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PubMed1994

Bidirectional modulation of GABA-gated chloride channels by divalent cations: inhibition by Ca2+ and enhancement by Mg2+.

The effects of the divalent cations Ca2+, Sr2+, Ba2+, Mg2+, Mn2+, and Cd2+ were studied on gamma-aminobutyric acidA (GABAA) responses in rat cerebral cortical synaptoneurosomes. The divalent cations produced bidirectional modulation of muscimol-induced 36Cl- uptake consistent with their ability to permeate and block Ca2+ channels. The order of potency for inhibition of muscimol responses was Ca2+ > Sr2+ > Ba2+, similar to the order for permeation of Ca2+ channels in neurons. The order of potency for enhancement of muscimol responses was Cd2+ > Mn2+ > Mg2+, similar to the order for blockade of Ca2+ channels in neurons. Neither Ca2+ nor Mg2+ caused accumulation of GABA in the extravesicular space due to increased GABA release or decreased reuptake of GABA by the synaptoneurosomes. The inhibition of muscimol responses by Ca2+ was most likely via an intracellular site of action because additional inhibition could be obtained in the presence of the Ca2+ ionophore, A23187. This confirms electrophysiologic findings in cultured neurons from several species. In contrast, the effects of Cd2+, Mn2+, and Mg2+ may be mediated via blockade of Ca2+ channels or by intracellular sites, although the results of these studies do not distinguish between the two loci. The effects of Zn2+ were also studied, because this divalent cation is reported to have widely divergent effects on GABAA responses. In contrast to other studies, we demonstrate that Zn2+ inhibits GABAA responses in an adult neuronal preparation. Zn2+ produced a concentration-dependent inhibition (limited to 40%) of muscimol responses with an EC50 of 60 microM. The inhibition of muscimol-induced 36Cl- uptake by Zn2+ was noncompetitive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

In vivo microdialysis study of GABA(A) and GABA(B) receptors modulating the glutamate receptor/NO/cyclic GMP pathway in the rat hippocampus.

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.

Animals↗
PubMed2003

Flavonoid modulation of ionic currents mediated by GABA(A) and GABA(C) receptors.

The modulation of ionotropic gamma-aminobutyric acid (GABA) receptors (GABA-gated Cl(-) channels) by a group of natural and synthetic flavonoids was studied in electrophysiological experiments. Quercetin, apigenin, morine, chrysin and flavone inhibited ionic currents mediated by alpha(1)beta(1)gamma(2s) GABA(A) and rho(1) GABA(C) receptors expressed in Xenopus laevis oocytes in the micromolar range. alpha(1)beta(1)gamma(2s) GABA(A) and rho(1) GABA(C) receptors differ largely in their sensitivity to benzodiazepines, but they were similarly modulated by different flavonoids. Quercetin produced comparable actions on currents mediated by alpha(4)beta(2) neuronal nicotinic acetylcholine, serotonin 5-HT(3A) and glutamate AMPA/kainate receptors. Sedative and anxiolytic flavonoids, like chrysin or apigenin, failed to potentiate but antagonized alpha(1)beta(1)gamma(2s) GABA(A) receptors. Effects of apigenin and quercetin on alpha(1)beta(1)gamma(2s) GABA(A) receptors were insensitive to the benzodiazepine antagonist flumazenil. Results indicate that mechanism/s underlying the modulation of ionotropic GABA receptors by some flavonoids differs from that described for classic benzodiazepine modulation.

Animals↗
PubMed1993

Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition?

The modulation of GABA activity by 3 alpha-OH-DHP (allopregnanolone, 3 alpha-hydroxy-5 alpha-pregnan-20-one) and PS (pregnenolone sulfate) has been studied in native GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors expressed in the 293 human embryonic kidney cell line (HEK 293). In cortical neurons 3 alpha-OH-DHP positively modulates GABA elicited Cl- currents while PS at 10 microM negatively modulates (50% decrease) this GABA response, but at 10 nM PS positively modulates the GABA current (40% increase). Both neurosteroids are equally active on various types of recombinant GABAA receptors, except for alpha 6 beta 1 gamma 2 receptors which are less sensitive to the positive allosteric modulation by 3 alpha-OH-DHP. In contrast the presence of the gamma 1 subunit doubles the efficacy of 3 alpha-OH-DHP. The negative modulation of PS is similar in recombinant GABAA receptors including various molecular forms of alpha or gamma units. A direct activation of Cl- current by 3 alpha-OH-DHP was observed in native and recombinant receptors but its efficacy on the various molecular forms of GABAA receptor tested was always smaller than that of identical concentrations (10 microM) of GABA.

Allosteric Regulation↗
PubMed2001

Mercury interaction with the GABA(A) receptor modulates the benzodiazepine binding site in primary cultures of mouse cerebellar granule cells.

Mercury compounds are neurotoxic compounds with a great specificity for cerebellar granule cells. The interaction of mercury compounds with proteins in the central nervous system may underlie some of their effects on neurotransmission. In this work we study the interaction of mercuric chloride (HgCl2) and methylmercury (MeHg) with the GABA(A) receptor in primary cultures of cerebellar granule cells. Both compounds increased, dose dependently, the binding of [3H]flunitrazepam to the benzodiazepine recognition site. EC50 values for this effect were 3.56 and 15.24 microM for HgCl2 and MeHg, respectively, after 30 min exposure of intact cultured cerebellar granule cells. The increase of [3H]flunitrazepam binding by mercury compounds was completely inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxinin, and by the organochlorine pesticide alpha-endosulfan. It was also partially inhibited by the anion transporter blocker DIDS, however this effect could be due to a possible chelation of mercury by DIDS. Intracellular events, like intracellular calcium, kinase activation/inactivation or antioxidant conditions did not affect [3H]flunitrazepam binding or its increase induced by mercury compounds. The sulfhydryl alkylating agent N-ethylmaleimide mimicked the effect of mercury compounds on [3H]flunitrazepam binding suggesting a common mechanism. We conclude that mercury compounds interact with the GABA(A) receptor by the way of alkylation of SH groups of cysteinyl residues found in GABA(A) receptor subunit sequences.

Alkylation↗
PubMed1999

Zn2+ differentially modulates glycine receptors versus GABA receptors in isolated carp retinal third-order neurons.

It was previously reported that strychnine-sensitive glycine receptors and GABAA receptors co-existed on carp retinal third-order neurons (amacrine/ganglion cells) (Li, P. and Yang, X.-L., Strong synergism between GABAA and glycine receptors on isolated carp third-order neurons. NeuroReport, 9 (1998) 2785-2789.). In this study, the effects of the divalent cation Zn2+ on these two receptors were studied in amacrine/ganglion cells acutely isolated from carp, with the use of the whole-cell patch clamp recording technique. The glycine-induced currents were steadily potentiated by Zn2+ of lower concentrations (0.1-10 microM), while being dose-dependently inhibited by Zn2+ of higher concentrations ( > 100 microM). Both the effects involved changes in apparent glycine affinity of the glycine receptor. In contrast, Zn2+ consistently suppressed the GABA(A) mediated currents of these cells, and did not show similar dual effect. The differential modulation by Zn2+ of glycine receptors versus GABA(A) receptors provides a versatility for regulating inhibitory glycinergic and GABAergic inputs converging on most amacrine/ganglion cells.

Animals↗
PubMed2006

The GABA(B) receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats.

GABA systems have been implicated as targets for ethanol at the cellular, molecular and behavioural level. The present study was designed to further examine the potential of the GABA(B) receptor as a target for regulating operant alcohol responding. Given that the prototypic agonist, baclofen, reduces the self-administration of alcohol, we hypothesized that the GABA(B) receptor allosteric modulator, CGP7930, might have similar actions but a reduced side-effect profile. In this context, inbred alcohol-preferring (iP) rats were trained to respond for 10% v/v ethanol in a fixed ratio paradigm; all drug testing was performed under an FR3 schedule. Both baclofen and CGP7930 independently reduced voluntary responding for 10% ethanol in a dose-related manner. Neither drug impacted upon responding for water. A combination of subthreshold doses of baclofen and CGP7930 was also able to reduce operant responding for ethanol, suggesting that CGP7930 is indeed acting to facilitate GABA(B) receptor-mediated signalling in this paradigm. These data demonstrate the potential of positive allosteric modulators of metabotropic GABA(B) receptors to regulate alcohol responding.

Alcohol Drinking↗
PubMed1990

Different classes of glutamate receptors and GABA mediate distinct modulations of a neuronal oscillator, the medullary pacemaker of a gymnotiform electric fish.

Gymnotiform electric fish generate distinct communicatory signals by modulating the rate of their electric organ discharges (EODs). Each EOD is triggered by a command pulse from the medullary pacemaker nucleus (PN), which contains pacemaker cells and relay cells. The firing rate of this nucleus is modulated by inputs from the diencephalic prepacemaker nucleus (PPN). The NMDA receptor blocker APV and the kainate/quisqualate receptor blocker CNQX, administered to the PN, suppress different types of modulations, indicating that different classes of glutamate receptors mediate the generation of different modulations. A comparison of the 2 genera, Hypopomus and Eigenmannia, reveals that sustained modulations, such as smooth rises in the rate of pacemaker cell firing and the selective silencing of the relay cells (only observed in Hypopomus), are mediated by NMDA receptors, whereas the brief and rapid acceleration, called "chirp" or "decrement burst," is mediated by kainate/quisqualate receptors. Application of the GABA blocker bicuculline reveals that the 2 genera differ in the mechanism by which they slow the firing rate of their pacemaker. Whereas Hypopomus uses GABAergic inhibition to slow down and ultimately silence its pacemaker cells, Eigenmannia reduces tonic, APV-sensitive excitation originating from its PPN and lacks GABAergic inhibition in the PN.

2-Amino-5-phosphonovalerate↗
PubMed2005

Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation.

Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABA(A) receptors, the mechanism of modulation is not well understood. The applicability of an allosteric model with two binding sites for gamma-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated. This model predicts that BZDs should enhance the efficacy of partial agonists. Consistent with this prediction, diazepam increased the efficacy of the GABA(A) receptor partial agonist kojic amine in chick spinal cord neurons. To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant alpha1(L263S)beta3gamma2 GABA(A) receptors expressed in HEK-293 cells. In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors. The results indicate that BZD-like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond.

Allosteric Regulation↗
PubMed1991

Evidence that 3 alpha-hydroxy-5 alpha-pregnan-20-one is a physiologically relevant modulator of GABA-ergic neurotransmission.

3 alpha-Hydroxy-5 alpha-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABAA receptor binding, by determining the allosteric properties of HPO on the in vitro binding of 3H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of 3H-muscimol to GABAA receptor sites by 52% and enhanced the number of accessible binding sites from 5.5 +/- 0.5 to 7.5 +/- 1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABAA receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.

Animals↗
PubMed2006

Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor.

The neurosteroid allopregnanolone (ALLO) or 3alpha-OH-5alpha-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3beta position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. In this study, five different 3beta-steroids were tested for their ability to modulate GABA-mediated chloride ion uptake in the absence and presence of ALLO in rat brain microsacs preparations. In addition, the effects of the 3beta-steroids and their interaction with ALLO were investigated by patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat hypothalamic neurons from the medial preoptic nucleus (MPN). All tested 3beta-steroids reduced the ALLO-enhanced GABA response in cerebral cortex, in hippocampus and in MPN. In cerebellum, only one had this effect. However, in the absence of ALLO, two of the 3beta-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3beta-steroids can act as positive GABA(A) receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3beta-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.

Analysis of Variance↗
PubMed2006

Anti-apoptotic effects of allopregnanolone on P19 neurons.

Progesterone and its metabolites are potent allosteric modulators of GABA(A) receptor function, through a direct, non-genomic interaction with specific receptor subtypes. In addition, fluctuations in the concentration of progesterone, and allopregnanolone in particular, have been shown to modulate GABA(A) receptor gene expression and activity. In this study, mouse P19 cells were induced to differentiate into post-mitotic neurons which express specific neuronal markers, including GABA(A) and N-methyl-d-aspartate (NMDA) receptors. Apoptotic cell death, induced in the presence of NMDA, was efficiently prevented by allopregnanolone and dehydroepiandrosterone (DHEA) but not DHEA sulfate. Apoptosis was accompanied by cytochrome c release to the cytoplasm and Bax translocation to the mitochondria, while the levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL remained unchanged. In the presence of the most potent neurosteroid, allopregnanolone, DNA fragmentation as well as cytochrome c and Bax translocation were prevented. On the other hand, short-term exposure (1-20 microm, 24 h) of P19-derived neurons to allopregnanolone and DHEA significantly increased the levels of alpha1 and beta2 mRNAs of GABA(A) receptor, while the levels of NR1 mRNA of NMDA receptor were not altered. These results suggest that neurosteroids, interfering with the mitochondrial apoptotic pathway, are able to act as survival factors in neuronal cells, while they contribute to GABA(A) receptor plasticity modulating the expression of its subunits.

Animals↗
PubMed1991

Modulation of GABA-mediated Synaptic Potentials by Glutamatergic Agonists in Neonatal CA3 Rat Hippocampal Neurons.

Intracellular recordings were made from slices of adult and neonatal hippocampal neurons. During the first 2 weeks of life the majority of pyramidal cells exhibited spontaneous gamma-aminobutyric acid (GABA)-mediated synaptic potentials, which were depolarizing at birth and became hyperpolarizing by the end of the first postnatal week. These synaptic potentials were reduced in frequency or blocked by the N-methyl-d-aspartate (NMDA) receptor antagonist d(-)2-amino-5-phosphonovalerate (AP-5, 50 microM) (13/15 cells). The non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 - 10 microM) abolished the GABA-mediated synaptic potentials in all the cells tested (n=12), Superfusion of l-glutamate (up to 100 microM) increased the frequency of both depolarizing and hyperpolarizing GABA-mediated synaptic potentials. This effect was reduced by AP-5 or dl-2-amino-7-phosphonoheptanoate (AP-7, 50 microM) and fully blocked by concomitant application of AP-5 (50 microM) and CNQX (5 - 10 microM). NMDA (0.5 - 2 microM) increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by AP-5 (50 microM) and by bicuculline (10 microM). Quisqualate (100 - 300 nM), (RS)-alpha-amino-3-hydroxy-5-methyl-4-izopropionate (AMPA, 100 - 300 nM) and kainate (100 nM) also increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by CNQX (5 - 10 microM) and by bicuculline (10 microM) but not by AP-5 (50 microM). In the presence of tetrodotoxin (TTX, 1 microM), quisqualate (up to 300 nM), AMPA (up to 500 nM) and kainate (100 nM) had no effect on membrane potential or input resistance. In conclusion, our experiments suggest that, in early postnatal life, NMDA and non-NMDA receptors located on GABAergic interneurons modulate GABAergic synaptic potentials.

Journal Article↗
PubMed1996

[Fast modulation of glutamate and GABA receptor--mediate electrophysiological responses by glucocorticoid].

Fast modulation by glucocorticoid on gluatmate and GABA receptor-mediated electrophysiological responses was investigated by extracellular iontophoresis and intracellular techniques in rat hypothalamic brain slices and guinea pig coeliac ganglion preparations respectively. The results were as follows: Glucocorticoid inhibited the glutamate receptor-mediated excitatory response and potentiated the GABA receptor-mediated inhibitory response within 5 min after perfusion. All these responses are reversible after removal of the glucocorticoid. Low Ca2+ high Mg2+ medium was ineffective to block the fast modulatory effects of glucocorticoid on the gluatmate and GABA receptor-mediated responses. It appears that the latter responses are mediated through some non-genomic mechanism without an involvement of synaptic circuitry.

Animals↗
PubMed2000

Prenatally protein-malnourished rats are less sensitive to the amnestic effects of medial septal infusions of chlordiazepoxide.

Evidence is mounting that prenatal protein malnutrition affects the physiological properties of the GABAergic neurotransmitter system in rats. To investigate the functional behavioral consequences of these changes, chlordiazepoxide (CDP, a positive modulator of the GABA(A) receptor) was applied directly to the medial septum and the amnestic response appraised. In adulthood, male offspring of rats provided with a protein-deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy underwent stereotaxic surgery to implant steel cannulae aimed at the medial septum. After recovery, spatial learning performance in the submerged platform version of the Morris water maze task was assessed immediately following a 1 microl infusion of either artificial cerebrospinal fluid (aCSF), or one of three doses of CDP (15, 30 and 60 nmol). Well-nourished control rats demonstrated a robust amnestic response to intraseptal CDP. During task acquisition, well-nourished rats administered each of the doses exhibited significantly longer escape latencies than those given aCSF. On the probe trial (platform removed) a lower proportion of time was spent in the target quadrant (all three doses) at a greater average distance from the former platform location (30 and 60 nmol doses). In contrast, prenatally malnourished rats exhibited a muted sensitivity to CDP, most notable at the 30 nmol dose. These findings provide further support for functional changes within the GABAergic system consequent to malnutrition.

Animals↗
PubMed2002

Role of presynaptic 5-HT1A and 5-HT3 receptors in modulation of synaptic GABA transmission in dissociated rat basolateral amygdala neurons.

Serotonin (5-HT) is considered to play a significant role in anxiety-related behaviors in animals through actions on the amygdaloid complex. To evaluate this role from the point of neurotransmitter release regulation, nystatin-perforated patch recording was employed on mechanically dissociated basolateral amygdala neurons containing functional synaptic boutons. GABAAergic miniature inhibitory postsynaptic currents (mIPSCs) were pharmacologically separated. In subsets of neurons, 8-OH-DPAT (1 microM), a specific 5-HT1A agonist, continuously inhibited mIPSC frequency without effects on mIPSC amplitude. By comparison, mCPBG (1 microM), a specific 5-HT3 agonist, transiently facilitated mIPSC frequency without effects on mIPSC amplitude. Together these results suggest the presynaptic existence of both 5-HT receptor subtypes. In these neurons, application of 8-OH-DPAT and its subsequent removal still suppressed mCPBG-induced responses on mIPSCs. This suppression was not caused by a reduction of presynaptic 5-HT3 receptor affinities to mCPBG and was completely eliminated by pretreatment with N-ethylmaleimide, a pertussis toxin sensitive GTP-binding protein inhibitor. In the neurons exhibiting presynaptic modulation with mCPBG but not 8-OH-DPAT, such suppression by exposure to 8-OH-DPAT was not observed. In conclusion, activation of presynaptic 5-HT1A receptors inhibited mIPSC frequency and at the same time suppressed, via a G-protein-mediated mechanism, the transient facilitation of mIPSC frequency produced by activation of presynaptic 5-HT3 receptors.

Amygdala↗
PubMed1999

Modulation of striatal neuronal activity by glutamate and GABA: iontophoresis in awake, unrestrained rats.

To examine the effects of glutamate (GLU) and gamma-aminobutyric acid (GABA) and their interactions in the striatum under behaviorally relevant conditions, single-unit recording was combined with microiontophoresis in awake, unrestrained rats. Iontophoretically applied GLU (0-40 nA, 20 s) excited all spontaneously active neurons in dorsal (caudate-putamen) and ventral (accumbens, core) striatum; phasic GLU-induced excitations (mean threshold 19.7 nA) were dose-dependent, inversely correlated with rate of basal activity (excitation limit approximately 65 imp/s), and highly stable during repeated GLU applications. GLU also excited silent and sporadically active units, which greatly outnumbered spontaneously active cells, and enhanced neuronal excitations associated with movement. Both spontaneously active and GLU-stimulated striatal neurons were highly sensitive to GABA (0-40 nA, 20 s); most showed short-latency inhibitions during GABA diffusion from the pipette (0 nA) and the response quickly progressed to complete silence with a small increase in current. The GABA-induced inhibition was current-dependent, equally strong on spontaneously active and GLU-stimulated units, and independent of neuronal discharge rate, but less stable than the GLU-induced excitation during repeated drug applications. Prolonged GABA application (0-20 nA, 2-4 min) reduced basal impulse activity, but was less effective in attenuating the neuronal excitations induced by GLU or associated with movement. Our data support the role of GLU afferents in the phasic activation of striatal neurons and suggest that the effects of GLU strongly depend on the level of ongoing neuronal activity. The ability of GABA to modulate both basal and GLU-evoked activity suggests that GABA, released from efferent collaterals and interneurons, plays a critical role in regulating neuronal activity and responsiveness to phasic changes in excitatory input.

Action Potentials↗
PubMed2004

Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys.

RATIONALE: Interactions among compounds at GABA(A) receptors might have important implications for the therapeutic and other effects of positive GABA(A) modulators (e.g. benzodiazepines). OBJECTIVES: This study examined whether a midazolam discriminative stimulus is modified by GABA(A) agonists that act at sites other than benzodiazepine sites. METHODS: Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA(A) receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA(A) receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam. RESULTS: When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive. CONCLUSIONS: Direct-acting GABA(A) receptor agonists are qualitatively different from positive GABA(A) modulators in rhesus monkeys trained to discriminate midazolam. Although GABA(A) receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA(A) receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl(-) flux at the GABA(A) receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.

Animals↗