Home About us Contact
|
Home About us Contact | ||
|
|
||
Tonic Inhibition (tonic + inhibition)
Selected AbstractsThe impact of diazepam's discovery on the treatment and understanding of status epilepticusEPILEPSIA, Issue 9 2009Howard P. Goodkin Summary The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of ,-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a ,2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive , subunit,containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA-mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABAA receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity-dependent, subunit-specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine-sensitive ,2 subunit,containing receptors and the preserved surface expression of the benzodiazepine-insensitive , subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE. [source] GAT-1 regulates both tonic and phasic GABAA receptor-mediated inhibition in the cerebral cortexJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Luca Bragina Abstract ,-Aminobutyric acid 1 (GAT-1) is the most copiously expressed GABA transporter; we studied its role in phasic and tonic inhibition in the neocortex using GAT-1 knockout (KO) mice. Immunoblotting and immunocytochemical studies showed that GAT-2 and GAT-3 levels in KOs were unchanged and that GAT-3 was not redistributed in KOs. Moreover, the expression of GAD65/67 was increased, whereas that of GABA or VGAT was unchanged. Microdialysis studies showed that in KOs spontaneous extracellular release of GABA and glutamate was comparable in WT and KO mice, whereas KCl-evoked output of GABA, but not of glutamate, was significantly increased in KOs. Recordings from layer II/III pyramids revealed a significant increase in GABAAR-mediated tonic conductance in KO mice. The frequency, amplitude and kinetics of spontaneous inhibitory post-synaptic currents (IPSCs) were unchanged, whereas the decay time of evoked IPSCs was significantly prolonged in KO mice. In KO mice, high frequency stimulation of GABAergic terminals induced large GABAAR-mediated inward currents associated with a reduction in amplitude and decay time of IPSCs evoked immediately after the train. The recovery process was slower in KO than in WT mice. These studies show that in the cerebral cortex of GAT-1 KO mice GAT-3 is not redistributed and GADs are adaptively changed and indicate that GAT-1 has a prominent role in both tonic and phasic GABAAR-mediated inhibition, in particular during sustained neuronal activity. [source] Lactobacillus reuteri ingestion and IKCa channel blockade have similar effects on rat colon motility and myenteric neuronesNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2010B. Wang Abstract, Background, We have previously shown that ingestion of Lactobacillus reuteri may modulate colonic enteric neuron activity but with unknown effects on colon motility. The aim of the present report was to elucidate the neuronal mechanisms of action of the probiotic by comparing the effects on motility of L. reuteri ingestion with blockade of a specific ionic current in enteric neurons. Methods, We have used intraluminal pressure recordings from ex vivo rat colon segments and whole cell patch clamp recordings from neurons of rat longitudinal muscle myenteric plexus preparations to investigate the effects of L. reuteri and TRAM-34 on colon motility and neurophysiology. The effects of daily feeding of 109L. reuteri bacteria or acute application of TRAM-34 on threshold fluid filling pressure or pulse pressure was measured. Key Results,Lactobacillus reuteri increased intraluminal fluid filling pressure thresholds for evoking pressure pulses by 51% from 0.47 ± 0.17 hPa; the probiotic also decreased the pulse pressure amplitudes, but not frequency, by 18% from 3.91 ± 0.52 hPa. The intermediate conductance calcium-dependent potassium (IKCa) channel blocker TRAM-34 (3 ,mol L,1) increased filling threshold pressure by 43% from 0.52 ± 0.22 hPa and reduced pulse pressure amplitude by 40% from 2.63 ± 1.11 hPa; contraction frequency was unaltered. TRAM-34 (3 ,mol L,1) reduced membrane polarization, leak conductance and the slow afterhyperpolarization current in 16/16 myenteric rat colon AH cells but 19/19 S cells were unaffected. Conclusions & Inferences, The present results are consistent with L. reuteri enhancing tonic inhibition of colon contractile activity by acting via the IKCa channel current in AH cells. [source] Pre- and postsynaptic modulation of monosynaptic reflex by GABAA receptors on turtle spinal cordTHE JOURNAL OF PHYSIOLOGY, Issue 14 2010Wendy Bautista There is growing evidence that activation of high affinity extrasynaptic GABAA receptors in the brain, cerebellum and spinal cord substantia gelatinosa results in a tonic inhibition controlling postsynaptic excitability. The aim of the present study was to determine if GABAA receptors mediating tonic inhibition participate in the modulation of monosynaptic reflex (MSR) in the vertebrate spinal cord. Using an in vitro turtle lumbar spinal cord preparation, we show that conditioning stimulation of a dorsal root depressed the test monosynaptic reflex (MSR) at long condition,test intervals. This long duration inhibition is similar to the one seen in mammalian spinal cord and it is dependent on GABAA as it was completely blocked by 20 ,m picrotoxin (PTX) or bicuculline (BIC) or 1 ,m gabazine, simultaneously depressing the dorsal root potential (DRP) without MSR facilitation. Interestingly 100 ,m picrotoxin or BIC potentiated the MSR, depressed the DRP, and produced a long lasting motoneurone after-discharge. Furosemide, a selective antagonist of extrasynaptic GABAA receptors, affects receptor subtypes with ,4/6 subunits, and in a similar way to higher concentrations of PTX or BIC, also potentiated the MSR but did not affect the DRP, suggesting the presence of ,4/6 GABAA receptors at motoneurones. Our results suggest that (1) the turtle spinal cord has a GABAA mediated long duration inhibition similar to presynaptic inhibition observed in mammals, (2) GABAA receptors located at the motoneurones and primary afferents might produce tonic inhibition of monosynaptic reflex, and (3) GABAA receptors modulate motoneurone excitability reducing the probability of spurious and inappropriate activation. [source] Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 8 2010Martin Mortensen The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of ,1,3,2, ,4,3,2 and ,4,3, receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At , subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on ,4,3, receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. [source] Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal culturesTHE JOURNAL OF PHYSIOLOGY, Issue 2 2006Jin-shun Qi Deficits in GABAergic inhibitory transmission are a hallmark of temporal lobe epilepsy and have been replicated in animal and tissue culture models of epilepsy. GABAergic inhibition comprises phasic and tonic inhibition that is mediated by synaptic and extrasynaptic GABAA receptors, respectively. We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo. Here, we report a downregulation of tonic GABA inhibition after chronic epileptogenic stimulation of rat hippocampal cultures. Chronic pretreatment of hippocampal neurons with CTZ or KA resulted in a marked reduction in GABAergic inhibition, as shown by a significant decrease in whole-cell GABA currents and in the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Interestingly, synaptically localized GABAA receptors remained relatively stable, as evidenced by the unaltered amplitude of mIPSCs, as well as the unchanged punctate immunoreactivity of ,2 subunit-containing postsynaptic GABAA receptors. In contrast, tonic GABA currents, assessed either by a GABAA receptor antagonist bicuculline or a selective extrasynaptic GABAA receptor agonist THIP, were significantly reduced following epileptogenic stimulation. These results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GABAA receptors unchanged. Thus, in addition to synaptic alteration of GABAergic transmission, regulation of tonic inhibition may also play an important role during epileptogenesis. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Effect of the Destruction of Cells Containing the Serotonin Reuptake Transporter on Urethrogenital ReflexesTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2007Karla Gravitt BSc ABSTRACT Introduction., The urethrogenital (UG) reflex is an autonomic and somatic response that mimics some of the physiological changes seen during ejaculation. The UG reflex is tonically inhibited by neurons in the ventral medulla, an area containing serotonin neurons. Aim., To examine the effect of lesions of brain neurons containing the serotonin reuptake transporter (SERT) on ejaculatory-like reflexes. Methods., Anti-SERT saporin (80 nL, 1 mM) or saline was injected bilaterally into the ventrolateral medulla of male Sprague,Dawley rats. Ten to 18 days later, animals were deeply anesthetized and the presence of the UG reflex was examined before and after acute spinal cord transection (T9,10). Following the experiment the presence and number of serotonin and norepinephrine containing neurons (using tryptophan hydroxylase and dopamine beta-hydroxylase, respectively) was performed. Main Outcome Measures., The UG reflex and cell counts. Results., In saline-injected controls the UG reflex was not evoked in the anesthetized, intact preparation, indicating the presence of the supraspinal inhibition, as previously reported. Injection of anti-SERT saporin into the ventrolateral medulla allowed the UG reflex to be activated in the intact preparation, thus removed the inhibition. This was associated with a decrease in the number of serotonin neurons in the ventrolateral medulla and raphe. No change in the number of noradrenergic neurons was observed. Conclusion., These studies suggest that ventral medullary neurons containing SERT are involved in the tonic inhibition of the UG reflex. Gravitt K, and Marson L. Effect of the destruction of cells containing the serotonin reuptake transporter on urethrogenital Reflexes. J Sex Med 2007;4:322,331. [source] Development of Galanin-Containing Nerve Fibres in Rat TibiaANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2 2009M. Gajda Summary Galanin exerts tonic inhibition of nociceptive input to the central nervous system. Recently, this peptide was demonstrated in several neuronal and non-neuronal structures in bones and joints. In this study, the time of appearance and topographic localization of galanin-containing nerve fibres in bone were studied in rats from gestational day 16 (GD16) to postnatal day 21 (PD21). The tibia was chosen as a model of developing long bone and indirect immunofluorescence combined with confocal laser scanning microscopy was used to identify galanin-immunoreactive (GAL-IR) nerve fibres. The earliest, sparse GAL-IR fibres were observed on GD21 in the perichondrium of both epiphyses and in the periosteum of the diaphysis. From PD1 onwards, GAL-IR fibres were also seen in the bone marrow cavity and in the region of the inter-condylar eminence of the knee joint. Intramedullary GAL-IR fibres in proximal and distal metaphyses appeared around PD1. Some of them accompanied blood vessels, although free fibres were also seen. GAL-IR fibres located in the cartilage canals of both epiphyses were observed from PD7, in the secondary ossification centres from PD10 and in the bone marrow of both epiphyses from PD14. The time course and localization of galanin-containing nerve fibres resemble the development of substance P- and CGRP-expressing nerve fibres, thus suggesting their sensory origin. [source] | |||||||||||||