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At least 703 records · Page 39Linked to original sources
PubMed2006

GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus.

Hypocretin/orexin (Hcrt) is a critical neurotransmitter for the maintenance of wakefulness and has been implicated in several other functions, including energy metabolism and reward. Using whole-cell patch-clamp recordings from transgenic mice in which enhanced green fluorescent protein was linked to the Hcrt promoter, we investigated GABAergic control of the Hcrt neurones in hypothalamic slices. Bath application of GABA or muscimol caused an early hyperpolarization mediated by Cl(-) and a late depolarization mediated by the efflux of bicarbonate. These GABA(A) receptor-mediated responses were blocked by picrotoxin and bicuculline. Under the GABA(A) blockade condition, GABA produced consistent hyperpolarization, decreased firing rate and input resistance. The selective GABA(B) agonist (R)-baclofen caused a similar response with an EC(50) of 7.1 mum. The effects of (R)-baclofen were blocked by the GABA(B) antagonist CGP 52432 but persisted in the presence of tetrodotoxin, suggesting direct postsynaptic effects. The existence of GABA(B) modulation was supported by GABA(B(1)) subunit immunoreactivity on Hcrt cells colabelled with antisera to the Hcrt-2 peptide. Furthermore, GABA(B) receptor activation inhibited the presynaptic release of both glutamate and GABA. (R)-Baclofen depressed the amplitude of evoked excitatory postsynaptic currents (EPSCs) and inhibitory synaptic currents (IPSCs), and also decreased the frequency of both spontaneous and miniature EPSCs and IPSCs with a modest effect on their amplitudes. These data suggest that GABA(B) receptors modulate Hcrt neuronal activity via both pre- and postsynaptic mechanisms, which may underlie the promotion of non-rapid eye movement sleep and have implications for the use of GABA(B) agonists in the treatment of substance addiction through direct interaction with the Hcrt system.

Action Potentials↗
PubMed2001

Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone.

Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including gamma-aminobutyric acid (GABA)(A), N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (5-HT)(3), and sigma(1) receptors. The present study used a drug discrimination procedure to assess further the receptor effects of pregnanolone in vivo. Rats were trained to discriminate 5 mg/kg pregnanolone from saline in a two-lever operant task maintained by food reinforcement. The opiate agonist morphine and the negative GABA(A) modulator dehydroepiandrosterone sulfate did not substitute for pregnanolone. All of the GABA(A) positive modulators tested (allopregnanolone, epipregnanolone, androsterone, pentobarbital, midazolam, and zolpidem) dose dependently substituted for pregnanolone. The direct GABA-site agonists 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol and muscimol failed to substitute for pregnanolone. Ethanol and the sigma(1) receptor agonist SKF 10047 fully substituted for pregnanolone, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT(3) antagonist tropisetron did not substitute at any dose tested. The 5-HT(3) agonist SR 57227A reached full substitution, whereas the other 5-HT(3) agonist tested, m-chlorophenylbiguanide, produced partial substitution. These results suggest that positive GABA(A) modulation, but not direct agonism, confers a discriminative stimulus effect similar to pregnanolone. Additionally, antagonism of NMDA receptors and activation of 5-HT(3) and sigma(1) receptors modulate stimulus effects similar to the pregnanolone cue. Overall, the data suggest that pregnanolone produces discriminative stimulus effects representative of a wide-spectrum sedative hypnotic.

Animals↗
PubMed1990

Flunitrazepam photoaffinity labeling of the GABA(A) receptor reduces inhibition of [3H]Ro15-4513 binding by GABA.

The benzodiazepine drugs modulate gamma-aminobutyric acid (GABA)-mediated synaptic transmission via a high-affinity binding site that is part of the GABA(A) receptor complex, but which is distinct from the GABA binding site. Ro15-4513 is a benzodiazepine negative modulator of GABA action that displays unique anti-ethanol properties both in vivo and in vitro. Ro15-4513 has been reported to photoaffinity label nearly 100% of the benzodiazepine binding sites in rat brain homogenates. In contrast, the benzodiazepine positive modulator flunitrazepam photoaffinity labels only 25% of the sites. Here, we have examined the reversible binding of [3H]Ro15-4513, [3H]flumazenil (Ro15-1788), and [3H]flunitrazepam to embryonic chick brain membranes, and to membranes that have been photoaffinity labeled with nonradioactive flunitrazepam. Photoaffinity labeling with flunitrazepam decreased the subsequent reversible binding of [3H]flunitrazepam and [3H]flumazenil, but increased the binding of [3H]Ro15-4513. The increase in [3H]Ro15-4513 binding after flunitrazepam photoaffinity labeling was due to a decrease in the apparent Kd, with no change in Bmax. Following photoaffinity labeling, negative modulation of [3H]Ro15-4513 binding by GABA was lost, whereas positive modulation of residual [3H]flunitrazepam binding was retained. We conclude that the site photoaffinity labeled by flunitrazepam is distinct from the site responsible for reversible binding of [3H]Ro15-4513.

Affinity Labels↗
PubMed2000

Neurosteroids: biosynthesis and function of these novel neuromodulators.

Over the past decade, it has become clear that the brain is a steroidogenic organ. The steroids synthesized by the brain and nervous system, given the name neurosteroids, have a wide variety of diverse functions. In general, they mediate their actions, not through classic steroid hormone nuclear receptors, but through ion-gated neurotransmitter receptors. This paper summarizes what is known about the biosynthesis of neurosteroids, the enzymes mediating these reactions, their localization during development and in the adult, and their function and mechanisms of action in the developing and adult central and peripheral nervous systems. The expression of the steroidogenic enzymes is developmentally regulated, with some enzymes being expressed only during development, while others are expressed during development and in the adult. These enzymes are expressed in both neurons and glia, suggesting that these two cell types must work in concert to produce the appropriate active neurosteroid. The functions attributed to specific neurosteroids include modulation of GABA(A) and NMDA function, modulation of sigma receptor function, regulation of myelinization, neuroprotection, and growth of axons and dendrites. Neurosteroids have also been shown to modulate expression of particular subunits of GABA(A) and NMDA receptors, providing additional sites at which these compounds can regulate neural function. The pharmacological properties of specific neurosteroids are described, and potential uses of neurosteroids in specific neuropathologies and during normal aging in humans are also discussed.

Animals↗
PubMed1998

Coexpression of multiple metabotropic glutamate receptors in axon terminals of single suprachiasmatic nucleus neurons.

Glutamate is the primary excitatory transmitter in axons innervating the hypothalamic suprachiasmatic nucleus (SCN) and is responsible for light-induced phase shifts of circadian rhythms generated by the SCN. By using self-innervating single neuron cultures and patch-clamp electrophysiology, we studied metabotropic glutamate receptors (mGluRs) expressed by SCN neurons. The selective agonists for group I (3,5-dihydroxy-phenylglycine), group II ((S)-4-carboxy-3-hydroxyphenylglycine), and group III ((+)-2-amino-4-phosphonobutyric acid) mGluRs all depressed the evoked IPSC in a subset (33%) of single autaptic neurons, suggesting a coexpression of all three groups of mGluRs in the same axon terminals of a single neuron. Other neurons showed a variety of combinations of mGluRs, including an expression of only one group of mGluR (18%) or coexpression of two groups of mGluRs (27%). Some neurons had no response to any of the three agonists (22%). The three mGluR agonists had no effect on postsynaptic gamma-aminobutyric acid (GABA) receptor responses, indicating a presynaptic modulation of GABA release by mGluRs. We conclude that multiple mGluRs that act through different second messenger pathways are coexpressed in single axon terminals of SCN neurons where they modulate the release of GABA presynaptically, usually inhibiting release.

Animals↗
PubMed2002

GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs.

This review is designed to describe the evolution of the seminal observation made simultaneously in 1975 by Dr. W. Haefely's laboratory (Hoffman La Roche, Basel, Switzerland) and in the Laboratory of Preclinical Pharmacology (NIH, St. Elizabeths Hospital, Washington DC), that benzodiazepine action was mediated by a modulation of GABA action at GABA(A) receptors. In fact, our suggestion was that the benzodiazepine receptor was "a receptor on a receptor" and that this receptor was GABA(A). Needless to say, this suggestion created opposition, but we did not abandon the original idea, in fact, as shown in this review, there is now universal agreement with our hypothesis on the mode of action of benzodiazepines. Hence, this review deals with the allosteric modulation of GABA(A) receptors by benzodiazepines, the role of GABA(A) receptors and benzodiazepine structure diversities in this modulation, and describes the results of our attempts to establish a benzodiazepine (imidazenil) devoid of tolerance, withdrawal symptoms, and changes in the expression of GABA(A) receptor subunits during tolerance. It also deals with the idea that the synthesis of GABA(A) receptor subunits triggered by tolerance resides in dendrites and spines where mRNAs and the apparatus for this translation is located. New analytic procedures may foster progress in the understanding of tolerance to and withdrawal from benzodiazepines.

Allosteric Regulation↗
PubMed2005

Escalated aggression as a reward: corticosterone and GABA(A) receptor positive modulators in mice.

RATIONALE: Individuals seek out the opportunity to fight, but the mechanisms behind this positively reinforcing effect of aggression have yet to be understood. OBJECTIVES: The aims of this study were to (1) describe behavioral and corticosterone elevations that occur in aggressive mice conditioned to respond for the opportunity to fight another mouse, (2) determine if corticosterone elevations are necessary for operant responding and escalated aggression, and (3) determine if corticosterone elevations alter the aggression-heightening effects of gamma-aminobutyric acid (GABA)(A) receptor positive modulators. METHODS AND RESULTS: Aggressive male CFW mice were conditioned to respond under the control of a fixed-interval 10-min (FI10) schedule that reinforced their operant behavior by the presentation of an intruder mouse into their home cage. After the FI10, aggressive behavior was ca. 75% higher than the species-typical levels of fighting and plasma corticosterone was more than twice as high after briefly fighting and/or responding on the FI10 schedule. Inhibition of corticosterone synthesis by metyrapone (30-100 mg/kg) reduced both conditioned responding as well as the aggressive behavior after the FI. Although the benzodiazepine midazolam (0.3-3 mg/kg) heightened species-typical aggressive behavior, it did not increase the high level of aggression engendered by the FI schedule. However, midazolam (0.3 mg/kg) and the neurosteroid allopregnanolone (17 mg/kg) both heightened aggression when given after corticosterone synthesis inhibition by metyrapone (56 mg/kg). CONCLUSIONS: These data suggest that corticosterone elevations are required for responding that is motivated by aggressive behavior and for escalated aggression that follows this responding. Corticosterone elevations also appear to inhibit the aggression heightening effect of GABA(A) receptor positive modulators.

Aggression↗
PubMed2004

Imidazenil: a potent and safe protective agent against diisopropyl fluorophosphate toxicity.

Convulsions are major and life-threatening signs of organophosphate (OP) nerve agents induced neurotoxicity. Thus, early intervention with anticonvulsant drugs to control seizure propagation and the consequent irreversible neuronal damage that may occur during OP exposure is essential. Diazepam is the standard anticonvulsant used in the therapeutic management of OP poisoning. However, its use has been associated with several unwanted effects including, sedation, amnesia, and in the large doses used for such treatment, respiratory depression. Moreover, protracted administration of diazepam has been associated with tolerance and dependence liabilities. In this study, we compared the efficacy and safety of diazepam (full allosteric modulator of GABA action) to that of imidazenil (partial, selective allosteric modulator of GABA action) as preventive treatment against diisopropyl fluorophosphate (DFP)-induced convulsions and mortality. Our results show that imidazenil is more potent and efficacious than diazepam in protecting rats against DFP-induced convulsions and death. Moreover, imidazenil was effective at doses (1 and 0.5 mg/kg) we have previously shown to be devoid of sedation, amnesia, respiratory depression, or tolerance and/or dependence. In contrast, diazepam was effective at doses (5 and 2.5 mg/kg) that produce sedation, amnesia, and ataxia. Furthermore, the combination of imidazenil with atropine was more potent and efficacious than that with diazepam.

Animals↗
PubMed1993

Modulation by intracellular Ca++ of GABA activated Cl- extrusion from Deiters' neuron.

The increase in 36Cl- in --> out permeation across plasma membranes from the Deiters' neurons by GABA on the cytoplasmic side is modulated by Ca++. The GABA stimulation was maximal with Ca++ on the intracellular side at the physiologically likely concentration of 3 x 10(-8) M. A lower effect was found in the 10(-7) - 10(-5) M [Ca++]i range with a total disappearance of it at [Ca++] of .2 mM. This Cl- extrusion mechanism is likely to be involved in the establishment of a Cl- out --> in electrochemical gradient. Modulation of it by intracellular Ca++ transients may be of physiological importance.

Animals↗
PubMed1994

Presynaptic modulation by dopamine and GABA opens a potassium channel in rat cortical, striatal and hippocampal synaptosomes via eicosanoids.

Using a K(+)-sensitive electrode in synaptosomal preparations, the presynaptic modulating effect of dopamine and GABA in opening a K+ channel was investigated. In cortical, striatal and hippocampal synaptosomes dopamine D1 and D2 agonists and a GABAB agonist promoted the efflux of K+ in all three preparations. The effect was blocked by the cyclooxygenase inhibitor, indomethacin suggesting that eicosanoids act as second messengers in these systems. The inference in these studies is that dopamine and GABA hyperpolarize presynaptic terminals thereby reducing Ca2+ influx and thus inhibiting the evoked release of transmitters.

Animals↗
PubMed2001

Modulation of Chelidonii herba on GABA activated chloride current in rat PAG neurons.

Modulation of Chelidonii herba on gamma-aminobutyric acid (GABA) activated chloride current in the acutely dissociated periaqueductal gray (PAG) neuron was studied by nystatin-perforated patch-clamp technique. High concentrations of Chelidonii herba elicited ion current, that was blocked by bicuculline. Low concentrations reduced the GABA activated current in PAG. Two types of inhibitory action of Chelidonii herba on GABA activated current have been implicated in PAG. One is the inhibitory action of Chelidonii herba on GABA was abolished by naltrexone and the other is that of Chelidonii herba was potentiated by naltrexone. In addition, all of two types of action of Chelidonii herba are linked to pertussis toxin-sensitive GTP-binding proteins. These results suggest that the inhibitory modulation of Chelidonii herba on GABA activated current via G-proteins in PAG neuron is an important analgesic mechanism.

Animals↗
PubMedDate not supplied

Modulation by Zn2+ of GABA responses in bipolar cells of the mouse retina.

The localization of endogenous Zn2+ in the mouse retina was examined histochemically and the inhibitory action of Zn2+ on GABA-induced responses was studied in bipolar cells isolated from the mouse retina. Accumulation of endogenous Zn2+ was detected in photoreceptors, bipolar, and/or amacrine cells by either the bromopyridylazo-diethylaminophenol method or the dithizone method. Under whole-cell recording conditions, GABA induced a Cl- current in isolated bipolar cells. The current consisted of two components. The first component was inhibited completely by application of 100 microM bicuculline, suggesting that this is a GABA(A)-receptor mediated current. The second component was inhibited completely by 100 microM 3-aminopropyl-(methyl)-phosphinic acid, suggesting that this is a GABA(C)-receptor mediated current. GABA(C) receptors were present at a higher density on the axon terminal than on dendrites. Zn2+ inhibited both GABA(A) and GABA(C) receptors. GABA(C) receptors were more susceptible to Zn2+; the IC50 for the GABA(A) receptor was 67.4 microM and that for the GABA(C) receptor was 1.9 microM. These results suggest that Zn2+ modulates the inhibitory interaction between amacrine and bipolar cells, particularly that mediated by the GABA(C) receptor.

Animals↗
PubMed1999

Mutant human alpha(1)beta(1)(T262Q) GABA(A) receptors are directly activated but not modulated by pentobarbital.

Pentobarbital activates GABA(A) receptors and enhances GABA-activated currents. A threonine residue (262) in the second membrane spanning region at the 12' position in the beta(1) subunit, alpha(1)beta(1)(T12'Q), is necessary for the potentiating action of pentobarbital. We examined whether T12'Q-mutated receptors expressed in Spodoptera frugipedra (Sf 9) cells responded to direct activation by pentobarbital. In both mutant and wild type receptors, pentobarbital (100 microM to 1 mM) evoked a current response. The pentobarbital EC(50) values were similar; 119 and 158 microM for alpha(1)beta(1) and alpha(1)beta(1)(T12'Q) receptors, respectively. The results show it is possible to discriminate between agonistic and potentiating effects of pentobarbital, suggesting these actions involve separate mechanisms.

Amino Acid Substitution↗
PubMed2001

Modulation of native and recombinant GABA(A) receptors by endogenous and synthetic neuroactive steroids.

Upon administration, certain pregnane steroids produce clear behavioural effects including, anxiolysis, sedation, analgesia, anaesthesia and are anti-convulsant. This behavioural profile is characteristic of compounds that act to enhance the actions of GABA acting at the GABA(A) receptor. In agreement, numerous studies have now demonstrated these steroids to be potent, positive allosteric modulators of the GABA(A) receptor. The pregnane steroids are synthesized in the periphery by endocrine glands such as the adrenals and the ovaries, but are also made by neurons and glial cells in the central nervous system itself. Hence, these compounds could play both an endocrine and a paracrine role to influence neuronal excitability by promoting inhibition. Here we review evidence that the pregnane steroids are highly selective and extremely potent GABA(A) receptor modulators and that their effects at 'physiological' concentrations (low nanomolar) may be influenced by the subunit composition of the GABA(A) receptor. This feature may underlie recent findings demonstrating the effects of the neurosteroids on inhibitory synaptic transmission to be brain region dependent, although recent reports suggest that phosphorylation mechanisms may additionally influence neurosteroid sensitivity of the GABA(A) receptor. Numerous synthetic steroids have been synthesized in an attempt to therapeutically exploit the behavioural effects of the pregnane steroids and progress with this approach will be discussed. However, the demonstration that the steroids may be made within the central nervous system offers the alternative strategy of targeting the enzymes that synthesize/metabolise the neurosteroids to exploit this novel endocrine/paracrine interaction.

Animals↗
PubMed2005

Development of subtype selective GABAA modulators.

Drugs modulating gamma-aminobutyric acid (GABA) transmission via the benzodiazepine (BZ) site on the gamma-aminobutyric acid type A (GABAA) receptor have been in widespread use for more than 40 years to treat anxiety, epilepsy, and sleep disorders. These drugs have been shown to be safe, well tolerated, and effective although the mechanism by they produce a myriad of pharmacologic effects remains elusive. In recent years it has been discovered that, although the GABAA receptor is widely distributed in the brain, the substructure and composition of the receptor differs from between brain regions. Termed "GABAA receptor subtypes" their discovery leads to speculation that different subtypes may mediate specific effects of BZs such as anxiety or sedation. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs.

Anxiety↗
PubMed2004

Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum.

Compelling evidence indicates that the long (D2L) and the short (D2S) isoform of dopamine (DA) D2 receptors serve distinct physiological functions in vivo. To address the involvement of these isoforms in the control of synaptic transmission in the striatum, we measured the sensitivity to D2 receptor stimulation of glutamate- and GABA-mediated currents recorded from striatal neurons of three mutant mice, in which the expression of D2L and D2S receptors was either ablated or variably altered. Our data indicate that both isoforms participate in the presynaptic inhibition of GABA transmission in the striatum, while the D2-receptor-dependent modulation of glutamate release preferentially involves the D2S receptor. Accordingly, the inhibitory effects of the DA D2 receptor agonist quinpirole (10 microM) on GABA(A)-mediated spontaneous inhibitory postsynaptic currents (IPSCs)correlate with the total number of D2 receptor sites in the striatum, irrespective of the specific receptor isoform expressed. In contrast, glutamate-mediated spontaneous excitatory postsynaptic currents (EPSCs) were significantly inhibited by quinpirole only when the total number of D2 receptor sites, normally composed by both D2L and D2S receptors in a ratio favoring the D2L isoform, was modified to express only the D2S isoform at higher than normal levels. Understanding the physiological roles of DA D2 receptors in the striatum is essential for the treatment of several neuropsychiatric conditions, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and drug addiction.

Animals↗
PubMed1999

Contribution of GABA(A) and GABA(B) receptors to the discriminative stimulus produced by gamma-hydroxybutyric acid.

The present study examined the involvement of GABA(A) and GABA(B) receptors in the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Rats were trained to discriminate either 300 or 700 mg/kg GHB IG from water using a T-maze, food-reinforced drug-discrimination procedure. The direct GABA(B) agonist, baclofen, substituted completely for both training doses of GHB; its potency to substitute for GHB increased moderately as the training dose of GHB was increased. The positive GABA(A) modulator, diazepam, substituted partially for 300 mg/kg GHB, but failed to elicit GHB-appropriate responding in rats trained with the higher GHB dose. Finally, the GABA(B) antagonist, CGP 35348, completely blocked the discriminative stimulus effects of the high training dose of GHB, but only partially antagonized the effects of the low training dose. These results suggest that (a) GHB produces a compound stimulus, and (b) both GABA(B)- and GABA(A)-mediated cues are prominent components of this compound stimulus; the contribution of each component, however, appears to vary as the training dose of GHB is increased.

3-Hydroxybutyric Acid↗
PubMed2001

Modulation by divalent cations of GABA rho 1 receptor from human retina expressed in Xenopus oocytes.

OBJECTIVE: To investigate functional homooligomeric GABA rho 1 receptors expressed in Xenopus oocytes and the modulation of divalent cations. METHODS: GABA rho 1 cDNA from human retina was transcribed in vitro to obtain sense rho 1 mRNA, which was microinjected into Xenopus oocytes. Two-electrodes voltage clamp technique was performed to record GABA-induced currents. RESULTS: Expressed receptors were found to have similar properties to GABAc receptors characterized in the retina. Cl-currents induced by GABA were blocked by picrotoxin instead of bicuculline. GABA-induced currents reversed at -19 +/- 2.5 mV, and EC50 was 3.3 mumol/L. Zn++ modulated GABA-induced currents with an IC50 = 9.6 mumol/L. Ni++, Cu++ and Cd++ inhibited GABA rho 1 obviously, too. Their rank order of potency was Zn++ > Ni++ > Cu++ > Cd++. CONCLUSION: Zinc (10 mumol/L) inhibited GABA-induced currents in a competitive manner, and its action was sensitive to extracellular pH. Site-directed mutagenesis revealed that substitution of a single histidine residue (H44 and H48) failed to affect zinc sensitivity.

Animals↗