Effects of ethanol and GABA<Subscript>B</Subscript> drugs on working memory in C57BL/6J and DBA/2J mice

Rationale It has been suggested that GABA_B receptors may be part of a neural substrate mediating some of the effects of ethanol.Objective The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA_B receptors.Methods Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice.Results Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance.Conclusions Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA_B drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice.

The present experiments examined the effects of the GABA(B) receptor agonist, baclofen, on the acquisition of ethanol-induced conditioned place preference (CPP) and conditioned taste aversion (CTA) in male DBA/2J mice. Mice in the CPP experiment received four pairings of ethanol (2g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). On intervening days (CS- sessions), mice received saline injections paired with a different floor type. On CS+ days, mice also received one of four doses of baclofen (0.0. 2.5, 5.0, or 7.5 mg/kg) 15 min before an injection of ethanol. For the preference test, all mice received saline injections, and were placed on a half-grid and half-hole floor for a 60-min session. Baclofen dose dependently reduced ethanol-stimulated activity, but did not alter the magnitude of ethanol-induced CPP at any dose. For the CTA experiment, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of saline or baclofen (2.0 and 6.0 mg/kg) 15 min before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Baclofen did not alter the magnitude of ethanol-induced CTA at any dose. In addition, baclofen alone did not produce a CTA. Overall, these studies show that activation of GABA(B) receptors with baclofen reduces ethanol-induced locomotor activation, but does not alter ethanol's rewarding or aversive effects in the CPP and CTA paradigms in DBA/2J mice.     

Effects of gamma-hydroxybutyrate (GHB) and its metabolic precursors on delayed-matching-to-position performance in rats

The purpose of the present study was to provide further information about the effects of gamma-hydroxybutyrate (GHB) on memory. Initially, the acute effects of gamma-butyrolactone (GBL, 75-200 mg/kg IP), 1,4-butanediol (1,4-BD, 100-300 mg/kg IP), and ethanol (1.0-3.0 g/kg, oral), as well as GHB (100-300 mg/kg IP), were examined in rats responding under a delayed-matching-to-position (DMTP) procedure with delays from 0 to 32 s. Acute administration of all four drugs reduced the number of trials completed and also reduced accuracy during delay trials, but not during trials without a delay. Some tolerance developed to the disruptive effects of GHB following exposure to 300 mg/kg/day for 29 consecutive days. These data indicate that GHB can disrupt working memory and speed of responding, and that tolerance can develop to these effects. Moreover, the acute effects of GHB under the DMTP procedure resemble those of its metabolic precursors, GBL and 1,4-BD, and of the prototypical CNS depressant drug, ethanol.     

Differential effects of GABAA and GABAB agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice

 Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA_A and GABA_B agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA_B receptors, but not GABA_A receptors, in development of sensitization to the locomotor stimulant effects of ethanol. Received: 11 April 1998 / Final version: 24 June 1998     

Effects of GABA(B) receptor antagonist, agonists and allosteric positive modulator on the cocaine-induced self-administration and drug discrimination

Preclinical and clinical findings indicate that a GABA(B) receptor agonist baclofen decreases cocaine use. The present study investigated the effects of the GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), the agonists baclofen and 3-aminopropyl(methyl)phoshinic acid (SKF 97541) and the allosteric positive modulator 3,5-bis(1,1-dimethylethyl-4-hydroxy-beta,beta-dimethylbenzenepropanol (CGP 7930) in cocaine-and food-maintained responding under a fixed ratio 5 schedule of reinforcement in male Wistar rats. The effects of the GABA(B) receptor ligands on cocaine (10 mg/kg)-induced discriminative stimulus in a two-lever, water-reinforced fixed ratio 20 task and on basal locomotor activity were also assessed. Baclofen (2.5-5 mg/kg), SKF 97541 (0.1-0.3 mg/kg) and CGP 7930 (30-100 mg/kg) decreased the cocaine (0.5 mg/kg/injection)-maintained responding; SCH 50911 (3-10 mg/kg) was inactive in this respect. Baclofen (5 mg/kg) and SKF 97541 (0.3 mg/kg), but not CGP 7930 or SCH 50911 attenuated the food-maintained responding. The inhibitory effects of the GABA(B) receptor agonists and the modulator were blocked by SCH 50911. SKF 97541 (0.1 mg/kg) or CGP 9730 (30-100 mg/kg) did not produce a significant shift in the cocaine (1.25-10 mg/kg) dose-response curve in a drug discrimination procedure, while baclofen (1.5 mg/kg) or SCH 50911 (10 mg/kg) attenuated the effects of separate doses of cocaine. Baclofen (5 mg/kg) and CGP 7930 (100 mg/kg) significantly reduced basal horizontal activity. We found that pharmacological stimulation of GABA(B) receptors by direct agonists or allosteric positive modulation reduces cocaine reinforcement while this property of cocaine is not related to tonic activation of GABA(B) receptors. The GABA(B) receptor stimulation-induced reduction of cocaine reinforcement was separated from its discriminative stimulus effects. Moreover, a dissociation between effects of direct GABA(B) receptor agonists and a GABA(B) allosteric positive modulator on cocaine vs. food-maintained responding was demonstrated.     

Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task

Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.     

Effects of the GABAB receptor agonist baclofen on primary drinking in rats

The effects of subcutaneous (s.c.) administration of the GABA(B) receptor agonist baclofen were investigated on primary drinking in rats. Baclofen (1-4 mg/kg) produced a dose-related reduction in cumulative water intake in 16 h water-deprived rats during the 120 min measurement period (Experiment 1). The suppressant effect of baclofen (2mg/kg) on water intake 16 h water-deprived rats was significantly attenuated by pretreatment with the GABA(B) receptor antagonist CGP 35348 (3-aminopropyl (diethoxymethyl)-phosphinic acid; 50mg/kg; s.c., Experiment 2.), indicating that the hypodipsic effects of the drug in thirsty rats are mediated by an action at GABA(B) receptors. Experiment 3 was undertaken to investigate the effects of baclofen on volemic drinking induced in rats pretreated with propylene glycol. S.C. administration of polyethylene glycol induces volemic drinking in rats by reducing extracellular fluid. Baclofen (2mg/kg, s.c.) significantly reduced the volemic drinking in rats pretreated with polyethylene glycol (30% w/v solution). Experiment 4 was conducted to investigate the effects of baclofen on osmotic drinking in non-deprived rats pretreated with hypertonic sodium chloride (NaCl) solution. Hypertonic NaCl will draw out intracellular fluid to stimulate osmotic drinking. Baclofen (2mg/kg; s.c.) significantly reduced osmotic drinking in rats pretreated with 1 ml hypertonic NaCl (16% w/v). The results of this study indicate that (i) the hypodipsic effect of baclofen in water-deprived rats is mediated by an action at GABA(B) receptors and (ii) baclofen suppresses both volemic and osmotic drinking.     

Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat

Withdrawal of rats from 5 weeks of a liquid ethanol diet (10%), resulted in anxiogenic responses in the social interaction and elevated plus-maze tests of anxiety. The rats withdrawn from ethanol also showed increased aggression, tremor and rearing. Baclofen (1.25 and 2.5 mg/kg), but not nitrendipine (25-100 mg/kg), reversed the anxiogenic withdrawal responses, without having any effect in control animals and without having significant sedative effects. Baclofen reduced the enhanced aggression during withdrawal of ethanol, but this may have reflected a more general anti-aggressive action. Baclofen (2.5 mg/kg) reduced the withdrawal tremor. Nitrendipine (100 mg/kg) significantly reduced withdrawal tremor, but this dose was sedative, so this was likely to be a non-specific effect. It is proposed that the anxiogenic response during withdrawal of ethanol is due to a reduced GABA function, involving both GABAA and GABAB receptors.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.     

Actions of baclofen and phaclofen upon ON- and OFF-ganglion cells in the cat retina

The effects of the GABAB (gamma-amino butyric acidB) receptor agonist, baclofen and its antagonist, phaclofen on physiologically identified retinal ganglion cells were studied in the optically intact eye of pentobarbitone-anaesthetized cats. These results were compared with the effects of the GABAA receptor agonist, muscimol and its antagonist, bicuculline. Baclofen inhibited the total visually driven firing of both ON- and OFF-cells more effectively upon OFF- than ON-cells; this action was weaker and slower than that of muscimol. Whilst bicuculline raised the firing level of only ON-cells in the area centralis together with all peripheral cells, phaclofen raised that of all OFF-cells. Paradoxically, in OFF-cells, baclofen enhanced the driven transient component and suppressed the sustained component, whilst phaclofen raised the sustained component. Thus, GABAB receptors activated by tonically released GABA may modulate the sustained and transient excitatory inputs to OFF-cells.     

Baclofen and midazolam alter c-fos induction by peripheral noxious or innocuous stimulation in the spinal cord of normal and monoarthritic rats

In order to further clarify the role of gamma-aminobutyric acid (GABA) receptors in spinal sensory processing we have studied the effects of baclofen, a GABA(B) agonist, and midazolam, a benzodiazepine agonist, on the activation of spinal neurones by peripheral innocuous or noxious stimulation, in normal or monoarthritic rats, as signalled by the induction of the proto-oncogene c-fos. Baclofen (10 mg/kg, i.v.) caused a significant reduction in the number of Fos-positive neurones following noxious stimulation of both normal and monoarthritic animals, which was prevented by the GABA(B) antagonist CGP 35348 (200 mg/kg, i.v.). The latter caused an increase of c-fos expression in normal animals subject to noxious stimulation, suggesting an endogenous tonic activation of GABA(B) receptors. This effect was not observed in monoarthritic animals. Baclofen also reduced the number of Fos-positive neurones in monoarthritic animals subject to innocuous stimulation. Midazolam (5 mg/kg, i.v.) had no effect in normal animals, but caused an increase in c-fos expression induced by noxious stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a benzodiazepine antagonist, prevented the effect of midazolam, and if given alone evoked a decrease in Fos-positive neurones. It can be concluded that although GABA(B) receptors modulate sensory input at the spinal level, high doses of systemic baclofen are required to inhibit nociceptive-induced c-fos expression. The paradoxical facilitation of c-fos expression by midazolam in monoarthritic animals, may be due to the reported increase in spinal GABA levels found in those animals.     

Effects of GABA antagonists and structural GABA analogues on baclofen stimulated gastric acid secretion in the rat

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABAA-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABAB antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABAA- and GABAB-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABA-ergic system.     

GABAergic modulation of binge-like ethanol intake in C57BL/6J mice

GABA receptor systems have long been implicated in alcoholism, and GABAergic drugs have demonstrated efficacy in altering alcohol intake in some rodent models. The present study was designed to assess the effects of baclofen, muscimol, and gaboxadol (THIP) in a variation on a new mouse model of binge-like ethanol intake. Three hours into their dark cycle, male and female C57BL/6J mice were given access to a 20% unsweetened ethanol solution for 2 h each day, for four days. On day five, mice received varying doses of baclofen, muscimol or THIP and were allowed access to 20% ethanol for 60 min. Baclofen dose-dependently increased binge-like ethanol intake, while both muscimol and THIP reduced ethanol intake. Subsequent studies testing the effect of baclofen, muscimol and THIP on water intake using the same procedure revealed that whereas baclofen had no significant effect, muscimol and THIP both reduced the measure. These results add to the growing literature suggesting a role for GABA receptor systems in the modulation of ethanol intake. However, whereas the role of GABA(B) receptor systems seems selective in the modulation of binge-like ethanol intake, the role for GABA(A) receptor systems appears to also extend to general fluid intake.     

Inhibition of baclofen on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity.

The effects of baclofen on the development of reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine were examined in mice. A single administration of morphine induced hyperactivity and the morphine-induced hyperactivity was inhibited dose dependently by the administration of a GABA(B)receptor agonist, baclofen (1.25, 2.5 and 5 mg kg(-1), i.p.). Daily repeated administration of morphine developed reverse tolerance to the hyperactivity of morphine. The concomitant administration of baclofen inhibited the morphine-induced hyperactivity and the baclofen administration prior to and during the chronic administration of morphine in mice inhibited the development of reverse tolerance to the hyperactivity of morphine (10 mg kg(-1), s.c.). Postsynaptic dopamine receptor supersensitivity was also developed in reverse-tolerant mice that had received the same morphine. The development of postsynaptic dopamine receptor supersensitivity was evidenced by the enhanced ambulatory activity of apomorphine (2 mg kg(-1), s.c.). Baclofen also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine may be modulated via the activation of GABA(B)receptors induced by baclofen.     

Activation of GABAB receptors reverses spontaneous gating deficits in juvenile DBA/2J mice

Rationale Gamma-amino-butyric acid (GABA)_B receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical GABA_B agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia. Objectives We studied the role of GABA_B receptors in the spontaneous PPI deficits displayed by DBA/2J mice. Materials and methods We tested the effects of baclofen (1.25–5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, we investigated the expression of GABA_B receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography. Results Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABA_B antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABA_B receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions. Conclusions Our data highlight GABA_B receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA_B receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances. M. Paola Castelli, Giampaolo Mereu, and Francesco Marrosu have contributed equally to the study.     

Effects of the potassium channel blockers, apamin and 4-aminopyridine, on scopolamine-induced deficits in the delayed matching to position task in rats: a comparison with the cholinesterase inhibitor E2020

 The effects of the muscarinic antagonists, scopolamine HBr and MeBr, a cholinesterase inhibitor, E2020, and K⁺ channel blockers, 4-aminopyridine (4-AP) and apamin, on the performance of rats in a delayed matching to position (DMTP) task were examined. The percentage of correct choices (choice accuracy), number of trials completed and intertrial intervals were measured. Discriminability and response bias were also calculated, using signal detection analysis. Scopolamine HBr (0.1 mg/kg), but not scopolamine MeBr (0.1 mg/kg), significantly and consistently reduced the choice accuracy and discriminability, but neither affected the other measurements. E2020 (0.03–1.0 mg/kg) had no effect on the baseline performance in the DMTP task, but at 1.0 mg/kg, it significantly attenuated the deficits in choice accuracy induced by scopolamine. 4-AP (0.001–0.1 mg/kg) had no effect on either baseline performance or deficits induced by scopolamine. Apamin (0.1–0.4 mg/kg) had no effect on choice accuracy and discriminability. Apamin also failed to attenuate the scopolamine-induced deficits. When administered in combination with scopolamine, apamin at 0.4 mg/kg significantly decreased the number of trials completed and increased the intertrial interval relative to that of the control group. Taken together, these results demonstrate that K⁺ channel blockers (4-AP and apamin), unlike a cholinesterase inhibitor (E2020), fail to reverse the scopolamine-induced deficits in the DMTP task. Received: 27 March 1997/Final version: 19 June 1997     

Inhibition of baroreflex bradycardia by ethanol involves both GABAA and GABAB receptors in the brainstem of the rat.

The effects of ethanol on baroreceptor reflex bradycardia and its interactions with cardiovascular effects mediated by GABA receptors in the dorsal vagal complex were studied in urethane-anaesthetised rats. Ethanol, 1 g kg-1 administered i.v. or 25-200 nmol microinjected bilaterally into the dorsal vagal complex, inhibited the reflex bradycardic response to bolus i.v. doses of phenylephrine both in spontaneously breathing and in paralysed, artificially ventilated animals, and this effect could be prevented by pretreatment with the GABA-depleting agent, 3-mercaptopropionate in both groups of rats. Ethanol, 1 g kg-1 i.v., did not influence the bradycardic response to electrical stimulation of the cervical vagus. Microinjection of muscimol into the dorsal vagal complex caused a dose-dependent pressor response and inhibited baroreflex bradycardia. The pressor response was potentiated and a tachycardic response to muscimol emerged following microinjection of ethanol into the dorsal vagal complex. Similar administration of baclofen caused dose-dependent increases in blood pressure and heart rate and inhibited baroreflex bradycardia. Injection of ethanol into the dorsal vagal complex potentiated the pressor response to a low dose of baclofen but did not affect the tachycardic response. Bicuculline, 10 pmol/side into the dorsal vagal complex, blocked the effects of muscimol but not those of baclofen and reduced the baroreflex inhibitory action of ethanol. 2-Hydroxysaclofen, microinjected at 400 pmol to 1 nmol/side, blocked the effects of baclofen but not those of muscimol. 2-Hydroxysaclofen or phaclofen, 2 mg kg-1 s.c., prevented the baroreflex inhibitory action of ethanol and also prevented ethanol potentiation of the pressor and, less effectively, the tachycardic effects of muscimol. It is concluded that ethanol inhibits baroreflex bradycardia through potentiation of the actions of endogenous GABA in the dorsal vagal complex. Both GABAA and GABAB receptors appear to be involved in this action of ethanol.     

GABAergic agents and clonidine attenuate footshock-induced aggression in mice

The effects of gamma aminobutyric acid (GABA), baclofen, and clonidine was studied on footshock-induced aggression in mice. A lower dose (200 mg/kg) of GABA enhanced the aggressive score, while at a higher dose (400 mg/kg) it attenuated the aggressive behavior, the latter effect being reversed both by bicuculline and picrotoxin (PTX). Clonidine (0.5 and 1 mg/kg) enhanced the aggressive score, and the effect of clonidine was reversed by idazoxan. GABA (400 mg/kg) and clonidine (1 mg/kg) significantly reduced the aggressive score in reserpinized mice. Baclofen (5 mg/kg) showed no effect per se in either reserpinized or non-reserpinized mice. On concomitant administration of clonidine (0.5 mg/kg) with a subeffective dose of either GABA, baclofen, or diazepam, there was significant reduction in the aggressive score. A modulatory role of GABAergic and noradrenergic systems in footshock-induced aggression is suggested.     

Baclofen prevents MDMA-induced rise in core body temperature in rats

A number of deaths have been attributed to severe hyperthermia resulting from the ingestion of 3,4-methylenedioxymethamphetamine (MDMA). The mechanisms underlying these events are unclear. In an attempt to further advance our understanding of these mechanism the present study investigated the effects of the selective GABA(A) agonist muscimol and the GABA(B) agonist baclofen on MDMA-induced responses in the rat. Baclofen at 1 and 3 mg/kg and muscimol at 0.3 and 1 mg/kg administered alone had no effect on heart rate, core body temperature or spontaneous locomotor activity as measured by radiotelemetry. MDMA at 15 mg/kg produced a significant increase in heart rate, body temperature and locomotor activity (P < 0.005) which were unaffected by prior treatment with muscimol. In contrast, prior treatment with baclofen (3 mg/kg) resulted in MDMA causing a sustained lowering of body temperature (P < 0.05), with no effect on heart rate and a small transient delay in the increase in locomotor activity. Baclofen pretreatment (3 mg/kg) not only prolonged the time taken for animals to reach a core body temperature of 40 degrees C (P < 0.001), but also reduced the percentage of rats attaining a core body temperature of 40 degrees C. These data suggest that stimulation of GABA(B) receptors may provide a mechanism for the treatment of MDMA-induced hyperthermia.     

Baclofen induces catatonia in rats

Baclofen (10 and 20 mg/kg, i.p.) induced catatonia in rats within 10 min of its administration and the effect lasted for 3 hr. Muscimol (100 ng i.c.v. or 1 mg/kg, i.p.) as well as GABA (5 micrograms i.c.v.) potentiated the effect without producing any effect per se. Bicuculline, bromocriptine and scopolamine failed to modify the catatonia induced by baclofen, thereby ruling out the involvement of GABAA receptors, dopaminergic and cholinergic mechanisms. However, GABAB receptor antagonists, such as homotaurine and delta-amino-n-valeric acid, reversed the catatonia induced by baclofen in rats. Since baclofen is known to bind to a subpopulation of GABA receptors (bicuculline-insensitive) and baclofen-induced catatonia was susceptible to reversal by homotaurine and delta-amino-n-valeric acid, it is suggested that this effect could be mediated through GABAB receptors.