UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.
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PMID:Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons. 946 16

1508-1517, 1998. Whole cell recordings (nystatin-perforated patch) were carried out on magnocellular neurons of the rat supraoptic nucleus (SON) to study the modulation of inhibitory postsynaptic currents (IPSCs) by gamma-aminobutyric acid-B (GABAB) receptors. Field stimulation adjacent to the SON in the presence of kynurenic acid, evoked monosynaptic GABAergic IPSCs. Baclofen reversibly reduced the amplitude of the IPSCs in a dose-dependent manner (EC50: 0.68 microM) without apparent effect on the holding current (Vh = -80 mV) or input resistance and altered neither the kinetic properties, nor the reversal potential of IPSCs. Concomittant to IPSC depression, baclofen enhanced the paired-pulse ratio for two consecutive IPSCs [interstimulus interval (ISI): 50 ms], an effect consistent with a presynaptic locus of action. Both actions of baclofen were abolished by CGP35348 (500 microM), a GABAB receptor antagonist. In testing for involvement of synaptically activated presynaptic GABAB receptors, we only recorded paired-pulse facilitation at most ISIs tested (50-500 ms), suggesting that the classical GABAB autoreceptors may not normally be activated in our conditions. However, enhancement of local GABA concentration by perfusion of a GABA uptake inhibitor (NO-711) revealed an action of endogenous GABA at these presynaptic GABAB receptors. The nonselective K+ channel blocker Ba2+ abolished baclofen's effect and pertussis toxin (PTX) pretreatment (200-500 ng/ml for 18-24 h) was ineffective in blocking the baclofen-induced inhibition, making an involvement of PTX-sensitive G protein unlikely. The present results show that presynaptic GABAB receptors that are coupled to PTX-insensitive G-proteins may be activated by endogenous GABA under conditions of reduced GABA uptake, thus regulating the inhibitory synaptic input to SON.
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PMID:Activation of presynaptic GABAB receptors inhibits evoked IPSCs in rat magnocellular neurons in vitro. 949 28

The role of G proteins in the functional modulation and potentiation by mercury chloride of the GABA(A) receptor-channel complex in rat dorsal root ganglion neurons was studied by using the whole-cell patch clamp technique. Stimulation of Gs proteins by application of GTP-gamma-S in the patch pipette or by incubation of neurons with cholera toxin reduced GABA-induced currents, suggesting modulation of GABA-induced currents via a Gs-protein-coupled pathway. GDP-beta-S in the pipette solution or pretreatment of dorsal root ganglion neurons with pertussis toxin suppressed GABA-induced currents, suggesting that basal Gi/Go-protein activity positively modulates the GABA(A) receptor-channel complex. Mercury chloride potentiation of GABA-activated currents was blocked by application of GTP-gamma-S in the patch pipette or by incubation of neurons with cholera toxin. Mercury chloride potentiation of GABA-activated currents was blocked by application of GDP-beta-S in the patch pipette or by incubation of neurons with pertussis toxin. G proteins, probably Gi/Go proteins, underlie the mercury chloride potentiation of GABA-induced currents.
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PMID:The role of G proteins in the activity and mercury modulation of GABA-induced currents in rat neurons. 951 33

GABA and the GABA(B) receptor agonist (-)-baclofen inhibited 4-aminopyridine (4AP)- and KCl-evoked, Ca2+-dependent glutamate release from rat cerebrocortical synaptosomes. The GABA(B) receptor antagonist CGP 35348, prevented this inhibition of glutamate release, but phaclofen had no effect. (-)-Baclofen-mediated inhibition of glutamate release was insensitive to 2 microg/ml pertussis toxin. As determined by examining the mechanism of GABA(B) receptor modulation of glutamate release, (-)-baclofen caused a significant reduction in 4AP-evoked Ca2+ influx into synaptosomes. The agonist did not alter the resting synaptosomal membrane potential or 4AP-mediated depolarization; thus, the inhibition of Ca2+ influx could not be attributed to GABA(B) receptor activation causing a decrease in synaptosomal excitability. Ionomycin-mediated glutamate release was not affected by (-)-baclofen, indicating that GABA(B) receptors in this preparation are not coupled directly to the exocytotic machinery. Instead, the data invoke a direct coupling of GABA(B) receptors to voltage-dependent Ca2+ channels linked to glutamate release. This coupling was subject to regulation by protein kinase C (PKC), because (-)-baclofen-mediated inhibition of 4AP-evoked glutamate release was reversed when PKC was stimulated with phorbol ester. This may therefore represent a mechanism by which inhibitory and facilitatory presynaptic receptor inputs interplay to fine-tune transmitter release.
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PMID:Presynaptic GABA(B) receptor modulation of glutamate exocytosis from rat cerebrocortical nerve terminals: receptor decoupling by protein kinase C. 952 68

1. Voltage-dependent Ca2+ currents of dissociated rat supraoptic nucleus (SON) neurones were measured using the whole-cell configuration of the patch-clamp technique to examine direct postsynaptic effects of GABAB receptor activation on SON magnocellular neurones. 2. The selective GABAB agonist baclofen reversibly inhibited voltage-dependent Ca2+ currents elicited by voltage steps from a holding potential of -80 mV to depolarized potentials in a dose-dependent manner. The ED50 of baclofen for inhibiting Ca2+ currents was 1.4 x 10-6 M. Baclofen did not inhibit low threshold Ca2+ currents elicited by voltage steps from -120 to -40 mV. 3. Inhibition of high threshold Ca2+ currents by baclofen was rapidly and completely reversed by the selective GABAB antagonists, CGP 35348 and CGP 55845A, when the antagonists were added at the molar ratio vs. baclofen of 10 : 1 and 0.01 : 1, respectively. It was also reversed by a prepulse to +150 mV lasting for 100 ms. 4. The inhibition of Ca2+ currents was abolished when the cells were pretreated with pertussis toxin for longer than 20 h or with N-ethylmaleimide for 2 min. It was also abolished when GDPbetaS was included in the patch pipette. When GTPgammaS was included in the patch pipette, baclofen produced irreversible inhibition of Ca2+ currents and this inhibition was again reversed by the prepulse procedure. 5. The inhibition of N-, P/Q-, L- and R-type Ca2+ channels by baclofen (10-5 M) was 24.1, 10.5, 3.1 and 3. 6 %, respectively, of the total Ca2+ currents. Only the inhibition of N- and P/Q-types was significant. 6. These results suggest that GABAB receptors exist in the postsynaptic sites of the SON magnocellular neurones and mediate selective inhibitory actions on voltage-dependent Ca2+ channels of N- and P/Q-types via pertussis toxin-sensitive G proteins, and that such inhibitory mechanisms may play a role in the regulation of SON neurones by the GABA neurones.
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PMID:Inhibition of N- and P/Q-type calcium channels by postsynaptic GABAB receptor activation in rat supraoptic neurones. 957 87

The cytotoxic action of the gamma-isomer of hexachlorocyclohexane (gamma-HCH, lindane) was studied in cultured mouse cerebellar granule neurons maintained in the presence or absence of the GABA(A) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). The cells were exposed for 24 hr to lindane (30-300 microM) in the culture medium. Changes in mitochondrial function were investigated by using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. The results showed that lindane-induced cytotoxicity was concentration-dependent. In cerebellar granule cells not treated with THIP, lindane-induced cytotoxicity did not appear to be related to GABA(A) or GABA(B) receptors. However, in THIP-treated cultures, lindane-induced cytotoxicity was found to be mediated by an action of the insecticide on GABA receptors. In the latter case, GABA reduced the lindane-induced cytotoxicity, but the protective effect was not potentiated by flunitrazepam. The GABA(A) receptor agonist muscimol (50 microM) also protected the THIP-treated cultures against lindane-induced cytotoxicity. In addition, the GABA(B) receptor agonist R(+)baclofen protected the cells from lindane-induced cytotoxicity and the effect of baclofen was blocked by GABA(B) receptor antagonists. Pertussis toxin was found to reverse the protective effect of baclofen only at the highest lindane concentration (300 microM). The lindane-induced cytotoxicity could be partly explained as being secondary to excitotoxicity as a mixture of the excitatory amino acid receptor antagonists APV (D-(-)-2-amino-5-phosphonopentanoate) and CNQX (6-cyano-7-nitro-quinoxaline-2,3-dione) shifted the concentration-response curve for lindane-induced cytotoxicity to the right. It is suggested that the cytotoxic effects of lindane in THIP-treated cerebellar granule neurons are primarily related to an action of lindane on GABA(B) receptors and to a lesser extent on inducible low-affinity, benzodiazepine insensitive GABA(A) receptors.
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PMID:Cytotoxic action of lindane in cerebellar granule neurons is mediated by interaction with inducible GABA(B) receptors. 959 Apr 37

Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 micromol/kg, and 2.6 and 1.2 micromol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 micromol/site, and 0.4 and 0.9 micromol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 micromol/kg, 2.2 micromol/paw, 0.4 micromol/site and 0.14 micromol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 micromol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin. interaction of ATP-sensitive K+ channels, GABA(B) receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
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PMID:Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action. 959 21

The effect of pretreatment with pertussis toxin at the doses of 0.25 and 0.50 microg per mouse ICV on the amnesic effect produced by baclofen (0.1 4 mg kg(-1) i.p.), diphenhydramine (15-30 mg kg(-1) i.p.) and scopolamine (0.5-5 mg kg(-1) i.p.) was investigated in the mouse passive avoidance test. Ten days after a single injection of pertussis toxin, baclofen (2 4 mg kg(-1) i.p.) amnesia was prevented. By contrast, pertussis toxin had no effect on diphenhydramine- and scopolamine-induced amnesia. Pretreatment with pertussis toxin at both doses used did not impair motor coordination of the mice, as revealed by the rota-rod test. The present results indicate that the activation of pertussis toxin-sensitive G-proteins represents an important transduction step in memory impairment induced by GABA(B) (gamma-aminobutyric acid B) agonists, but not by antihistaminic and antimuscarinic drugs.
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PMID:Effect of pertussis toxin on baclofen- and diphenhydramine-induced amnesia. 960 May 77

The mechanism through which kainate receptors downregulate the release of GABA in the hippocampus is not known. We have found that the action of kainate on the hippocampal inhibitory postsynaptic current (IPSC) is mediated by a metabotropic process that is sensitive to Pertussis toxin (PTx) and independent of ion channel current. The downregulation of GABA IPSCs by kainate was also prevented in a dose-dependent manner by calphostin C, a specific inhibitor of PKC, and the inhibition of phospholipase C (PLC) drastically reduced the action of kainate. The effect of kainate was completely occluded by phorbol esters and by increasing extracellular Ca2+ but remained unaltered after inhibition or activation of protein kinase A (PKA). These results demonstrate that the activation of kainate receptors triggers a second messenger cascade, which results in the stimulation of PKC, and therefore document a metabotropic action of kainate receptors, which results in the inhibition of GABA release.
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PMID:Kainate receptor modulation of GABA release involves a metabotropic function. 965 8

1. The modulatory effect of 5-hydroxytryptamine (5-HT) on the gamma-aminobutyric acid(A) (GABA(A)) response was investigated in the neurones freshly dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under the voltage-clamp conditions. 2. 5-HT potentiated GABA-induced Cl- current (IGABA) without affecting the reversal potential of IGABA and the apparent affinity of GABA to its receptor. 3. Alpha-Methyl-5-HT mimicked the potentiation effect of 5-HT on IGABA while ketanserine blocked it. 1-Oleoyl-2-acetyl-glycerol (OAG) potentiated IGABA, and the effect of 5-HT on IGABA was occluded by OAG pretreatment. In the presence of chelerythrine, 5-HT failed to potentiate IGABA, suggesting that protein kinase C (PKC) is involved in the pathway through which the activation of the 5-HT2 receptor potentiates the IGABA. 4. The facilitatory effect of 5-HT on IGABA remained in the presence of BAPTA-AM. LiCl also had no effect on 5-HT-induced potentiation of IGABA. 5. H-89, genistein, okadaic acid and pervanadate all had no effects on 5-HT potentiation of IGABA. Pertussis toxin treatment for 6-8 h did not block the facilitatory effect of 5-HT on IGABA. 6. The present results show that GABA(A) receptor in the rat SDCN could be modulated in situ by 5-HT, one of the major transmitters involved in the supraspinal control of nociception, and that the phosphorylation of GABA(A) receptor by PKC may be sufficient to support such modulation. The results also strongly support the hypothesis that the cotransmission by 5-HT and GABA has an important role in the spinal cord.
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PMID:5-HT potentiation of the GABA(A) response in the rat sacral dorsal commissural neurones. 969 Aug 71

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