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PubMed2004

Dopamine excites nucleus accumbens neurons through the differential modulation of glutamate and GABA release.

Afferent activity into the nucleus accumbens (NAc) occurs in bursts of action potentials. However, it is unclear how synapses in this nucleus respond to such bursts, or how these responses are altered by dopamine (DA). I examined the effects of DA on excitatory and inhibitory responses to trains of stimuli in rat NAc slices. Both EPSCs and IPSCs showed use-dependent depression during trains. Although DA inhibited both glutamate and GABA release in the NAc, it differentially inhibited release during trains. The inhibition of IPSCs persisted throughout the train of stimuli, whereas the inhibition of EPSCs progressively diminished. This differential modulation may be explained by a calcium-dependent change in the recovery from depression at the GABA synapses, where DA acts by decreasing Ca2+ entry. Thus, at later stages of sustained stimulation, DA preferentially inhibits GABA release, producing a net excitatory effect during bursts suggesting a mechanism for enhancing the contrast between competing inputs into the NAc, as well as for affecting long-term plasticity in this structure.

Action Potentials↗
PubMedDate not supplied

[New directions in GABAergic pharmacology of anxiety and depression].

New prospects in the use of drugs affecting central GABAergic system for the treatment of anxiety and depressive states are critically assessed. Both clinical (human) and experimental (animal) data on the mutual influence of various GABA-receptor modulators as well as the interaction of GABAergic system with neurohumoral mechanisms of stress are considered. Based on this analysis, new strategies in the GABAergic pharmacotherapy of anxiety and depression spectrum disorders are outlined.

Animals↗
PubMed2006

GABA(B) receptor-positive modulation decreases selective molecular and behavioral effects of cocaine.

Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug-induced neuroadaptive changes. Recent attention has been given to compounds activating GABA(B) receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA(B) receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA(B) receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA(B) receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor deltaFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited deltaFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA(B) receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

Animals↗
PubMed2005

6-Methylflavanone, a more efficacious positive allosteric modulator of gamma-aminobutyric acid (GABA) action at human recombinant alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus oocytes.

6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho1 GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC(10-20) GABA responses were 22 microM, 10 microM and 6 microM and the maximum potentiations were 120%, 417% and 130% at alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha2-containing GABA(A) receptors, while sedation is thought to be mediated via alpha1-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 microM) produced positive allosteric modulation at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha2beta2gamma2L GABA(A) receptors and found to maximally potentiate the EC(10-20) GABA response by 183+/-39% which is similar to that previously observed for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha2beta2gamma2L over alpha1beta2gamma2L GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha2beta2gamma2L GABA(A) receptors, and less efficacious at alpha1beta2gamma2L GABA(A) receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors, the positive modulation of GABA responses at alpha1beta2gamma2L and alpha2beta2gamma2L GABA(A) receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via "high-affinity" benzodiazepine sites.

Allosteric Regulation↗
PubMed2003

Evaluation of the reinforcing and discriminative stimulus effects of 1,4-butanediol and gamma-butyrolactone in rhesus monkeys.

Metabolic precursors and prodrugs of gamma-hydroxybutyrate (GHB), including 1,4-butanediol (BDL) and gamma-butyrolactone (GBL), have sedative and anesthetic effects and might have positive reinforcing effects. BDL and GBL were evaluated using behavioral procedures that measure positive reinforcing effects and discriminative stimulus effects of drugs that modulate gamma-aminobutyric acid (GABA) at the GABA(A) receptor complex. One group of rhesus monkeys could respond for saline or the barbiturate methohexital (i.v.) in a self-administration paradigm. Two other groups of monkeys discriminated the barbiturate pentobarbital (i.g.) or the benzodiazepine midazolam (s.c.) from saline in a drug discrimination paradigm; another group of monkeys was treated with the benzodiazepine diazepam (5.6 mg/kg/day, p.o.) and discriminated the benzodiazepine antagonist flumazenil (s.c.) from vehicle. In self-administration experiments, methohexital and not BDL (0.1-3.2 mg/kg/injection) or GBL (0.1-3.2 mg/kg/injection) reliably maintained responding above saline levels. BDL and GBL, up to doses that suppressed responding, did not substitute for pentobarbital, midazolam or flumazenil. The onset of action for both drugs to decrease response rate was delayed (90 min for GBL and 150 min for BDL). These results suggest that any abuse-related effects of BDL and GBL are qualitatively different from the abuse-related effects of GABA(A) receptor modulators and further indicate that BDL and GBL do not have positive reinforcing effects in rhesus monkeys experienced with self-administration of a short-acting sedative-hypnotic.

4-Butyrolactone↗
PubMed1991

Pharmacological evidence for the possible involvement of repetitive action potentials in facilitation by GABA of catecholamine secretion in bovine adrenal chromaffin cells.

1. gamma-Aminobutyric acid (GABA) evokes catecholamine (CA) secretion and enhances the stimulation-evoked CA secretion via facilitation of Ca2+ entry in a Cl(-)-dependent manner. The present study was designed to investigate further the ionic mechanism of modulation by GABA of CA secretion from adrenal medulla, using a primary culture of bovine chromaffin cells. 2. Tetrodotoxin (TTX), a voltage-sensitive Na+ channel blocker, reduced GABA-evoked CA secretion. 3. Inhibition of the sodium pump by ouabain or removal of extracellular K+ enhanced GABA-evoked CA secretion in a TTX-sensitive manner. 4. Tetraethylammonium (TEA) and cesium, which are known to block some types of K+ channels, markedly enhanced GABA-evoked CA secretion in a concentration-related fashion. TEA-induced enhancement of the GABA-evoked CA secretion was attenuated by TTX or replacement of extracellular Na+ by choline. On the other hand, ouabain accelerated the effect of TEA. 5. TEA and ouabain also enhanced GABA-induced Ca2+ influx and accumulation of cytosolic Ca2+, assessed with 45Ca2+ uptake and quin2 fluorescence. 6. Veratridine increased accumulation of cytosolic Ca2+ in a TTX-sensitive manner. GABA facilitated the veratridine-induced elevation of cytosolic Ca2+ even when the GABA-induced rise of cytosolic Ca2+ levelled off. 7. These results suggest the involvement of repetitive action potentials in modulation of GABA by Ca2+ mobilization and, as a consequence, of the CA secretion in chromaffin cells.

Action Potentials↗
PubMed2004

Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats.

Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetamine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetamine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole.

Animals↗
PubMed2005

The neurosteroid pregnenolone sulfate neutralized the learning impairment induced by intrahippocampal nicotine in alcohol-drinking rats.

The effects of intrahippocampal administration of nicotine and the neurosteroids pregnenolone sulfate and allopregnanolone on acquiring the lever-press response and extinction in a Skinner box were examined using voluntary alcohol-drinking rats. A free-choice drinking procedure that implies early availability of the alcoholic solution (10% ethanol v/v+3% glucose w/v in distilled water) was used. Alcohol and control rats were deprived of food and assigned at random to six groups. Each group received two consecutive intrahippocampal (dorsal CA1) injections immediately after 1-h of drinking ethanol and before the free lever-press response shaping and extinction session. The groups were: saline-saline; saline-pregnenolone sulfate (5 ng, 24 microM); saline-allopregnanolone (0.2 microg, 1.26 microM); nicotine (4.6 microg, 20 mM)-saline; nicotine-pregnenolone sulfate; nicotine-allopregnanolone. Blood alcohol concentrations were assessed the day before conditioning. The combination of the oral self-administration of ethanol and the intrahippocampal injection of nicotine deteriorated the ability to acquire the lever-press response. This effect was neutralized by intrahippocampal pregnenolone sulfate (negative modulator of the GABA(A) receptor complex), and it was not affected by intrahippocampal allopregnanolone (positive GABA receptor complex A modulator). Pregnenolone sulfate and allopregnanolone had no effects per se on lever-press acquisition, neither in alcohol-drinking rats nor in controls. Alcohol consumption facilitated operant extinction just as anxiolytics that act as positive modulators of the GABA receptor complex A receptors do, possibly reducing the anxiety or aversion related to non-reinforcement. This effect was increased by intrahippocampal nicotine.

Alcohol Drinking↗
PubMed2003

Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.

Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

Animals↗
PubMed2001

Ethanol enhances naloxone sensitization and disrupts morphine discrimination--comparison to dizocilpine and pentobarbital: explanation of enhancing acute and attenuating chronic effects.

1. Ethanol affects ligand-gated ion channels as a positive modulator of gamma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartate (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accordingly, we found that ethanol decreased morphine dependence and locomotor sensitization. We now test whether ethanol alters sensitization to the disrupting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered ethanol (1 g/kg; i.p.), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; i.p.), the GABA(A) agonist pentobarbital (PB; 3 mg/kg i.p.), or vehicle with morphine (5 mg/kg s.c.). Separate groups received naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days. Ethanol enhanced the suppressive effects of higher naloxone doses on all three days. DZ and PB altered this behavior differentially by day and naloxone dose. 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/kg; s.c.) on morphine discrimination. Rats, trained to discriminate morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations. Naloxone blocked dose-related responding to morphine, demonstrating pharmacological specificity, and altered response rates. Both ethanol and DZ, but not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiate receptor function followed by secondary NMDA-mediated processes induced by morphine administration.

Animals↗
PubMed1999

Synaptic response patterns of neurons in the cortex of rat inferior colliculus.

The present study examined synaptic potentials of neurons in inferior colliculus (IC) cortex slice and the roles of GABA and glutamate receptors in generating these potentials. Multipolar (82%) and elongated (18%) cells were observed with intracellular biocytin staining. Electrical stimulation of the IC commissure (CoIC) elicited only inhibitory postsynaptic potentials (IPSPs) (10% of cells), only excitatory postsynaptic potentials (EPSPs) (51%), or both (38%). IPSPs were elicited at lower thresholds and shorter latencies than EPSPs (mean: 1.6+/-1.2 ms) and IPSPs were observed in all neurons following membrane depolarization. Short-latency EPSPs were blocked by non-NMDA receptor antagonists, and longer-latency EPSPs were blocked by NMDA antagonists. CoIC stimulation evoked short-latency IPSPs (mean: 0.55+/-0.33 ms) in 48% of neurons, and the IPSPs persisted despite glutamate receptor blockade, which implies monosynaptic inhibitory input. A GABA(A) antagonist blocked IPSPs and paired pulse inhibition of EPSPs, suggesting GABA(A) receptor mediation. A GABA(B) antagonist reduced paired pulse inhibition of IPSPs, suggesting GABA(B) receptor modulation. Thus, GABA-mediated inhibition plays a critical role in shaping synaptic responses of IC cortex neurons. Normal GABAergic function in IC has been shown to be important in acoustic coding, and reduced efficacy of GABA function in IC neurons is critical in IC pathophysiology in presbycusis, tinnitus and audiogenic seizures.

2-Amino-5-phosphonovalerate↗
PubMed2006

Functional expression of the GABAB receptor in human airway smooth muscle.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA(A)/GABA(C)) and metabotropic (GABA(B)) receptors (R). In addition to their location on neurons, GABA and functional GABA(B) receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABA(B)R has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABA(B) receptors to G(i) in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABA(B)R1 and GABA(B)R2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABA(B)R1 and GABA(B)R2 proteins in human native and cultured airway smooth muscle. The GABA(B)R1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABA(B)R agonist, elicited a concentration-dependent stimulation of [(35)S]GTPgammaS binding in HASM homogenates that was abrogated by the GABA(B)R antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABA(B)R agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen's effect on ERK phosphorylation, implicating G(i) protein coupling. Functional GABA(B) receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABA(B) receptors coupled to the G(i) protein in airway smooth muscle.

Adenylyl Cyclases↗
PubMed2004

Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin.

Evidence suggests that oxidative stress is involved in the pathophysiology of diabetic complications and that insulin has a neuroprotective role in oxidative stress conditions. In this study, we evaluated the in vitro effect of insulin in the susceptibility to oxidative stress and in the transport of the amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate in a synaptosomal fraction isolated from male type 2 diabetic Goto-Kakizaki (GK) rat brain cortex. The ascorbate/Fe(2+)-induced increase in thiobarbituric acid reactive substances (TBARSs) was similar in Wistar and GK rats and was not reverted by insulin (1 micromol/l), suggesting that other mechanisms, rather than a direct effect in membrane lipid peroxidation, may mediate insulin neuroprotection. Diabetes did not affect GABA and glutamate transport, despite the significant decrease in membrane potential and ATP/ADP ratio, and insulin increased the uptake of both GABA and glutamate in GK rats. Upon oxidation, there was a decrease in the uptake of both neurotransmitters and an increase in extrasynaptosomal glutamate levels and in ATP/ADP ratio in GK rats. Insulin treatment reverted the ascorbate/Fe(2+)-induced decrease in GABA accumulation, with a decrease in extrasynaptosomal GABA. These results suggest that insulin modulates synaptosomal GABA and/or glutamate transport, thus having a neuroprotective role under oxidizing and/or diabetic conditions.

Animals↗
PubMedDate not supplied

[Modulatory effects of polyamines and GABA on rat ileal motility in vitro].

AIM: The aim of our work was to determine the effects of polyamines and GABA on rat ileum motility in vitro. METHODS: Longitudinal strips dissected from control ileum or ileum without myenteric plexus after benzalkonium chloride (BAC) treatment were placed in organ bath chambers. RESULTS: Spermine significantly inhibited spontaneous activity and nerve stimulation-induced response. Inhibition of spontaneous activity was not altered by BAC treatment or tetrodotoxin but was antagonized by BAY K 8644, a L-type calcium channel agonist. Spermine inhibitory effect on nerve-stimulation induced response disappeared after BAC treatment. GABA enhanced the response induced by nerve stimulation but did not antagonize spermine effects; its action was inhibited in presence of atropine and was mimicked by baclofen, a GABAB agonist. CONCLUSION: Polyamines and GABA can modulate rat ileum motility in vitro. GABA acted via neural GABAB receptors. We demonstrate for the first time that spermine exerts a dual action through different mechanisms on both smooth muscle cells and probably intramural neurons.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Effects of pregnanolone in rats discriminating cocaine.

The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA(A) receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaine's discriminative effects and to examine the interaction between cocaine and pregnanolone, a drug that can modulate the GABA(A) receptor complex. Rats (n=15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d-amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA(A) modulators pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D(2) receptor antagonist haloperidol and pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose-effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA(A) receptors by pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.

Animals↗
PubMed2002

Prenatal diazepam exposure functionally alters the GABA(A) receptor that modulates [3H]noradrenaline release from rat hippocampal synaptosomes.

In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the gamma-aminobutyric (GABA)(A) receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABA(A) receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 microM, and the ED(50) was 1.7 microM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3alpha-pregnan-5alpha-ol-20-one (3alpha,5alpha-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 microM), muscimol stimulated the release of [3H]NA with an ED(50) of 0.5 microM; in the presence of 3alpha,5alpha-P (0.1 microM), the ED(50) of muscimol was 0.3 microM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3alpha,5alpha-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABA(A) receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABA(A) receptor complex. Exposure to DZ while the GABA(A) receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3alpha,5alpha-P.

Allosteric Regulation↗
PubMed1999

Effects of anticonvulsant lactams on in vitro seizures in the hippocampal slice preparation.

Some 3,3-disubstituted 2-pyrrolidinones and 2-piperidinones (five- and six-membered ring lactams, respectively) possess potent in vivo anticonvulsant activity. In vitro these lactams potentiate GABA(A) receptor-mediated chloride currents, which is thought to be the mechanism by which they exert their therapeutic effects. However, the apparent affinity for these GABA(A) interactions is low: EC50s range from hundreds of micromolar to low millimolar values. In order to more completely characterize the activities of these compounds, it was necessary to know the concentrations required to curtail epileptiform activity in an intact neural network, and the mechanism by which this occurs. To address these questions, we used two methods of inducing ictal activity in hippocampal-entorhinal cortical slices: 4-aminopyridine (4-AP) and low Mg2+. We found that 3,3-diethyl-2-pyrrolidinone (diethyl-lactam) prevents seizure-like discharges with IC50s of 1.1 and 2.1 mM in the two models, respectively. These values are nearly identical to the EC50 value obtained in whole-cell studies of diethyl-lactam's GABA(A) receptor modulation. The addition of the GABA(A) antagonist picrotoxin to the low Mg2+ ACSF produced seizures which persisted during diethyl-lactam application. Neither 3-benzyl-3-ethyl-2-piperidinone (3-BEP) nor alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL), two compounds which are similar to diethyl-lactam, but demonstrate picrotoxin-insensitive inhibition of voltage-dependent currents, diminished low Mg2+/picrotoxin seizure activity. Our results support the hypothesis that diethyllactam and related compounds exert their anticonvulsant activity primarily, if not exclusively, by modulating the GABA(A) receptor.

4-Butyrolactone↗