GABA-transaminase Inhibitor Research Articles

GABA Exerts Stimulatory and Inhibitory Influences on Gonadotropin II Secretion in the Atlantic Croaker (Micropogonias undulatus)

Possible involvement of γ-aminobutyric acid (GABA) in the control of gonadotropin II (GTH II) secretion was investigated during different phases of the seasonal gonadal cycle of the Atlantic croaker (Micropogonias undulatus). Intraperitoneal administration of GABA (100 µg/g) elicited a significant increase in plasma GTH II levels in croaker with regressed or pre-recrudescence phase gonads, whereas it did not significantly affect GTH II levels during the early- to mid-recrudescence phase of the gonadal cycle in this species. On the other hand, GABA induced a dose-related inhibition of GTH II secretion in fish with fully recrudesced gonads. Similar opposite changes in GTH II levels were observed when croaker with regressed and fully recrudesced gonads were injected with the GABA transaminase inhibitor, γ-vinyl GABA (10 and 100 µg/g). This suggests an involvement of endogenous GABA in the control of GTH II secretion. GABA (1–100 µM) did not significantly alter GTH II release from pituitary fragments from regressed or fully recrudesced fish incubated in vitro, suggesting the lack of a major direct influence at the pituitary level. Muscimol (GABA_A receptor agonist, 1 µg/g) treatment mimicked both the stimulatory and inhibitory effects of GABA, whereas injection of baclofen (GABA_B receptor agonist, 1 µg/g) had no significant effect on basal or a gonadotropin-releasing hormone (GnRH) analog-induced GTH II secretion. Pretreatment of fish with bicuculline (1 µg/g), a GABA_A antagonist, completely blocked the stimulatory influence of GABA on GTH II secretion in croaker with regressed gonads and partially blocked the inhibitory effect in individuals with fully recrudesced gonads. The results demonstrate that GABA exerts opposite influences on GTH II secretion at two different stages of the gonadal cycle of croaker, and acts primarily via GABA_A type receptors. Thus, GABAergic pathways may be important in mediating seasonal influences on GTH II secretion in this species.

Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography

A deficit in gamma-aminobutyric acid (GABA) levels in the brain or the cerebrospinal fluid (CSF) is found in many epilepsy patients. Frequency and severity of seizures may be reduced by treatment with GABA increasing medicaments as e.g. vigabatrin, an irreversible inhibitor of GABA-transaminase. For a better understanding of the associated effects, healthy volunteers were examined with magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) before and after intake of different doses of vigabatrin. For the MRS examinations, a dedicated localized spectral editing method was developed to determine GABA levels. The 11C-flumazenil (FMZ)-PET protocol allowed determination of GABA-A receptor binding. The results show a clear and dose-dependent increase in the brain GABA levels after the medication period as compared to the baseline values. The GABA-A receptor binding, on the other hand, did not change significantly.

Effects of increasing doses of vigabatrin on platelet γ-aminobutyric acid-transaminase and brain γ-aminobutyric acid in rats

We report the relationship of GABA-transaminase inhibition in platelets and brain with the increase in brain γ-aminobutyric acid (GABA), as percents of the control, at 24 h after single and after 3 and 8 days of treatment with increasing doses (1, 3, 10, 30, 100 and 300 mg kg −1 day −1) of vigabatrin in rats. The inhibition of GABA-transaminase in platelets correlated at least as well as that in brain with the increase in brain GABA after 3 days ( r=−0.87 vs. r=−0.78), and 8 days of treatment ( r=−0.77 vs. r=−0.74), and when the data of single and multiple doses were pooled ( r=−0.77 vs. r=−0.75). The correlation between platelet GABA-transaminase and brain GABA fitted to a power curve, the increase in brain GABA being significant only when platelet GABA-transaminase was inhibited to less than 50% of the control. Our results suggest that platelet GABA-transaminase could be a peripheral marker of the effect of vigabatrin on brain GABA in rats.

P–448 - Effect of vigabatrin, a GABA transaminase inhibitor, on abnormal excitability of CA3 pyramidal neurons of spontaneously epileptic rats (SER)

P–448 - Effect of vigabatrin, a GABA transaminase inhibitor, on abnormal excitability of CA3 pyramidal neurons of spontaneously epileptic rats (SER)

GABA-transaminase antisense oligodeoxynucleotide modulates cocaine- and pentylenetetrazol-induced seizures in mice.

The mechanism of action of many anticonvulsive agents is to increase the function of the GABAergic system. Inhibition of GABA-Transaminase (GABA-T), the degradative enzyme for GABA, increases GABA levels in the brain. In this study, antisense oligodeoxynucleotides (ASO) targeted at the start codon region of GABA-Transaminase mRNA were used to modify seizure activity. Mice were treated, by intracerebroventricular injection, with antisense oligos or appropriate controls. At various times after treatment, the animals were challenged with cocaine (70 mg/kg, i.p.) and observed for seizure activity. At 15 hours after treatment, 1.152 and 1.44 nmol antisense oligo blocked cocaine-induced seizures. There was no effect of antisense oligo 8 or 36 hours after treatment. In addition, treatment with 7.2 nmol antisense oligo prevented pentylenetetrazol-induced seizures. These data demonstrate the modulation of seizure threshold using antisense oligodeoxynucleotides to GABA-T.

A pharmacologic strategy for the treatment of nicotine addiction.

Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiting nicotine's biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine-induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine-induced increases in both naive and chronically nicotine-treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C-raclopride in primates, GVG (100 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction.

Mediodorsal Thalamus Plays a Critical Role in the Development of Limbic Motor Seizures

Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex. A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAA agonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures.

A novel strategy for the treatment of cocaine addiction.

Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction.

Elevation of brain GABA levels with vigabatrin (gamma-vinylGABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain.

Previous studies have demonstrated that the expression of one of the isoforms of glutamate decarboxylase, GAD67, is selectively reduced in cultured cortical neurons and in rat cerebral cortex when the concentration of GABA is elevated. We asked whether the expression of GAD67 was similarly affected by elevated GABA throughout the brain. The concentration of GABA in rat brain was increased by inhibiting GABA transaminase (GABA-T) with vigabatrin (gamma-vinylGABA, GVG), an antiepileptic drug and selective inhibitor of GABA-T. Rats were injected with saline or vigabatrin (150 mg/kg) daily for 5 days, and the effects of accumulated GABA on total GAD activity and the expression of GAD65 and GAD67 proteins were determined in twelve brain regions. The GABA concentration was significantly elevated in all regions except amygdala and olfactory bulb after vigabatrin treatment. Total GAD activity was significantly lower than controls in six regions: cerebellum, frontal cortex, thalamus, substantia nigra, ventral tegmentum, and the remaining midbrain. The decrease in GAD activity was largest in cerebellum and thalamus (33% and 29%), while the changes in the other four areas were 15-18%. Vigabatrin treatment significantly reduced GAD67 protein in all regions except olfactory bulb, whereas GAD65 protein decreased significantly only in cerebellum. The failure to detect significant changes in GAD activity in regions having a significant change in GAD67 levels is attributable to the small contribution of GAD67 to total GAD in those regions. It is evident that there are marked regional differences in the effects of tissue GABA levels on the expression of GAD67.

Modulation by GABA transmission in the substantia nigra compacta and reticulata of locomotor activity in rats exposed to high pressure.

Helium pressure of > 20 bar causes neuroexcitatory changes referred to as the high pressure neurological syndrome. In rodents, symptoms include locomotor and motor activity (LMA), myoclonia and, at greater pressure, convulsions. We studied the effects of the GABA reuptake inhibitor nipecotic acid, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen. Whatever the drug used, bilateral administration in the substantia nigra reticulata (SNR) or in the substantia nigra compacta (SNC) showed no significant effects on myoclonia. In contrast, administration in the SNR of nipecotic acid, GVG, and baclofen resulted in a significant decrease of LMA; administration of muscimol in the SNR increased LMA. No significant effect was seen when drugs were injected in the SNC. These results suggest that changes in GABA transmission in the SNR, but not in the SNC, play a crucial role in the control of motor activity and the regulation of movement.

Gabapentin potentiation of the antiepileptic efficacy of vigabatrin in an in vitro model of epilepsy.

1. An enhancement of promoted release of gamma-aminobutyric acid (GABA) and a change in GABA-metabolism have been suggested as mechanisms of action of gabapentin. Vigabatrin is supposed to act mainly via inhibition of GABA-transaminase but it also interferes with GABA-release and GABA-uptake. On the basis of these mechanisms of action, a pharmacodynamic interaction of the two antiepileptic drugs could be supposed which might be of relevance in the sense of a rational polypharmacy. 2. To address the aforementioned hypothesis, experiments were carried out on hippocampal slices (n=107) of guinea-pigs (n=70). Epileptiform field potentials (e.f.p.) were induced by omission of magnesium from the bath solution and recorded in the stratum pyramidale of the CA3 region. Gabapentin (30-600 microM; 5.1-102.72 microg ml(-1)), vigabatrin (50-200 microM, 6.45-25.8 microg ml(-1)) and the GABA(A)-receptor antagonist bicuculline (100 microM) were added to the bath solution for 3 h. 3. Gabapentin, in concentrations up to 600 microM, failed to decrease the repetition rate or duration of e.f.p. (n=19). However, vigabatrin, evoked a dose-dependent reduction of the repetition rate of e.f.p. For a concentration of 100 microM (12.9 microg ml(-1)) there was a reduction down to 48+/-5% (mean+/-s.e.mean) of the initial value within 3 h (n=11). With simultaneous administration of vigabatrin (100 microM) and gabapentin (60 microM) for 3 h (n=15), the repetition rate of e.f.p. decreased down to 8+/-3%, which is significantly different from the values obtained after administration of 100 microM vigabatrin alone (P<0.0001). Both, the antiepileptic effect of vigabatrin alone and the enhancement by gabapentin were blocked by the GABA(A)-receptor antagonist bicuculline (100 microM, n=16). 4. These results demonstrate that gabapentin is able to augment the antiepileptic effects of vigabatrin significantly. It is possible that a change in the GABA-release machinery is induced by vigabatrin which then can be augmented by gabapentin.

Muscimol-Like Discriminative Stimulus Effects of GABA Agonists in Rats

The discriminative stimulus effects of GABAergic drugs were evaluated in rats trained to discriminate the direct GABA A agonist, muscimol (1.0 mg/kg IP), from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. Another direct GABA A agonist, THIP, produced full substitution for muscimol, however, at doses producing response rate decreasing effects. Diazepam, an allosteric modulator of GABA-mediated postsynaptic inhibition, yielded a maximum of 50% muscimol-lever responding at a dose that also decreased rates of responding. Partial substitution for muscimol (maximal levels of 71% muscimol-lever responding) was also produced by the GABA agonist progabide. Propofol, an anesthetic that potentiates GABA A receptor function, and the GABA uptake inhibitor, tiagabine, produced no greater than 53 and 48% muscimol-lever responding, respectively. Valproic acid, a reversible GABA transaminase inhibitor, failed to substitute for muscimol, and vigabatrin, an irreversible GABA transaminase inhibitor, yielded a maximal 46% muscimol-lever responding. These results demonstrate the pharmacological specificity of muscimol discrimination by showing that only direct agonists for the GABA site on the GABA A receptor complex produce full substitution. GABA agonists acting by other mechanisms can be distinguished from muscimol and THIP in this procedure.

Interactions Between Dopamine and GABA in the Control of Ambulatory Activity and Neophobia in the Mouse

ÅGMO, A. AND C. BELZUNG. Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse. PHARMACOL BIOCHEM BEHAV 59(1) 239–247, 1998.—Ambulatory activity in a familiar and novel environment as well as the time spent in a novel environment were evaluated using the free exploratory paradigm. Male mice treated with D-amphetamine, 2 mg/kg, displayed enhanced ambulatory activity in the familiar environment. The time spent in the novel environment was reduced by amphetamine, 1 and 2 mg/kg. The GABA transaminase inhibitor γ-acetylen GABA (GAG) reduced ambulatory activity and rearing as well as the time spent in the novel environment. The mixed GABA A/GABA B agonist progabide, 200 mg/kg, reduced rearing both in the familiar and novel environments without affecting the time spent in the novel environment. Amphetamine, 1 mg/kg, was then combined with ineffective doses of GAG and progabide (50 and 100 mg/kg, respectively). The GABAergics did not reliably modify the effects of amphetamine on the time spent in the novel environment. Ambulatory activity and rearing were reduced both in comparison to amphetamine + saline and to control. These data show that GABAergic drugs are potentiated by enhanced dopaminergic neurotransmission with regard to their actions on ambulatory activity and rearing. The effects of progabide + amphetamine were then evaluated after treatment with the GABA A antagonist bicuculline or the GABA B antagonist CGP 35348. Neither bicuculline, 1 mg/kg, nor CGP 35348, 100 mg/kg, blocked the actions of progabide. The combined treatment with both antagonists was also unable to reduce the effects of progabide. These data suggest that the interaction between amphetamine and progabide with regard to motor effects depends on a non-GABA A, non-GABA B receptor.

Effect of chronic treatment with the GABA transaminase inhibitors gamma-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus.

1. The effects of 2, 8 and 21 day oral treatment with the specific gamma-aminobutyric acid transaminase (GABA-T) inhibitors gamma-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated. 2. Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65-80% compared with control values, with a concomitant increase in brain GABA content of 40-100%. 3. Basal hippocampal GABA release was increased to 250-450% of control levels following inhibition of GABA-T activity. No Ca2+ dependence was observed in either control or treated tissues. 4. GVG and EOS administration led to a significant elevation in the potassium stimulated release of GABA from cross-chopped hippocampal slices compared with that of controls. Although stimulated GABA release from control tissues was decreased in the presence of a low Ca2+ medium, GVG and EOS treatment abolished this Ca2+ dependency. 5. GABA compartmentalization, Na+ and Cl- coupled GABA uptake carriers and glial release may provide explanations for the loss of the Ca2+ dependency of stimulated GABA release observed following GVG and EOS treatment. 6. Administration of GABA-T inhibitors led to increases in both basal and stimulated hippocampal GABA release. However, it is not clear which is the most important factor in the anticonvulsant activity of these drugs, the increased GABA content 'leaking' out of neurones and glia leading to widespread inhibition, or the increase in stimulated GABA release which may occur following depolarization caused by an epileptic discharge.

GABAergic Drugs and Socio-Sexual Behavior

To elucidate the role of GABA in the control of sexual behavior, the effects of the GABA A agonist 4,5,6,7-tetrahydroisoxazolo[5,4 c]-pyridin-3-ol (THIP), the GABA transaminase inhibitors sodium valproate and γ-acetylen-GABA (GAG), and the GABA synthesis inhibitors isoniazide and deoxypyridoxine were evaluated in sexual behavior, exploration, and sociosexual interactions with a receptive female or a castrated male. Furthermore, to discriminate possible general inhibitory effects from those specific to sexual behavior, the doses of the drugs that produced a significant inhibition of copulation were tested in a free drinking procedure. THIP (16 mg/kg), sodium valproate (400 mg/kg), GAG (100 mg/kg), and deoxypyridoxine (400 mg/kg) produced a strong inhibition of sexual behavior. The percentage of animals displaying mounts and intromissions as well as the mean number of mounts and intromissions were significantly reduced. Sociosexual interactions with a receptive female or a castrated male and exploratory behaviors were also reduced. The most consistent effects observed were reductions in sniffing, self-grooming, and rearing. Drinking behavior was significantly reduced in doses that inhibited sexual behavior. These results further support the hypothesis that altered GABAergic neurotransmission produces reduced sensitivity to environmental stimuli and thereby inhibits sexual and drinking behavior in a nonspecific way.

GABAergic Drugs Inhibit Amphetamine-Induced Distractibility in the Rat

ÅGMO, A., A. MEDRANO, N. GARRIDO AND P. ALONSO. GABAergic drugs inhibit amphetamine-induced distractibility in the rat. PHARMACOL BIOCHEM BEHAV 58 [1]119–126, 1997.—Drugs facilitating GABAergic neurotransmission have been reported to block some behavioral actions of dopaminergic stimulation but not others. The present experiments were performed with the purpose to extend the range of behaviors in which the interaction between GABA and dopamine have been studied. The ability of the GABA B agonist baclofen and the GABA transaminase inhibitor sodium valproate to block the enhanced distractibility produced by amphetamine was evaluated in a procedure especially designed for analyzing drugs' effects on distractibility. Briefly, rats were trained to traverse a straight runway with a sucrose solution as reinforcement. Once the response had been acquired, an additional runway ending in an empty box was connected. The time spent investigating this additional runway is the measure of distractibility. Male rats treated with amphetamine, 1 mg/kg, displayed an increase of the time spent in the additional runway. Baclofen, 2.5 and 5 mg/kg, and sodium valproate, 100 and 200 mg/kg, had no effect on distraction behavior when administered alone. However, when these drugs were administered together with amphetamine, 1 mg/kg, they completely inhibited the effects of the stimulant on distractibility. These data show that distractibility is similar to discrimination learning with regard to the capacity of GABAergic drugs to block the effects of dopaminergic stimulation. It is different from locomotor activity, however, where GABAergic drugs are ineffective in this respect.

Pharmacokinetics of the S(+) and R(-) enantiomers of vigabatrin during chronic dosing in a patient with renal failure.

To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5 g every 12 h) and in whom impaired renal function was diagnosed. The patient received vigabatrin (0.5 g day(-1)). A pharmacokinetic study of the S(+) and R(-) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24 h by a specific GCMS assay. Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady-state were lower for the S(+) than for the R(-) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(-) enantiomer (2.97 vs 0.48 l h(-1)). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l h(-1)). Vigabatrin is an irreversible inhibitor of GABA-transaminase, effective in the treatment of drug-resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(-) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(-) enantiomer.

GABA in the Nucleus Accumbens Shell Participates in the Central Regulation of Feeding Behavior

We have demonstrated previously that injections of 6, 7-dinitroquinoxaline-2,3-dione into the nucleus accumbens shell (AcbSh) elicits pronounced feeding in satiated rats. This glutamate antagonist blocks AMPA and kainate receptors and most likely increases food intake by disrupting a tonic excitatory input to the AcbSh, thus decreasing the firing rate of a population of local neurons. Because the application of GABA agonists also decreases neuronal activity, we hypothesized that administration of GABA agonists into the AcbSh would stimulate feeding in satiated rats. We found that acute inhibition of cells in the AcbSh via administration of the GABAA receptor agonist muscimol or the GABAB receptor agonist baclofen elicited intense, dose-related feeding without altering water intake. Muscimol-induced feeding was blocked by coadministration of the selective GABAA receptor blocker bicuculline, but not by the GABAB receptor blocker saclofen. Conversely, baclofen-induced feeding was blocked by coadministration of saclofen, but was not affected by bicuculline. Furthermore, we found that increasing local levels of GABA by administration of a selective GABA-transaminase inhibitor, gamma-vinyl-GABA, elicited robust feeding in satiated rats, suggesting a physiological role for endogenous AcbSh GABA in the control of feeding. A mapping study showed that although some feeding can be elicited by muscimol injections near the lateral ventricles, the ventromedial AcbSh is the most sensitive site for eliciting feeding. These findings demonstrate that manipulation of GABA-sensitive cells in the AcbSh can have a pronounced, but specific, effect on feeding behavior in rats. They also constitute the initial description of a novel and potentially important component of the central mechanisms controlling food intake.

GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat.

Female rats were allowed to pace sexual interactions in a bilevel chamber, where a sexually vigorous male was tethered to the bottom level. Exploratory behaviors (sniffing, rearing), locomotor activity (expressed as number of level changes and periods of inactivity) as well as items of sexual motivation (latency to descend to the male's level, approaches towards the male and genital exploration) were recorded. In addition, sexual receptivity was evaluated in a non-paced situation. A test for motor impairment was also performed. The GABA transaminase inhibitor gamma-acetylene GABA reduced exploratory behaviors at doses much lower than those needed to reduce receptivity. The GABA reuptake inhibitor SKF 100330A did not affect any behavior category at doses of 15 and 30 mg/kg, but had a sedative action at 60 mg/kg. This was shown as impaired motor coordination and an almost total absence of activity in the bilevel chamber. Receptivity was not impaired, however. The mixed GABAA/ GABAB agonist progabide reduced exploratory behaviors and receptivity without producing motor impairment at a dose of 400 mg/kg. The GABAA agonist THIP impaired motor coordination and reduced receptivity and exploratory behaviors at a dose of 10 mg/kg. A larger dose, 20 mg/kg, had a strong sedative action. Only a small proportion of the animals descended to the males level. The GABAB agonist baclofen reduced receptivity at a dose that had no effect on motor coordination or exploratory behaviors. None of the drugs had a specific effect on sexual motivation. Whenever behaviors reflecting motivation were reduced, there were also other behavioral effects indicative of sedation. These data show that GABA receptor agonists, particularly the GABAB agonist baclofen, reduce sexual receptivity at doses that have only slight effect on motor functions or exploratory behaviors. In contrast, non-specific enhancement of GABAergic activity by a transaminase or reuptake inhibitor have effects on motor functions and exploratory behaviors at doses much lower than those needed to reduce receptivity.

Basic aspects of GABA-transmission in alcoholism, with particular reference to GABA-transaminase

Neuronal dysfunction is the neurobiological basis for alcoholic behaviour, and ethanol craving seems related to hypofunction of the GABA-ergic activity. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In several studies, GABA has been shown to be an important target of ethanol in the CNS, partly, as a consequence of damage to membrane-bound enzymes and receptors. GABA is involved in mediating pre- and post-synaptic inhibition of neuronal activity. It is speculated that the initial excitatory effects of ethanol may be due to inhibition of GABA-ergic activity whereas the sedative effects of the higher doses may be mediated by the activation of this inhibitory system. In the CNS, GABA is synthesised from glutamic acid by the enzyme glutamate decarboxylase (GAD) and catabolized into succinic semialdehyde by the enzyme GABA-transaminase (GABA-T), which are pyridoxal phosphate (PLP) dependent enzymes. Platelet GABA-T was characterized as being similar to central GABA-T. Inhibition of GABA-T with certain potent and selective compounds markedly increases the levels of brain GABA. Experimentally, acute ethanol treatment does not alter GABA-T activity whereas chronic treatment produces an increase in the activity, though, with some reservations since a bimodal effect has been found in chronically ethanol-treated rats. Thus, as it will be discussed below, it may be suggested that GABA-T inhibitors (e.g. vigabatrin) could have a potential role in the treatment of alcoholism and in some of the problems of ethanol withdrawal and of other drugs of abuse. Related studies on metabolism and concentrations of GABA are also promising and show a greater increase in our understanding of the aetiology and treatment of ethanol dependence and withdrawal. In general, this article also reviews both the animal and clinical observations in the field of alcoholism with regard to the GABA system.