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PubMed1997

Alpha subunit isoform influences GABA(A) receptor modulation by propofol.

We have investigated the role of the alpha subunit in the modulation of gamma-aminobutyric acid type A (GABA(A)) receptors by the general anesthetic propofol, using whole-cell patch clamp recordings made from distinct stable fibroblast cell lines which expressed only alpha1beta3gamma2 or alpha6beta3gamma2 GABA(A) receptors. At clinically relevant anesthetic concentrations, propofol potentiated submaximal GABA currents in alpha1beta3gamma2 receptors to a far greater degree than those in alpha6beta3gamma2 receptors. The alpha subunit influenced the efficacy of propofol for modulation, but not its potency. In contrast, direct gating of the ion channel by propofol, in the absence of GABA, was significantly larger in the alpha6 than the alpha1 containing receptors. The potentiation of submaximal GABA by trichloroethanol, and the potentiation and direct gating by methohexital was also studied, and showed the same relative trends as propofol.

Anesthetics, Intravenous↗
PubMed2000

Redox modulation of recombinant human GABA(A) receptors.

We previously reported that GABA-evoked currents of rat retinal ganglion cells were modulated by redox agents. In this study, we further characterized the effects of redox modulation on GABA receptors using recombinant human subunits in the Xenopus oocyte expression system with two-electrode voltage-clamp recording. GABA receptors composed of subunits alpha(1-3), beta(1-3), gamma(1), gamma(2S,) and rho(1) were expressed. The sulfhydryl reducing agent dithiothreitol reversibly potentiated the responses of various combinations of functional recombinant GABA(A) subunits, whether expressed as triplets (alpha(1)beta(1-3)gamma(1,2S)), pairs (alpha(1-3)beta(1-3); beta(1-3)gamma(1,2S)), or singly (beta(2)). These effects of dithiothreitol were rapidly reversible, and the oxidizing agent 5-5'-dithiobis-2-nitrobenzoic acid exerted the opposite effect. In contrast to these effects on GABA(A) receptors, dithiothreitol had no effect on the responses of homomeric GABA rho(1) (GABA(C)) receptors. The degree of dithiothreitol potentiation of GABA(A) receptor responses depended on subunit composition. Co-expression of gamma(2S) with alpha(1)beta(1-3) subunits resulted in markedly less dithiothreitol potentiation of GABA-evoked currents than that observed for alpha(1-3)beta(1-3) subunits in the absence of gamma(2S). None the less, the magnitude of dithiothreitol potentiation could be restored by using a combination of lower GABA concentrations (5-10 microM) and higher dithiothreitol concentrations (5-20mM). N,N,N', N'-tetrakis(2-pyridyl-methyl)ethylenediamine, a high-affinity Zn(2+) chelator, also potentiated GABA(A) receptor currents. However, the potentiation produced by 10mM dithiothreitol was larger than that produced by saturating concentrations of N,N,N', N'-tetrakis(2-pyridyl-methyl)ethylenediamine (100 microM), implying that at least part of the effect of dithiothreitol was due to redox modulation rather than Zn(2+) chelation. Dithiothreitol also potentiated the spontaneous current of homomeric GABA(A) receptors composed of beta subunits. Mutation of a single cysteine residue in the M3 domain, yielding homomeric beta(3)(C313A) receptors, abrogated dithiothreitol potentiation of the spontaneous current. In summary, this study further characterizes the modulatory effects of redox agents on recombinant GABA(A) receptors. The degree of redox modulation of GABA(A) receptors depended on subunit composition. In contrast to their effect on GABA(A) receptors, redox agents were not found to modulate GABA(C) receptors composed of homomeric rho(1) subunits. Using site-directed mutagenesis, a cysteine residue was located in the beta(3) subunit which may comprise one of the redox-active sites that underlies the modulation of heteromeric GABA(A) receptors by reducing and oxidizing agents.

Animals↗
PubMed2002

The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents.

1. In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra) may involve modulation of inhibitory neurotransmission. 2. GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The effect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3. LEV contrasted the reference AEDs by an absence of any direct effect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4. These minor direct effects contrasted with a potent ability of LEV (EC(50)=1 - 10 microM) to reverse the inhibitory effects of the negative allosteric modulators zinc and beta-carbolines on both GABA(A) and glycine receptor-mediated responses. 5. Clonazepam, phenobarbital and valproate showed a similar ability to reverse the inhibition of beta-carbolines on GABA-gated currents. Blockade of zinc inhibition of GABA responses was observed with clonazepam and ethosuximide. Phenytoin was the only AED together with LEV that inhibited the antagonism of zinc on glycine-gated currents and only clonazepam and phenobarbital inhibited the action of DMCM. 6. LEV (17 mg kg(-1)) produced a potent suppression of sound-induced clonic convulsions in mice. This protective effect was significantly abolished by co-administration of the beta-carboline FG 7142, from a dose of 5 mg kg(-1). In contrast, the benzodiazepine receptor antagonist flumazenil (up to 10 mg kg(-1)) was without any effect on the protection afforded by LEV. 7. The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the anti-epileptic mechanism(s) of action of LEV.

Allosteric Regulation↗
PubMed1999

The influence of menstrual cycle phase on sensitivity to ethanol-like discriminative stimulus effects of GABA(A)-positive modulators.

Previous studies showed that sensitivity to the ethanol-like discriminative stimulus effects of allopregnanolone and ethanol are enhanced during the luteal phase of the menstrual cycle when progesterone levels peak in monkeys trained to discriminate 1.0 g/kg ethanol. The present study further explored the influence of the menstrual cycle phase on the discriminative stimulus effects of ethanol, allopregnanolone, and midazolam. Female adult cynomolgus monkeys (Macaca fascicularis) were trained to discriminate 1.0 g/kg ethanol (n = 3) or 2.0 g/kg ethanol (n = 4) (20% w/v; i.g.) from water (i.g.). A cumulative dosing procedure was used to test discriminative stimulus effects of ethanol (0.5-2.5 g/kg; i.g.) and the ethanol-like discriminative stimulus effects of allopregnanolone (0.1-1.0 mg/kg; i.v.) or midazolam (1.0-17 mg/kg; i.g.) during the follicular vs. luteal phase of the menstrual cycle. In the 2.0-g/kg group, sensitivity to the ethanol-like effects of allopregnanolone was increased during the luteal vs. follicular phase in two of three monkeys. In contrast, average sensitivity to ethanol was not different in the luteal compared to the follicular phase in the 2.0-g/kg group. Finally, there was no difference in sensitivity to midazolam between the follicular and luteal phases in monkeys trained with either 2.0 g/kg or 1.0 g/kg ethanol. Overall, the ethanol-like discriminative stimulus effects of midazolam are not sensitive to the menstrual cycle phase. In addition, there was less influence of the menstrual cycle phase on allopregnanolone and ethanol sensitivity in a 2.0-g/kg compared to a 1.0-g/kg ethanol training dose.

Animals↗
PubMed2002

Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors.

Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.

Algorithms↗
PubMedDate not supplied

Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain.

Gamma-aminobutyric acid (GABA) receptors are ubiquitous inhibitory receptors in the central and peripheral nervous systems. Valproic acid (2-propylpentanoic acid), which enhances GABA synthesis and blocks degradation, is useful in migraine treatment and may act through activation of GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. To investigate this possibility, we tested the effect of valproate and allopregnanolone, a metabolite of progesterone, which binds and modulates the GABA receptor in an animal model of cephalic pain. One hundred ten Hartley guinea pigs were pretreated with either valproate or allopregnanolone 30 minutes prior to activation of trigeminal afferent fibers via intracisternal injection of the irritant, capsaicin. The effects of valproic acid and allopregnanolone were examined on c-fos expression within the trigeminal nucleus caudalis (lamina I, II), the termination site for small unmyelinated C fibers projecting from the meninges. C-fos positive cells were counted at three representative levels (rostral, middle, and caudal) by an observer naive to the treatment group. We found that valproate (> or = 10 mg/kg, IP) reduced labeled cells by 52% (P < 0.05) and allopregnanolone (> or = 100 mg/kg, IP) reduced labeled cells by 42% (P < 0.01). Bicuculline (GABAA antagonist), but not phaclofen (GABAB antagonist), blocked the valproate effect, thereby documenting the importance of GABAA receptors. We conclude that the attenuation of c-fos-LI by valproate and allopregnanolone is mediated via GABAA receptors. These studies complement prior experiments showing that valproic acid and allopregnanolone block neurogenic inflammation within the meninges via GABAA receptor-mediated mechanisms. The findings suggest a potential strategy for discovering new antimigraine drugs with high affinity for the GABAA receptor and its modulatory sites.

Animals↗
PubMed2004

Clustering of extrasynaptic GABA(A) receptors modulates tonic inhibition in cultured hippocampal neurons.

Tonic inhibition plays a crucial role in regulating neuronal excitability because it sets the threshold for action potential generation and integrates excitatory signals. Tonic currents are known to be largely mediated by extrasynaptic gamma-aminobutyric acid type A (GABA(A)) receptors that are persistently activated by submicromolar concentrations of ambient GABA. We recently reported that, in cultured hippocampal neurons, the clustering of synaptic GABA(A) receptors significantly affects synaptic transmission. In this work, we demonstrated that the clustering of extrasynaptic GABA(A) receptors modulated tonic inhibition. Depolymerization of the cytoskeleton with nocodazole promoted the disassembly of extrasynaptic clusters of delta and gamma(2) subunit-containing GABA(A) receptors. This effect was associated with a reduction in the amplitude of tonic currents and diminished shunting inhibition. Moreover, diffuse GABA(A) receptors were less sensitive to the GAT-1 inhibitor NO-711 and to flurazepam. Quantitative analysis of GABA-evoked currents after prolonged exposure to submicromolar concentrations of GABA and model simulations suggest that clustering affects the gating properties of extrasynaptic GABA(A) receptors. In particular, a larger occupancy of the singly and doubly bound desensitized states can account for the modulation of tonic inhibition recorded after nocodazole treatment. Moreover, comparison of tonic currents recorded during spontaneous activity and those elicited by exogenously applied low agonist concentrations allows estimation of the concentration of ambient GABA. In conclusion, receptor clustering appears to be an additional regulating factor for tonic inhibition.

Animals↗
PubMed2006

8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABA A receptor.

8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.

Allosteric Regulation↗
PubMed2001

Allopregnanolone and pentobarbital infused into the nucleus accumbens substitute for the discriminative stimulus effects of ethanol.

BACKGROUND: The discriminative stimulus effects of ethanol are mediated in part by the gamma-aminobutyric acid type A (GABA(A)) receptor system. We have previously shown that microinjections of the competitive GABA(A) agonist muscimol in the nucleus accumbens and amygdala fully substitute for the discriminative stimulus effects of systemic ethanol. However, it is not known whether allosteric binding sites on GABA(A) receptors located within specific limbic brain regions contribute to the discriminative stimulus effects of ethanol. METHODS: Male Long-Evans rats were trained to discriminate between intraperitoneal injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. Injector guide cannulae, aimed at both the nucleus accumbens core and the hippocampus area CA1, were then implanted to allow site-specific infusion of GABA(A)-positive modulators. RESULTS: Infusion of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, or 3alpha-5alpha-P) in the nucleus accumbens resulted in dose-dependent full substitution for intraperitoneal ethanol (50% effective dose = 0.38 ng/microl per side). Likewise, injection of the barbiturate pentobarbital into the nucleus accumbens also substituted dose-dependently for ethanol (50% effective dose = 1.55 microg/microl per side). However, infusions of either 3alpha-5alpha-P or pentobarbital in the hippocampus failed to substitute for ethanol and produced inverted U-shaped dose-response curves. CONCLUSIONS: These results demonstrate that allosteric positive modulation of GABA(A) receptors in the nucleus accumbens produces full substitution for the stimulus effects of ethanol. This suggests that GABA(A) receptors in the nucleus accumbens may play a more influential role in the discriminative stimulus effects of ethanol than those in the hippocampus.

Animals↗
PubMed2004

Microglia express GABA(B) receptors to modulate interleukin release.

gamma-Aminobutyric acid (GABA) can act as a neuroprotective agent besides its well-established role as the main inhibitory neurotransmitter in the CNS. Here we report that microglial cells express GABA(B) receptors indicating that these prominent immunocompetent cells in the brain are a target for GABA. Agonists of GABA(B) receptors triggered the induction of K(+) conductance in microglial cells from acute brain slices and in culture. Both subunits of GABA(B) receptors were identified in cultured microglia by Western blot analysis and immunocytochemistry, and were detected on a subpopulation of microglia in situ by immunohistochemistry. In response to facial nerve axotomy, we observed an increase in GABA(B) receptor expressing microglial cells in the facial nucleus. We activated microglial cells in culture with lipopolysaccharide (LPS) to induce the release of interleukin-6 and interleukin-12p40. This release activity was attenuated by simultaneous activation of the GABA(B) receptors indicating that GABA can modulate the microglial immune response.

Animals↗
PubMed1988

GABA-related drugs modulate the behavioral effects of lorazepam.

The behavioral effects of the GABA-related drugs SL 75102 (4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino]butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the fixed-interval schedule. Neither SL 75102 (1.0-30.0 mg/kg) nor THIP (0.1-3.0 mg/kg) significantly altered rates of either suppressed or nonsuppressed responding, whereas lorazepam (0.01-0.3 mg/kg) produced dose-related increases in response rate under both schedules. Pretreatment with 1.0 mg/kg SL 75102 significantly enhanced the rate-increasing effects of lorazepam on suppressed responding. Pretreatment with 10.0 mg/kg SL 75102 also enhanced the rate-increasing effects of lorazepam on nonsuppressed responding. In contrast, the rate-increasing effects of lorazepam were not enhanced by pretreatment with 0.3 or 1.0 mg/kg THIP under either schedule. Moreover, pretreatment with 1.0 mg/kg THIP attenuated the rate-increasing effects of lorazepam on nonsuppressed responding. Enhancement of the behavioral effects of lorazepam by SL 75102 may reflect positive allosteric interactions between the two drugs at the benzodiazepine-GABA receptor complex.

Animals↗
PubMed1988

Modulation of the GABA autoreceptor by benzodiazepine receptor ligands.

The effects of various benzodiazepine receptor ligands on the GABA autoreceptor have been studied in slices of cerebral cortex of the rat. The GABAA receptor agonist muscimol inhibited the K+-stimulated release of [3H]GABA with a pIC25 of 7.65 +/- 0.11. This effect was antagonised by the GABAA receptor antagonist bicuculline, which had an IC50 of 0.36 +/- 0.03 microM. Small concentrations (less than 1 microM) of the benzodiazepine full agonist clonazepam did not significantly alter K+-evoked release of [3H]GABA but shifted the concentration-effect curve for muscimol to the left. This effect was blocked by the benzodiazepine antagonist flumazenil. By contrast, the benzodiazepine full inverse agonist methyl beta-carboline-3-carboxylate shifted the muscimol concentration-effect curve to the right and this too was blocked by flumazenil. The results suggest that the GABA autoreceptor in cortical slices from the rat is modulated by a benzodiazepine receptor.

Animals↗
PubMed2006

GABA(A) receptor modulation of 5-HT neuronal firing in the median raphe nucleus: implications for the action of anxiolytics.

5-HT neurones in the median raphe nucleus (MRN) are involved in anxiety and the sleep/wake cycle. Here, using in vitro electrophysiology, we examined if the firing of MRN 5-HT neurones is regulated by GABA(A) receptors. The GABA(A) receptor agonists THIP and muscimol caused concentration dependent inhibition of MRN 5-HT neurones. The GABA(A) receptor antagonist bicuculline blocked the responses to THIP and muscimol. Bicuculline alone increased the basal firing activity. Responses to THIP were enhanced by the Z hypnotic zolpidem at concentrations selective for the alpha(2)/alpha(3) subunits of the GABA(A) receptor (0.2 and 1microM) but not at a concentration selective for the alpha(1) subunit (0.02microM). Consistent with these functional data, 5-HT neurones have been shown to express the alpha(3) (but not alpha(2)) subunit. The anxiolytic effects of GABA(A) receptor modulators are reportedly mediated by alpha(3)-containing receptors. Hence the MRN 5-HT system may be a target for anxiolytic drugs.

Action Potentials↗
PubMed1994

Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.

Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding.

Animals↗
PubMed1999

Mechanism by which GABA, through its GABA(A) receptor, modulates glutamate release from rat cortical neurons in culture.

In cortical neurons, the GABA(A) agonist, muscimol, increases: (a) basal glutamate release (with a EC50 of 99 +/- 7 microM); (b) intracellular calcium and (c) membrane potential, all of these in a dose-dependent manner. These muscimol effects were specific since they were reversed by bicuculline, a GABA(A) antagonist. When the action of muscimol was measured at different KCl concentrations, an increase or decrease of the glutamate secretion was observed, depending on the KCl concentration in the medium. At low KCl concentration (5.6 mM of KCl), it depolarized, at 20 mM of KCl it had no effect, but at higher KCl concentrations (30-100 microM of KCl), it produced a hyperpolarization in these cells. The mechanism by which the GABA-Cl(-)-channel permits Cl- fluxes, inward or outward, depending on the membrane potential.

Animals↗
PubMed2005

Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex.

GABAergic inhibition in the brain can be classified as either phasic or tonic. gamma-Aminobutyric acid (GABA) uptake by GABA transporters (GATs) can limit the time course of phasic currents arising from endogenous and exogenous GABA, as well as decrease a tonically active GABA current. GABA transporter subtypes 1 and 3 (GAT-1 and GAT-3) are the most heavily expressed of the four known GAT subtypes. The role of GATs in shaping GABA currents in the neocortex has not been explored. We obtained patch-clamp recordings from layer II/III pyramidal cells and layer I interneurons in rat sensorimotor cortex. We found that selective GAT-1 inhibition with NO711 decreased the amplitude and increased the decay time of evoked inhibitory postsynaptic currents (IPSCs) but had no effect on the tonic current or spontaneous IPSCs (sIPSCs). GAT-2/3 inhibition with SNAP-5114 had no effect on IPSCs or the tonic current. Coapplication of NO711 and SNAP-5114 substantially increased tonic currents and synergistically decreased IPSC amplitudes and increased IPSC decay times. sIPSCs were not resolvable with coapplication of NO711 and SNAP-5114. The effects of the nonselective GAT antagonist nipecotic acid were similar to those of NO711 and SNAP-5114 together. We conclude that synaptic GABA levels in neocortical neurons are controlled primarily by GAT-1, but that GAT-1 and GAT-2/3 work together extrasynaptically to limit tonic currents. Inhibition of any one GAT subtype does not increase the tonic current, presumably as a result of increased activity of the remaining transporters. Thus neocortical GAT-1 and GAT-2/3 have distinct but overlapping roles in modulating GABA conductances.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMedDate not supplied

The role of phosphorylation in the activity and mercury modulation of GABA-induced currents in rat neurons.

The role of protein kinase A (PKA) and protein kinase C (PKC) in the function and modulation by mercury chloride of the GABA(A) receptor-chloride channel complex was studied with rat dorsal root ganglion cells using the whole-cell patch clamp technique. When added to the internal pipette solutions, both KT 5720, a selective PKA inhibitor, and calphostin C, a selective PKC inhibitor, increased the maximal current and shifted the EC50 for GABA in the direction of higher GABA concentrations. GABA-activated currents were decreased by the addition of 5 mM cAMP to the internal pipette solution, and by external perfusion of 100 nM phorbol 13-myristate 13-acetate. Mercury chloride potentiation of GABA-activated currents was blocked by internal application of 5 mM cAMP. PKA in the recording pipette abolished the mercury chloride potentiation of GABA-activated currents. In contrast, 0.56 microM KT 5720, but not calphostin C, in the internal pipette solution enhanced the effect of mercury chloride. In conclusion, both PKA and PKC negatively regulate the activity of the GABA(A) receptor-channel complex probably through phosphorylation of the receptor, and the PKA system underlies the mechanism of mercury chloride potentiation of GABA-activated currents.

Animals↗
PubMed2002

Ventral tegmental area region governs GABA(B) receptor modulation of ethanol-stimulated activity in mice.

Locomotor stimulation in response to ethanol in mice may model human ethanol-induced euphoria. The associated neural substrates, possibly relevant to alcoholism, have not been fully elucidated. Systemic injection of baclofen, a GABA(B) receptor agonist, attenuates ethanol's stimulant effects. GABA(B) receptors on dopamine cell bodies in the ventral tegmental area (VTA) may modulate ethanol-induced dopamine release, a postulated mechanism for ethanol's stimulant effects. However, baclofen's attenuating effects could be associated with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation, to test the hypotheses that (1) central GABA(B) receptors influence baclofen's effects on ethanol-stimulated activity, and (2) VTA GABA(B) receptors specifically modulate ethanol's stimulant effects. I.c.v. baclofen dose-dependently attenuated ethanol stimulation, supporting a central locus for baclofen's effects. Anterior VTA baclofen also attenuated ethanol stimulation. However, more posterior VTA infusions unexpectedly potentiated ethanol stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice. GABA(B) receptor autoradiography using [(3)H]CGP 54626, a potent GABA(B) receptor antagonist, did not reveal line differences in binding density in the VTA, or in the substantia nigra pars compacta, a nearby brain structure associated with motor control. These results suggest that anterior VTA GABA(B) receptors play a role in baclofen's attenuation of ethanol's stimulant effects, and that posterior VTA GABA(B) receptors serve an opposite role that is normally masked. Selection for differential ethanol stimulant sensitivity has altered VTA GABA(B) systems that influence locomotor behavior. However, differences in GABA(B) receptor densities in the VTA or substantia nigra pars compacta cannot explain the selected line difference.

Animals↗