Ethanol blocks nicotine-induced seizures in mice: comparison with midazolam and baclofen

Low doses of ethanol may antagonize the pharmacological effects of nicotine. Recently, it has been shown that the effects of ethanol on nicotine discrimination are not correlated with blood ethanol levels. The aim of the present study was to evaluate whether ethanol (0.5–2 g/kg, i.p.) could block nicotine-induced seizures in C57BL/6J mice and to correlate ethanol's actions with blood ethanol concentrations. For comparison, the effects of a γ-aminobutyric acid A (GABA_A)/benzodiazepine receptor positive modulator, midazolam (0.25–40 mg/kg, i.p.), and a γ-aminobutyric acid B receptor agonist, baclofen (2.5–20 mg/kg, i.p.), were assessed in the same procedure. Nicotine (3–9 mg/kg, s.c.) induced clonic–tonic seizures in a dose-dependent manner. Ethanol, administered 5 or 50 min before nicotine, dose dependently antagonized seizures elicited by 6 mg/kg nicotine. The anticonvulsant effects of ethanol correlated with blood ethanol levels and were comparable to those exerted by midazolam. Baclofen antagonized only the tonic component of nicotine-induced convulsions. The anticonvulsant doses of ethanol (0.5–2 g/kg), midazolam (0.5–1 mg/kg), and baclofen (5–10 mg/kg) did not affect spontaneous locomotor activity in a control experiment. The present results indicate that (i) ethanol may block nicotine-induced seizures in mice at doses that do not alter locomotor activity and (ii) the antiseizure effects of ethanol depend on blood ethanol levels and are comparable to those exerted by the GABA_A positive modulator midazolam.     

Stimulation of GABAB receptors in thebasal forebrain selectively impairs working memory of rats in the double Y-maze

The present experiments were conducted to evaluate the possible contribution of GABAergic inputs to the basal forebrain in the region of the nucleus basalis magnocellularis (nbm) to memory. In two experiments, rats implanted with bilateral intra-nbm guide cannulae were trained in the double Y-maze task to perform working- and reference-memory components. Animals were placed in one of two start arms of the first “Y” and the reference-memory component required travelling to its central stem for food. Access to the second “Y” then was given and the working-memory component for Expt. 1 required travelling to the goal arm diagonally opposite the start arm in the first “Y” of that trial. In Expt. 2, the working-memory component required travelling to the goal opposite to the goal arm entered in the second “Y” on the preceding trial, with 0- and 15-s delays between trials. In Expt. 1, pretrained rats (n = 8) received the GABA_A agonist, muscimol (0.1 μg in 0.5 μl), the GABA_B agonist, R(+)-baclofen (0.01, 0.05 and 0.1 μg), and its less active enantiomer, S(−)-baclofen (0.1 μg), in a counterbalanced order with retraining to criterion between injections. In Expt. 2, pretrained rats(n = 9) received saline (0.5 μl), R(+)-baclofen (0.1 μg), the GABA_B antagonist, phaclofen (1 μg), and R(+)-baclofen + phaclofen. Results of Expt. 1 revealed that intra-nbm muscimol and, in a dose-dependent manner, R(+)-baclofen differentially affected working but not reference memory. In Expt. 2, the differential mnemonic impairment produced by R(+)-baclofen was replicated and co-injection with phaclofen reversed this effect. A 15-s delay between trials significantly impaired working but not reference memory. Results suggest that both GABA_A and GABA_B receptors may be involved in modulating the possible mnemonic functions of nbm cholinergic neurons.     

Baclofen and γ-aminobutyric acid differentially suppress the cutaneous responsiveness of primary somatosensory cortical neurones

Extracellular recordings from neurones in the cat's primary somatosensory cortex (S1) have been made with carbon fibre-filled multibarrel pipettes used for microiontophoresis. gamma-Aminobutyric acid (GABA) and baclofen elevated the thresholds to tactile and airpuffer stimulation, reduced the sizes of cutaneous receptive fields (RFs), depressed spontaneous activity and decreased the magnitudes of thalamically evoked responses. However, the manner in which baclofen produced its alterations in response properties could be differentiated from that of GABA in several respects. Specifically, responses which reflected spatially integrated driving of cutaneous RFs across peripheral and central regions were suppressed more readily by GABA than by baclofen. Furthermore, baclofen was observed to exert suppressions of responses which were evoked from the peripheral regions of cutaneous RFs more effectively than it could those responses which were evoked from the central regions. GABA affected central and peripheral RF subregions relatively indiscriminately. These results suggest that not only bicuculline-sensitive processes, but also those activated by baclofen, are involved in controlling the sensitivity of S1 cortical neurones to afferent stimuli.     

l-Baclofen-sensitive GABAB binding sites in the medial vestibular nucleus localized by immunocytochemistry

l-Baclofen-sensitive GABA_B binding sites in the medial vestibular nucleus (MVN) were identified immunocytochemically and visualized ultrastructurally inl-baclofen-preinjected rats and monkeys, using a mouse monoclonal antibody with specificity for the p-chlorophenyl moiety of baclofen. Saline-preinjected animals showed no immunostain. In drug-injected animals, there was evidence for both pre- and postsynaptic GABAergic inhibition in MVN mediated by GABA_B receptors. These neural elements could be utilized in control of velocity storage in the vestibulo-ocular reflex.     

The GABAB antagonist phaclofen inhibits the late K-dependent IPSP in cat and rat thalamic and hippocampal neurones

Phaclofen (0.5–1 mM) reversibly inhibited the late, bicuculline resistant, K⁺ dependent IPSP recorded in projection cells of the cat and rat dorsal lateral geniculate nucleus and in rat hippocampal CA1 pyramidal neurones. At the same concentrations, phaclofen reversibly blocked the K⁺ dependent, bicuculline insensitive hyperpolarization evoked by GABA and baclofen but had no effect on the GABA_A IPSP. These results represent conclusive evidence that GABA_B receptors mediate the late K⁺ dependent IPSP in cortical and subcortical neurones.     

Baclofen-induced modification of conditioned discriminative avoidance behaviour and contraversive turning in the rat

The effects of baclofen, a gamma-aminobutyric acid derivative, on conditioned avoidance behaviour and on the turning produced by unilateral 6-OHDA lesions of the s. nigra were investigated in rats. The small impairment of conditioned avoidance behaviour induced by baclofen (1-4 mg/kg i.p.) was potentiated by combination with benztropine, an anticholinergic agent. Moreover, baclofen reversed the suppression of avoidance responses and the inhibition of turning induced by physostigmine, suggesting an interaction of baclofen with cholinergic transmission processes at the nigrostriatal level. After alpha-methyltyrosine, baclofen like haloperidol, produced a marked increase in avoidance response failures suggesting an additional inhibitory effect of the compound on dopaminergic transmission. The pattern of results indicates that baclofen affects the feedback-loop regulation processes in the nigrostriatal area of the brain.     

Intrathecal baclofen management of poststroke spastic hypertonia: implications for function and quality of life

OBJECTIVES: To evaluate the impact of intrathecal baclofen (ITB) on function and quality of life (QOL) and to obtain efficacy and safety data in poststroke spastic hypertonia. DESIGN: Prospective open-label multicenter trial with follow-up at 3 and 12 months. SETTING: Twenty-four stroke treatment centers in the United States. PARTICIPANTS: Ninety-four stroke participants (age range, 24-82 y) with spastic hypertonia. Seventy-four participants underwent ITB pump implantation. INTERVENTION: Participants were implanted with an ITB pump. MAIN OUTCOME MEASURES: FIM instrument and QOL (Sickness Impact Profile [SIP]) changes, spastic hypertonia (Ashworth Scale), and safety. RESULTS: FIM scores improved overall in repeated-measures analysis of variance (ANOVA) (P = .005) and by 3.00 +/- 7.69 (P = .001) at 3 months and by 2.86 +/- 10.13 (P = .017) at 12 months. Significant improvements in SIP scores were noted overall (repeated-measures ANOVA, P < .001) and at 3 (P = .003) and 12 months (P < .001). The combined average Ashworth Scale score of the upper and lower limbs decreased by 1.27 +/- 0.76 (P < .001) at 3 months and by 1.39 +/- 0.73 (P < .001) at 12 months from baseline, which was significant overall (repeated-measures ANOVA, P<.001). Strength in the unaffected side did not change overall (repeated-measures ANOVA, P = .321) or at either 3 (P = .553) or 12 months (P = .462). Minimal adverse events and device complications were reported. CONCLUSIONS: There was significant improvement in function, QOL, and spastic hypertonia at 3 and 12 months after implant, without adversely affecting muscle strength of the unaffected limbs. Data suggest that ITB therapy is a safe and efficacious treatment for spastic hypertonia resulting from stroke.     

Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam

Purpose

Benzodiazepines are the drugs of choice in the treatment of alcohol withdrawal syndrome (AWS). Recent data have shown that baclofen may reduce AWS symptoms. At present, no comparative studies between baclofen and any benzodiazepine used in AWS treatment are available. Accordingly, the present study was designed to compare efficacy, tolerability and safety of baclofen versus diazepam in the treatment of AWS.

Subjects and methods

Thirty-seven patients with AWS were enrolled in the study and randomly divided into 2 groups. Baclofen (30 mg/day for 10 consecutive days) was orally administered to 18 patients (15 males, 3 females; median age: 46.5 years). Diazepam (0.5-0.75 mg/kg/day for 6 consecutive days, tapering the dose by 25% daily from day 7 to day 10) was orally administered to 19 patients (17 men, 2 women; median age: 42.0 years). The Clinical Institute Withdrawal Assessment (CIWA-Ar) was used to evaluate physical symptoms of AWS.

Results

Both baclofen and diazepam significantly decreased CIWA-Ar score, without significant differences between the 2 treatments. When CIWA-Ar subscales for sweating, tremors, anxiety and agitation were evaluated singly, treatment with baclofen and diazepam resulted in a significant decrease in sweating, tremors and anxiety score, without significant differences between the 2 drug treatments. Both treatments decreased the agitation score, although diazepam was slightly more rapid than baclofen.

Conclusion

The efficacy of baclofen in treatment of uncomplicated AWS is comparable to that of the “gold standard” diazepam. These results suggest that baclofen may be considered as a new drug for treatment of uncomplicated AWS.     

Baclofen: a new drug for the treatment of alcohol dependence

Recent preclinical and clinical studies have suggested that baclofen, the prototypic gamma-aminobutyric acid B (GABA(B)) receptor agonist, is a promising pharmacological compound for use in the treatment of alcohol dependence. In particular, baclofen has been found to suppress symptoms of alcohol withdrawal syndrome with an efficacy comparable with that of the 'gold standard' diazepam. Moreover, baclofen has proven effective in the prevention of relapse due to its ability to reduce alcohol intake and craving in alcoholic patients. Baclofen proved to be manageable, producing no significant side effects and displaying no addictive properties. The efficacy of the drug in the management of both alcohol withdrawal syndrome and relapse prevention should entail a vastly simplified pharmacotherapy of alcohol dependence.     

芍药甘草汤联合西医治疗中风后痉挛性偏瘫随机平行对照研究

[目的]观察芍药甘草汤联合西医治疗中风后痉挛性偏瘫腹泻疗效。[方法]使用随机平行对照方法,将40例门诊患者按抽签法简单随机分为两组。降糖、降压、纠正水电解质紊乱和酸碱平衡。对照组20例巴氯芬,初始剂量5mg,3次/d,后逐量增加,每3d加5mg,直至90mg/d。治疗组20例芍药甘草汤(伸筋草、木瓜、生白芍各30g,地龙、川芎、甘草各10g,丹参15g,生姜、当归、桂枝各6g,大枣5枚),1剂/d,水煎200m L,早晚口服。连续治疗10d为1疗程。观测临床症状、中风病灶、不良反应。连续治疗7疗程,判定疗效。[结果]治疗组痊愈10例,显效5例,有效4例,无效1例,总有效率95.00%。对照组痊愈7例,显效6例,有效3例,无效4例,总有效率80.00%。治疗组疗效优于对照组(P0.05)。[结论]芍药甘草汤联合西医治疗中风后痉挛性偏瘫效果显著,值得推广。