Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

gamma-Aminobutyrate, alpha-carboxy-2-nitrobenzyl ester (cGABA) is a stable photoactivatable probe used to study gamma-aminobutyrate (GABA) receptors. GABA is released from this compound when it is exposed to ultraviolet light, but little is known about the electrophysiological effects of the compound itself. Whole cell patch clamp recordings on rat hippocampal slices demonstrated that cGABA blocked polysynaptic inhibitory postsynaptic currents (IPSCs) evoked in dentate granule cells by antidromic stimulation of the mossy fibers. It also reduced monosynaptically evoked IPSCs with an IC(50) of 28 microM. In contrast, cGABA had no effect on excitatory postsynaptic currents (EPSCs) evoked by perforant path stimulation. The effect of cGABA was not mediated by depression of GABA release through activation of presynaptic GABA(B) receptors. cGABA inhibited muscimol-evoked currents by only 15% at a concentration of 40 microM. At this same concentration, it reduced the mean frequency of miniature inhibitory postsynaptic potentials by 71%, their mean peak amplitude by 44%, their mean decay time constant by 26% and the mean charge transfer per event by 52%. These effects may be explained by a phenothiazine-like modification of GABA(A) receptor kinetics and/or a selective block of somatic GABA synapses.
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PMID:gamma-Aminobutyrate, alpha-carboxy-2-nitrobenzyl ester selectively blocks inhibitory synaptic transmission in rat dentate gyrus. 1072 66

Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS gamma-aminobutyric acid (GABA) levels. To evaluate the effects of GABA(A) receptor blockade on the ventilatory response to hypoxia in hypothermic piglets, 31 anesthetized paralyzed mechanically ventilated newborn piglets (2-7 d) were studied at a brain temperature of 38.5 +/- 0.5 degrees C [normothermia (NT), n = 15] or 34 +/- 0.5 degrees C [hypothermia (HT), n = 16]. The central respiratory output was evaluated by measuring burst frequency and moving time average area of phrenic nerve activity. Measurements of minute phrenic output (MPO), arterial blood pressure, heart rate, oxygen consumption, and arterial blood gases were obtained at room air and during 20 min of isocapnic hypoxia [fraction of expired oxygen (FiO2) = 0.10]. After 10 min of hypoxia, a bolus injection of 20 microL of bicuculline methiodide (BM; 10 microg) or Ringer's solution was administered into the cisterna magna over a 1-min period, and the piglets remained in hypoxia for an additional 10 min. There was an initial increase of 50 +/- 6% in MPO during the first minute of hypoxia followed by a decrease to values 24 +/- 8% above baseline at 10 min in the NT group. In contrast, in the HT group, the initial increase in MPO with hypoxia was eliminated, and, at 10 min, there was a decrease to a mean value 35 +/- 4% below baseline level (NT versus HT, p < 0.03). After administration of BM, a significant increase in MPO with hypoxia was observed in both groups compared with their placebo groups (p < 0.002 in NT-BM group, p < 0.0001 in HT-BM group). However, the magnitude of the increase in MPO during hypoxia was significantly greater in the HT group after administration of BM (NT versus HT, p < 0.0001). Changes in oxygen consumption, arterial blood pressure, heart rate, pH, partial pressure of oxygen (PaO2), and base excess with hypoxia were not different between NT and HT groups before and after the administration of BM. The cardiorespiratory response to hypoxia was not modified after administration of Ringer's solution to NT and HT placebo groups. These data suggest that the depression in hypoxic ventilatory response produced by HT is in part modulated by an increased CNS GABA concentration.
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PMID:Effects of GABA receptor blockade on the ventilatory response to hypoxia in hypothermic newborn piglets. 1081 94

The present study demonstrated the antidepressant-like effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT(1B/1C) receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT(2A/1C) receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3alpha, 5alpha THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3alpha, 5alpha THP. Such a potentiating effect of the 5-HT(1A) or the 5-HT(2A/1C) receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s. c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300x3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3alpha, 5alpha THP. The accelerated effect of 3alpha, 5alpha THP in presence of serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3alpha, 5alpha THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.
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PMID:Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice. 1082 35

In the progress of science, as in life, timing is important. The acidic dipeptide, N-acetylaspartylglutamate (NAAG), was discovered in the mammalian nervous system in 1965, but initially was not considered to be a neurotransmitter candidate. In the mid-1980s, a few laboratories revisited the question of NAAG's role in the nervous system and pursued hypotheses regarding its function that ranged from a precursor for the transmitter pool of glutamate to a direct role as a peptide transmitter. Since that time, NAAG has been tested against nearly all of the established criteria for identification of a neurotransmitter. It successfully meets each of these tests, including a concentrated presence in neurons and synaptic vesicles, release from axon endings in a calcium-dependent manner following initiation of action potentials, and extracellular hydrolysis by membrane-bound peptidase activity. NAAG is the most prevalent and widely distributed neuropeptide in the mammalian nervous system. NAAG activates NMDA receptors with a low potency that may vary among receptor subtypes, and it is a highly selective agonist at the type 3 metabotropic glutamate receptor (mGluR3). Acting through this receptor, NAAG reduces cyclic AMP levels, decreases voltage-dependent calcium conductance, suppresses excitotoxicity, influences long-term potentiation and depression, regulates GABA(A) receptor subunit expression, and inhibits synaptic release of GABA from cortical neurons. Cloning of peptidase activities against NAAG provides opportunities to study the cellular and molecular mechanisms by which synaptic NAAG peptidase activity is controlled. Given the codistribution of this peptide with a spectrum of traditional transmitters and its ability to activate mGluR3, we speculate that one role for NAAG following synaptic release is the activation of metabotropic autoreceptors that inhibit subsequent transmitter release. A second role is the production of extracellular glutamate following NAAG hydrolysis.
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PMID:N-Acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. 1089 18

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
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PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

The role of internal calcium stores in the induction of long-term depression at GABAergic synapses was investigated in the neonatal rat hippocampus. Whole-cell recordings of CA3 pyramidal neurons were performed on hippocampal slices from neonatal (2-4 d old) rats. In control conditions, tetanic stimulation (TS) evoked an NMDA-dependent long-term depression of GABA(A) receptor-mediated postsynaptic responses (LTD(GABA-A)). LTD(GABA-A) was prevented when the cells were loaded with ruthenium red, a blocker of Ca2+-induced Ca2+ release (CICR) stores, whereas loading the cells with heparin, a blocker of IP3-induced Ca2+ release stores, had no effect. The effects of ryanodine, another compound that interferes with CICR stores, were also investigated. Intracellular injection of ryanodine prevented the induction of LTD(GABA-A) only when the TS was preceded by depolarizing pulses that increase intracellular Ca2+ concentration. When applied in the bath, ryanodine prevented the induction of LTD(GABA-A). Altogether, these results suggest that ryanodine acts as a Ca2+-dependent blocker of CICR stores and that the induction of LTD(GABA-A) required the activation of both presynaptic and postsynaptic CICR stores.
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PMID:Activation of presynaptic and postsynaptic ryanodine-sensitive calcium stores is required for the induction of long-term depression at GABAergic synapses in the neonatal rat hippocampus. 1095 33

Nitric oxide (NO) is implicated in the regulation of various endocrine functions, but the effect of NO on GABA(A) receptor transmission has never been reported in endocrine cells. In the present study, we have investigated the effects of various agents acting on the NO transduction pathway on GABA(A) receptor function in frog pituitary melanotrophs. Histochemical studies using the NADPH-diaphorase reaction and immunohistochemical labeling with antibodies against neuronal NO synthase (nNOS) revealed that nNOS is expressed in the intermediate lobe of the pituitary and in cultured melanotrophs. Whole-cell patch-clamp recordings showed that the specific substrate of NOS L-arginine (L-Arg, 10(-4) M) or the NO donor sodium nitroprusside (10(-5) M) provoked a long-lasting inhibition of the current evoked by GABA (5 x 10(-6) M). The NOS inhibitor L-nitroarginine (10(-5) M) produced a biphasic effect, i.e. a transient decrease followed by a delayed increase of the GABA-evoked current amplitude. Similarly, the specific nNOS inhibitor 7-nitroindazole and the specific inducible NOS (iNOS) inhibitor aminoguanidine (10(-5) M each) provoked a transient depression of the current followed by a sustained potentiation. Formation of cGMP in neurointermediate lobes was enhanced by L-Arg (10(-4) M) and by the calcium-releasing agent caffeine (10(-4) M), and inhibited by the calmodulin (CaM)/Ca2+ complex blocker W7 (10(-5) M). The GABA-evoked current was potentiated by the guanylyl cyclase inhibitor ODQ (10(-8)-10(-7) M) and inhibited by the protein kinase G (PKG) activator 8pCPT-cGMP (3 x 10(-7)-3 x 10(-5) M). The present data indicate that NO, produced by a CaM/Ca2+-dependent NOS in frog melanotrophs, exerts an autocrine inhibitory effect on the GABA-evoked current. The action of NO on the GABA(A) receptor function is mediated through activation of the cGMP/PKG pathway.
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PMID:Regulation of the GABA(A) receptor by nitric oxide in frog pituitary melanotrophs. 1096 18

Synaptic circuitry in the rat lateral amygdala (AL) was studied in brain slices using electrophysiological recordings. Electrical stimulation of external and internal capsules evoked an EPSC followed by a sequence of GABA(A) and GABA(B) receptor-mediated IPSC in principal neurons. Paired stimulation of either afferents resulted in a significant reduction ( approximately 45%) of the second GABA(A) receptor-mediated IPSC. A priming stimulation, consisting of a priming pulse to one pathway followed by a pulse to the other pathway, resulted in a strong depression of the second IPSC basically identical to that during paired stimulation. Paired- and primed-pulse depressions were largely relieved by 10 micrometer CGP 55845A, indicating regulation through presynaptic GABA(B) receptors. Furthermore, putative interneurons responded with EPSCs of constant latencies to minimal stimulation of both cortical and thalamic fibers, indicating convergent monosynaptic input. At higher stimulation strength, an approximately 15% reduction of EPSCs occurred in interneurons after paired and primed stimulation, which was not sensitive to CGP 55845A. These findings indicate that a rather homogeneous population of interneurons exists in the AL with respect to their afferent connectivity, in that they receive convergent input through putative thalamic and cortical fibers, both directly and indirectly (through principal neurons), and mediate inhibitory control of postsynaptic principal neurons. This symmetrically built GABAergic circuitry can be of functional significance, given the distinctive role of the two afferent input systems for the mediation of different components of fear responses and the importance of GABAergic mechanisms for limitation of excessive neuronal activity.
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PMID:Putative cortical and thalamic inputs elicit convergent excitation in a population of GABAergic interneurons of the lateral amygdala. 1110 1

The effects of 5-hydroxytryptamine (5-HT) on the inhibitory responses evoked by gamma-aminobutyric acid (GABA) in neurons of the red nucleus (RN) were studied using a microiontophoretic technique. Extracellular unitary recordings performed in anesthetized rats demonstrated that 5-HT ejection influenced GABA-evoked inhibition in 94% of RN neurons, enhancing them in 52% and depressing them in 46% of cases. Both effects were specific and dose-dependent,although enhancements or depressions of the GABA responses were respectively inversely and directly related to the doses of 5-HT applied. The type of modulation exerted by 5-HT on the GABA responses was independent of the action of the amine on background firing. In fact, 5-HT induced an enhancement of the GABA responses in neurons mostly located in the rostral RN and a depression in those in the caudal RN. The application of 8-hydroxy-2(di-n-propylamino)tetralin, a specific 5-HT(1A) receptor agonist, enhanced GABA responses, whereas alpha-methyl-5-hydroxytryptamine, a 5-HT(2A) receptor agonist, depressed them. Both the 5-HT(2) antagonist methysergide and the 5-HT(2A) selective antagonist ketanserin were able to block partially or totally the depressive action of 5-HT on GABA responses. In contrast, the same 5-HT antagonists mimicked the enhancing action of 5-HT on the GABA responses or were ineffective. Application of bicuculline, a GABA(A) receptor antagonist, enhanced the excitatory action of 5-HT on the background firing and slightly reduced the inhibitory action. It is concluded that 5-HT is able to modulate GABA-evoked responses in RN neurons by acting on both 5-HT(1A) and 5-HT(2A) receptors. The functional significance of a serotonergic control on GABAergic inhibitory effects in RN is discussed.
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PMID:Serotonin modifies the neuronal inhibitory responses to gamma-aminobutyric acid in the red nucleus: a microiontophoretic study in the rat. 1116 97

Metaplasticity is a higher-order form of synaptic plasticity that is induced by synaptic or cellular activity, which by itself may not produce changes in synaptic strength, but which modifies subsequent changes in synaptic efficacy. In this description of metaplasticity in the spinal dorsal horn, we report that a 50 Hz high-frequency tetanus, previously shown to elicit a potentiation of sciatic-evoked A-fiber spinal dorsal horn potentials, caused a depression when coupled with a more rapid rate of repetitive stimulation. This depression appeared to be dependent upon GABA(A) receptor activation because the 50 Hz tetanus elicited a persistent potentiation when the GABA(A) antagonist bicuculline was injected at 1 mg/kg (but not at 0.5 mg/kg) prior to tetanic stimulation. These data suggest the presence of strong inhibitory inputs in the spinal dorsal horn that are activated by an increased rate of primary afferent firing. The activation of these inputs may be necessary to prevent prolonged bursts of afferent activity from modifying synaptic strength because the latter may contribute to the development of persistent pain following peripheral nerve injury.
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PMID:Contribution of GABA-A receptors to metaplasticity in the spinal dorsal horn. 1116 82


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