Glutamatergic and dopaminergic contributions to rat bladder hyperactivity after cerebral artery occlusion.
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The contribution of glutamatergic and dopaminergic mechanisms to bladder hyperactivity after left middle cerebral artery occlusion was evaluated by determining the effects of intravenous cumulative doses of an N-methyl-D-aspartate (NMDA) glutamatergic antagonist (MK-801) and D1-selective (Sch-23390), D2-selective (sulpiride), or nonselective (haloperidol) dopaminergic antagonists on bladder activity in sham-operated (SO) and cerebral-infarcted (CI) rats. MK-801 (1 and 10 mg/kg) or sulpiride (3-30 mg/kg) significantly increased bladder capacity (BC) in CI but decreased or had no effect, respectively, on BC in SO. Sch-23390 (0.1-3 mg/kg) decreased BC in both SO and CI. In both CI and SO, low doses of haloperidol (0.1-1 mg/kg) increased BC, but a higher dose (3 mg/kg) reversed this effect. Administration of haloperidol (0.3 mg/kg) or sulpiride (10 mg/kg) in combination with MK-801 (0.01-10 mg/kg) markedly increased BC in CI but produced small decreases or increases in BC depending on the dose of MK-801 in SO. These results indicate that the bladder hyperactivity induced by cerebral infarction is mediated in part by NMDA glutamatergic and D2 dopaminergic excitatory mechanisms. (+info)
Midline medullary depressor responses are mediated by inhibition of RVLM sympathoexcitatory neurons in rats.
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Mechanisms underlying the depressor and sympathoinhibitory responses evoked from the caudal medullary raphe (MR) region were investigated in pentobarbital sodium-anesthetized, paralyzed rats. Intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 200 microA) of the MR elicited a mixed sympathetic response that consisted of a long-latency sympathoexcitatory (SE) peak (onset = 146 +/- 7 ms) superimposed on an inhibitory phase (onset = 59 +/- 10 ms). Chemical stimulation of the MR (glutamate; Glu) most frequently elicited depressor responses accompanied by inhibition of sympathetic nerve discharge. Occasionally, these responses were preceded by transient pressor and SE responses. We examined the influence of intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 25-200 microA) and Glu stimulation of the MR on the discharge of rostral ventrolateral medulla (RVLM) premotor SE neurons. Peristimulus-time histograms of RVLM unit discharge featured a prominent inhibitory phase in response to MR stimulation (onset = 20 +/- 2 ms; duration = 42 +/- 4 ms; n = 12 units). Glu stimulation of the MR reduced blood pressure (-37 +/- 2 mmHg, n = 19) and inhibited the discharge of RVLM SE neurons (15 of 19 neurons). Depressor and sympathoinhibitory responses elicited by chemical and electrical stimulation of the MR region are mediated by inhibition of RVLM premotor SE neurons and withdrawal of sympathetic vasomotor discharge. (+info)
Cholinergic systems in the nucleus of the solitary tract of rats.
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The pharmacological and physiological properties of excitatory amino acid and ACh systems in the nucleus of the solitary tract (NTS) were studied in slices of rat brain stem by extracellular and intracellular recordings from neurons activated by solitary tract (ST) stimulation. These neurons were characterized as having several long dendrites with multiple varicosities. Synaptic activation of the medial NTS (mNTS) neurons by ST stimulation was mediated by non-N-methyl-D-aspartate (NMDA) glutamate (Glu) receptors, because the excitation was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione but not by NMDA, nicotinic, or muscarinic antagonists. Identified mNTS neurons were excited by iontophoresis of both Glu and ACh. The most sensitive region of the cell was on the dendrites approximately 100 micrometer from the cell body for both putative neurotransmitters. Nicotinic and/or muscarinic excitatory ACh responses were detected on the mNTS neurons. Our observations suggest that both types of ACh receptors may contribute to the attenuation of the baroreceptor reflex, but the functional correlation of this receptor profile remains to be determined. (+info)
Tonic drive to sympathetic premotor neurons of rostral ventrolateral medulla from caudal pressor area neurons.
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The responses of sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) to activation or inactivation of neurons in the caudal pressor area (CPA) were studied in urethan-anesthetized rats. Extracellular recordings were made from 32 barosensitive single units in the RVLM, of which 26 were antidromically activated from the cervical cord. Unilateral microinjections of L-glutamate (0.5-5 nmol) into the CPA increased firing in 13 of 14 premotor neurons by 90 +/- 30% while raising blood pressure. Both ipsilateral and contralateral injections were effective. Unilateral or bilateral inhibition of CPA neuron activity by microinjecting glycine (5-200 nmol/side) lowered blood pressure, while it reduced firing in 9 of 10 and 16 of 17 premotor neurons, respectively, by 45 +/- 9 and 39 +/- 6%. A significant proportion of tonic activity in RVLM sympathetic premotor neurons is thus driven, directly or indirectly, by neurons in the CPA. (+info)
Stimulation of cystine uptake by nitric oxide: regulation of endothelial cell glutathione levels.
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Nitric oxide (NO) is known to produce some of its biological activity through modification of cellular thiols. Return of cellular thiols to their basal state requires the activity of the GSH redox cycle, suggesting important interactions between NO signaling and regulation of cellular redox status. Because continuous exposure to NO may lead to adaptive responses in cellular redox systems, we investigated the effects of NO on cellular GSH levels in vascular endothelial cells. Acute exposure (1 h) of cells to >1 mM S-nitroso-N-acetyl-penicillamine (SNAP) led to depletion of GSH. On the other hand, chronic exposure to lower concentrations of SNAP (+info)
Glutamate regulates IP3-type and CICR stores in the avian cochlear nucleus.
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Neurons of the avian cochlear nucleus, nucleus magnocellularis (NM), are activated by glutamate released from auditory nerve terminals. If this stimulation is removed, the intracellular calcium ion concentration ([Ca2+]i) of NM neurons rises and rapid atrophic changes ensue. We have been investigating mechanisms that regulate [Ca2+]i in these neurons based on the hypothesis that loss of Ca2+ homeostasis causes the cascade of cellular changes that results in neuronal atrophy and death. In the present study, video-enhanced fluorometry was used to monitor changes in [Ca2+]i stimulated by agents that mobilize Ca2+ from intracellular stores and to study the modulation of these responses by glutamate. Homobromoibotenic acid (HBI) was used to stimulate inositol trisphosphate (IP3)-sensitive stores, and caffeine was used to mobilize Ca2+ from Ca2+-induced Ca2+ release (CICR) stores. We provide data indicating that Ca2+ responses attributable to IP3- and CICR-sensitive stores are inhibited by glutamate, acting via a metabotropic glutamate receptor (mGluR). We also show that activation of C-kinase by a phorbol ester will reduce HBI-stimulated calcium responses. Although the protein kinase A accumulator, Sp-cAMPs, did not have an effect on HBI-induced responses. CICR-stimulated responses were not consistently attenuated by either the phorbol ester or the Sp-cAMPs. We have previously shown that glutamate attenuates voltage-dependent changes in [Ca2+]i. Coupled with the present findings, this suggests that in these neurons mGluRs serve to limit fluctuations in intracellular Ca2+ rather than increase [Ca2+]i. This system may play a role in protecting highly active neurons from calcium toxicity resulting in apoptosis. (+info)
Long-term potentiation in the dentate gyrus is not linked to increased extracellular glutamate concentration.
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Long-term potentiation (LTP) of excitatory transmission is a likely candidate for the encoding and storage of information in the mammalian brain. There is a general agreement that LTP involves an increase in synaptic strength, but the mechanisms underlying this persistent change are unclear and controversial. Synaptic efficacy may be enhanced because more transmitter glutamate is released or because postsynaptic responsiveness increases or both. The purpose of this study was to examine whether increased extracellular glutamate concentration was associated with the robust and well-characterized LTP that can be induced in the rat dentate gyrus. To favor the detection of any putative change in extracellular glutamate associated with LTP, our experimental strategy included the following features. 1) Two separate series of experiments were carried out with animals under pentobarbital or urethan anesthesia; 2) changes in extracellular concentration of glutamate were monitored continuously by microdialysis coupled to enzyme amperometry; and 3) dialysate glutamate levels and changes in the slope of excitatory postsynaptic potential evoked by activation of the perforant path were recorded precisely at the same site. Tetanic stimulation of the perforant path increased persistently test-evoked responses in the dentate gyrus (by 19 and 14% in barbiturate and urethan group, respectively), but there was no glutamate change either during or after LTP induction and no indication of increased glutamate efflux when low-frequency stimulation was applied. The results do not rule out a possible contribution of enhanced glutamate exocytosis to LTP induction and/or maintenance because such a presynaptic change may not be detectable extracellularly. However, our findings and other data supporting the notion that neurotransmitter glutamate may hardly leak out of the synaptic cleft conflict with the hypothesis that LTP could also involve a broad synaptic spillover of glutamate. (+info)
We have previously shown that injection of mustard oil or glutamate into rat temporomandibular joint (TMJ) tissues, an experimental model of acute TMJ injury, can reflexly induce a prolonged increase in the activity of both digastric (jaw-opener) and masseter (jaw-closer) muscles. In this study, GABA was applied to the TMJ region by itself or in combination with glutamate, and the magnitude of evoked jaw muscle electromyographic (EMG) activity was measured. Application of GABA alone to the TMJ region did not evoke significant jaw muscle EMG activity when compared with normal saline controls. In contrast, co-application of GABA and glutamate into the TMJ region decreased the magnitude of glutamate-evoked EMG activity. This GABA-mediated inhibition of glutamate-evoked EMG activity followed an inverse dose-response relationship with an estimated median inhibitory dose (ID50) of 0.17 +/- 0.05 (SE) micromol and 0.031 +/- 0.006 micromol for the digastric and masseter muscles, respectively. Co-administration of the GABAA receptor antagonist bicuculline (0.05 micromol) but not the GABAB receptor antagonist phaclofen (0.05 or 0. 15 micromol) reversed the suppressive actions of GABA, indicating that this action of GABA may be mediated by peripheral GABAA receptors located within the TMJ region. Our results suggest that activation of peripheral GABAA receptors located within the TMJ region could act to decrease the transmission of nociceptive information. (+info)