance of controls.Conclusion These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.     

GABA<Subscript>B</Subscript> receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

Rationale A growing number of studies suggest that -aminobutyric acid type-B (GABA_B) receptor agonists reduce alcohol use and craving.Objectives This study was designed to further clarify behavioral mechanism(s) by which GABA_B agonists may decrease alcohol reinforcement.Methods Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA_B agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA_B agonists was examined in ethanol naive and self-administering mice.Results Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA_B agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA_B agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA_B agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.Conclusions GABA_B agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA_B agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA_B positive modulation. These data question the safety of prescribing GABA_B agonists to alcoholics since these drugs may potentiate ethanols sedative/hypnotic effects during relapse.