The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat

Rationale Previous work has indicated a potential role for -aminobutyric acid-B (GABA_B) receptor agonists in treating drug addiction in humans. Specifically, GABA_B receptor agonists decreased cocaine, heroin and nicotine self-administration in rats.Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABA_B receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats.Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABA_B receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules.Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (–)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule.Conclusion The present data demonstrate that administration of GABA_B receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA_B receptor agonists as therapeutics for smoking cessation.     

Potentiation of metabotropic GABAB receptors by L-amino acids and dipeptides in rat neocortex

Selected neutral l-α-amino acids, and their dipeptides, were reversible, stereospecific, potentiators of GABA_B receptor-mediated hyperpolarizing responses to baclofen (3-100 μM) in rat neocortical slices. These responses were sensitive to the GABA_B receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch50911) (30 μM). Most potent were l-Leu, l-Ile and l-Phe, as were the dipeptides l-Phe-Phe and l-Phe-Leu, and less potent were l-Met, l-Val, l-Cys, l-Cystine, l-Tyr, l-Thr, l-Arg and l-Ser. Inactive were l-Trp, l-His, l-Lys and l-Pro. These potentiators gave leftward shifts of the baclofen concentration-response curves with a Hill slope of 2, and a marked increase in the maximal hyperpolarizing responses. Selected l-amino acids and dipeptides are a class of naturally occurring GABA_B potentiators, which may be allosteric modulators.     

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.     

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.     

电针加强海马微量注射蝇蕈碱与氯苯氨丁酸的镇痛作用

目的观察电针对大鼠海马微量注射GABA受体激动剂蝇蕈碱（Mus）和氯苯氨丁酸(Bac)镇痛作用的影响。方法实验分生理盐水对照组、药物组和电针+药物组,在2分钟内将1μlMus或Bac（1×10-3mol.L-1）注射入海马,取双侧足三里进行电针,用甩尾法测定大鼠的痛阈。结果从给药后5min至60min,Mus或Bac均能明显提高大鼠的痛阈（P＜0.01）,20min时作用最显著,痛阈分别提高0.386±0.062mA和0.549±0.116mA。电针能加强Mus和Bac的镇痛作用（P＜0.05或P＜0.01）,痛阈最大提高值分别为0.603±0.117mA和0.704±0.099mA。结论海马微量注射Mus或Bac能产生镇痛作用,并且电针能加强其镇痛作用。     

Interaction between glutamate and GABA on H-noradrenaline release from rat hypothalamus

Glutamate has been shown to stimulate noradrenaline (NA) release from hypothalamic nerve terminals. In the present study, we evaluated the possible interaction between the excitatory amino acid glutamate and gamma-aminobutyric acid (GABA), an inhibitory transmitter, on noradrenaline (NA) release from mediobasal hypothalamus (MBH) of adult male rats. Hypothalamic slices loaded in vitro with ³H-NA were superfused and exposed to glutamate, N-methyl- -aspartic acid (NMDA), or kainate (KA). We found that ³H-NA release evoked by the excitatory amino acids glutamate and NMDA was dramatically decreased by GABA. The facilitatory effects of NMDA and KA were prevented concentration-dependently by the GABA_B receptor antagonist 2-hydroxy saclofen which restored the NMDA effect. In addition, beclofen blocked K⁺-induced ³H-NA release. Activation of GABA_A receptors by muscimol and THIP was ineffective. In conclusion, glutamate and GABA, through GABA_B receptors, may interact to modulate NA release from the rat mediobasal hypothalamus.     

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.     

G-protein-coupled GABAB receptors inhibit Ca2+ channels and modulate transmitter release in descending turtle spinal cord terminal synapsing motoneurons

Presynaptic gamma-aminobutyric acid type B receptors (GABA(B)Rs) regulate transmitter release at many central synapses by inhibiting Ca(2+) channels. However, the mechanisms by which GABA(B)Rs modulate neurotransmission at descending terminals synapsing on motoneurons in the spinal cord remain unexplored. To address this issue, we characterized the effects of baclofen, an agonist of GABA(B)Rs, on the monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in motoneurons by stimulation of the dorsolateral funiculus (DLF) terminals in a slice preparation from the turtle spinal cord. We found that baclofen depressed neurotransmission in a dose-dependent manner (IC(50) of approximately 2 microM). The membrane time constant of the motoneurons did not change, whereas the amplitude ratio of the evoked EPSPs in response to a paired pulse was altered in the presence of the drug, suggesting a presynaptic mechanism. Likewise, the use of N- and P/Q-type Ca(2+) channel antagonists (omega-conotoxin GVIA and omega-agatoxin IVA, respectively) also depressed EPSPs significantly. Therefore, these channels are likely involved in the Ca(2+) influx that triggers transmitter release from DLF terminals. To determine whether the N and P/Q channels were regulated by GABA(B)R activation, we analyzed the action of the toxins in the presence of baclofen. Interestingly, baclofen occluded omega-conotoxin GVIA action by approximately 50% without affecting omega-agatoxin IVA inhibition, indicating that the N-type channels are the target of GABA(B)Rs. Lastly, the mechanism underlying this effect was further assessed by inhibiting G-proteins with N-ethylmaleimide (NEM). Our data show that EPSP depression caused by baclofen was prevented by NEM, suggesting that GABA(B)Rs inhibit N-type channels via G-protein activation.     

CSF Baclofen levels after intrathecal administration in severe spasticity

Summary The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l·h^–1.In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).