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1.
Article in English | MEDLINE | ID: mdl-34263262

ABSTRACT

OBJECTIVE: To examine how 1Hz and 10Hz rTMS temporarily influence ratings of tinnitus loudness, annoyance, and awareness. The thalamocortical dysrhythmia (TCD) model of tinnitus was tested by examining changes in spectral power and coherence of resting state EEGs from baseline to each phase of treatment and correlating these data with change in tinnitus. METHODS: Nineteen participants completed a double-blind, placebo (sham rTMS) controlled, within-subjects study with crossover between the two active rTMS treatment conditions. An imposed order effect, sham rTMS first, eliminated drift of active treatment into the placebo condition. The primary outcome measures were analogue ratings of tinnitus loudness, annoyance, and awareness, assessed repeatedly at baseline and during treatment, and 64 channel, resting state EEGs collected at baseline and the end of each treatment phase. Active rTMS consisted of 1800 pulses at 110% of motor threshold over temporal cortex delivered at 1Hz and 10Hz over four days. The research design also examined the effect of rTMS immediately following stimulation, regression to the mean in tinnitus ratings made over multiple days, and differences between treatment responders and non-responders. RESULTS: There was no immediate effect of rTMS on tinnitus during a single rTMS session. Regression to the mean in tinnitus ratings occurred over three days of baseline and four days of treatment (both sham and active rTMS). After accounting for regression to the mean in the statistical model, 1Hz rTMS led to a significant decrease in tinnitus awareness from baseline and 10Hz rTMS trended in the same direction, whereas sham rTMS showed little change from baseline other than regression to the mean. Changes from baseline in spectral power of the resting state EEG provided partial support for predictions based on TCD model of tinnitus for active 1 and 10Hz rTMS but not sham rTMS. However, only an increase in beta coherence correlated significantly with a decrease in tinnitus awareness. Changes in the EEG were robust in treatment responders but absent among non-responders and during sham rTMS. CONCLUSIONS: A positive response to rTMS for tinnitus is associated with an rTMS-induced change in beta coherence of the EEG. Increased beta coherence may be a biomarker of the rTMS effect; a "top-down" modulation of the EEG that promotes habituation to tinnitus. Participants whose tinnitus did not improve after rTMS did not show any changes in the EEG.

2.
Neuroscience ; 169(3): 1438-48, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20542091

ABSTRACT

Ethanol exposure during postnatal days (PN) 4-6 in rats alters cerebellar development resulting in significant loss of Purkinje cells. There is little knowledge, however, on what happens to the neurons that survive. In this study, rat pups were treated with a daily dose of ethanol (either 3.6 or 4.5 g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. Then the interactions between climbing fibers and Purkinje cells were examined on PN14 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced in the PN4 and PN4-6 ethanol groups for the 4.5 g/kg dose level, compared to controls, indicating that the cerebellar circuitry was significantly altered following developmental ethanol exposure. Not only were there fewer Purkinje cells following ethanol exposure, but the surviving neurons had significantly fewer VGluT2-labeled synapses. These alterations in the synaptic integrity were both dose dependent and temporally dependent.


Subject(s)
Ethanol/pharmacology , Olivary Nucleus/drug effects , Purkinje Cells/drug effects , Synapses/drug effects , Animals , Animals, Newborn , Calbindin 1 , Calbindins , Cell Count , Cell Survival , Cerebellar Cortex/cytology , Cerebellar Cortex/drug effects , Cerebellar Cortex/growth & development , Ethanol/blood , Olivary Nucleus/growth & development , Olivary Nucleus/physiology , Purkinje Cells/cytology , Rats , Rats, Sprague-Dawley , S100 Calcium Binding Protein G/metabolism , Synapses/ultrastructure , Time Factors , Vesicular Glutamate Transport Protein 2/metabolism
3.
J Neurophysiol ; 104(1): 463-74, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20463196

ABSTRACT

The pedunculopontine nucleus (PPN) is involved in the activated states of waking and paradoxical sleep, forming part of the reticular activating system (RAS). The studies described tested the hypothesis that single unit and/or population responses of PPN neurons are capable of generating gamma band frequency activity. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. Regardless of cell type (I, II, or III) or type of response to the nonselective cholinergic receptor agonist carbachol (excitation, inhibition, biphasic), almost all PPN neurons fired at gamma band frequency, but no higher, when subjected to depolarizing steps (50 +/- 2 Hz, mean +/- SE). Nonaccommodating neurons fired at 18-100 Hz throughout depolarizing steps, while most accommodating neurons exhibited gamma band frequency of action potentials followed by gamma band membrane oscillations. These oscillations were blocked by the sodium channel blocker tetrodotoxin (TTX), suggesting that at least some are mediated by sodium currents. Population responses in the PPN showed that carbachol induced peaks of activation in the theta and gamma range, while glutamatergic receptor agonists induced overall increases in activity at theta and gamma frequencies, although in differing patterns. Gamma band activity appears to be a part of the intrinsic membrane properties of PPN neurons, and the population as a whole generates different patterns of gamma band activity under the influence of specific transmitters. Given sufficient excitation, the PPN may impart gamma band activation on its targets.


Subject(s)
Electroencephalography/drug effects , Pedunculopontine Tegmental Nucleus/physiology , Action Potentials/physiology , Animals , Carbachol/pharmacology , Electrophysiological Phenomena , Excitatory Amino Acid Agonists/pharmacology , Female , Kainic Acid/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Muscarinic Agonists/pharmacology , N-Methylaspartate/pharmacology , Neurons/drug effects , Neurons/physiology , Patch-Clamp Techniques , Pedunculopontine Tegmental Nucleus/cytology , Pedunculopontine Tegmental Nucleus/drug effects , Potassium Channel Blockers/pharmacology , Potassium Channels/physiology , Pregnancy , Rats , Rats, Sprague-Dawley , Sodium Channel Blockers/pharmacology , Tetrodotoxin/pharmacology , Theta Rhythm/drug effects
4.
Neuroscience ; 142(1): 203-21, 2006 Sep 29.
Article in English | MEDLINE | ID: mdl-16876327

ABSTRACT

Field potentials recorded in the olfactory bulb glomerular layer (GL) are thought to result mainly from activation of mitral and tufted cells. The contribution of juxtaglomerular cells (JG) is unknown. We tested the hypothesis that JG are the main driving force to novel spontaneous glomerular layer field potentials (sGLFPs), which were recorded in rat olfactory bulb slices maintained in an interface chamber. We found that sGLFPs have comparable magnitudes, durations and frequencies both in standard horizontal slices, where all layers with all cell types were present, and in isolated GL slices, where only JG cells were preserved. Hence, the impact of mitral and deep/medium tufted cells to sGLFPs turned out to be minor. Therefore, we propose that the main generators of sGLFPs are JG neurons. We further explored the mechanism of generation of sGLFPs using a neuronal ensemble model comprising all types of cells associated with a single glomerulus. Random orientation and homogenous distribution of dendrites in the glomerular neuropil along with surrounding shell of cell bodies of JG neurons resulted in substantial spatial restriction of the generated field potential. The model predicts that less than 20% of sGLFP can spread from one glomerulus to an adjacent one. The contribution of JG cells to the total field in the center of the glomerulus is estimated as approximately 50% ( approximately 34% periglomerular and approximately 16% external tufted cells), whereas deep/medium tufted cells provide approximately 39% and mitral cells only approximately 10%. Occasionally, some sGLFPs recorded in adjacent or remote glomeruli were cross-correlated, suggesting involvement of interglomerular communication in information coding. These results demonstrate a leading role of JG cells in activation of the main olfactory bulb (MOB) functional modules. Finally, we hypothesize that the GL is not a set of independent modules, but it represents a subsystem in the MOB network, which can perform initial processing of odors.


Subject(s)
Evoked Potentials/physiology , Nerve Net/physiology , Neurons/physiology , Olfactory Bulb/cytology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Animals, Newborn , Bicuculline/pharmacology , Electric Stimulation , Evoked Potentials/drug effects , Evoked Potentials/radiation effects , Excitatory Amino Acid Antagonists/pharmacology , Female , GABA Antagonists/pharmacology , In Vitro Techniques , Male , Models, Neurological , Nerve Net/drug effects , Neurons/drug effects , Neurons/radiation effects , Patch-Clamp Techniques/methods , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Reaction Time/physiology , Reaction Time/radiation effects , Valine/analogs & derivatives , Valine/pharmacology
5.
Neuroscience ; 133(3): 819-29, 2005.
Article in English | MEDLINE | ID: mdl-15896912

ABSTRACT

In the external plexiform layer (EPL) of the main olfactory bulb, apical dendrites of inhibitory granule cells form large numbers of synapses with mitral and tufted (M/T) cells, which regulate the spread of activity along the M/T cell dendrites. The EPL also contains intrinsic interneurons, the functions of which are unknown. In the present study, recordings were obtained from cell bodies in the EPL of mouse olfactory bulb slices. Biocytin-filling confirmed that the recorded cells included interneurons, tufted cells, and astrocytes. The interneurons had fine, varicose dendrites, and those located superficially bridged the EPL space below several adjacent glomeruli. Interneuron activity was characterized by high frequency spontaneous excitatory postsynaptic potential/currents that were blocked by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and largely eliminated by the voltage-sensitive Na+ channel blocker, tetrodotoxin. Interneuron activity differed markedly from that of tufted cells, which usually exhibited spontaneous action potential bursts. The interneurons produced few action potentials spontaneously, but often produced them in response to depolarization and/or olfactory nerve (ON) stimulation. The responses to depolarization resembled responses of late- and fast-spiking interneurons found in other cortical regions. The latency and variability of the ON-evoked responses were indicative of polysynaptic input. Interneurons expressing green fluorescent protein under control of the mouse glutamic acid decarboxylase 65 promoter exhibited identical properties, providing evidence that the EPL interneurons are GABAergic. Together, these results suggest that EPL interneurons are excited by M/T cells via AMPA/kainate receptors and may in turn inhibit M/T cells within spatial domains that are topographically related to several adjacent glomeruli.


Subject(s)
Excitatory Postsynaptic Potentials/physiology , Interneurons/physiology , Olfactory Bulb/cytology , Olfactory Bulb/physiology , Action Potentials/physiology , Animals , Cell Shape/physiology , Green Fluorescent Proteins/genetics , Interneurons/cytology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture Techniques
6.
Nature ; 426(6967): 623-9, 2003 Dec 11.
Article in English | MEDLINE | ID: mdl-14668854

ABSTRACT

Centre-surround inhibition--the suppression of activity of neighbouring cells by a central group of neurons--is a fundamental mechanism that increases contrast in patterned sensory processing. The initial stage of neural processing in olfaction occurs in olfactory bulb glomeruli, but evidence for functional interactions between glomeruli is fragmentary. Here we show that the so-called 'short axon' cells, contrary to their name, send interglomerular axons over long distances to form excitatory synapses with inhibitory periglomerular neurons up to 20-30 glomeruli away. Interglomerular excitation of these periglomerular cells potently inhibits mitral cells and forms an on-centre, off-surround circuit. This interglomerular centre-surround inhibitory network, along with the well-established mitral-granule-mitral inhibitory circuit, forms a serial, two-stage inhibitory circuit that could enhance spatiotemporal responses to odours.


Subject(s)
Olfactory Bulb/physiology , Smell/physiology , Animals , Axons/physiology , Contrast Sensitivity/physiology , Electrophysiology , In Vitro Techniques , Mice , Mice, Transgenic , Odorants , Olfactory Bulb/cytology , Rats
7.
J Neurophysiol ; 86(6): 2986-97, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11731555

ABSTRACT

Olfactory receptor neurons of the nasal epithelium project via the olfactory nerve (ON) to the glomeruli of the main olfactory bulb, where they form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the olfactory bulb, and with juxtaglomerular interneurons. The glomerular layer contains one of the largest population of dopamine (DA) neurons in the brain, and DA in the olfactory bulb is found exclusively in juxtaglomerular neurons. D2 receptors, the predominant DA receptor subtype in the olfactory bulb, are found in the ON and glomerular layers, and are present on ON terminals. In the present study, field potential and single-unit recordings, as well as whole cell patch-clamp techniques, were used to investigate the role of DA and D2 receptors in glomerular synaptic processing in rat and mouse olfactory bulb slices. DA and D2 receptor agonists reduced ON-evoked synaptic responses in mitral/tufted and juxtaglomerular cells. Spontaneous and ON-evoked spiking of mitral cells was also reduced by DA and D2 agonists, and enhanced by D2 antagonists. DA did not produce measurable postsynaptic changes in juxtaglomerular cells, nor did it alter their responses to mitral/tufted cell inputs. DA also reduced 1) paired-pulse depression of ON-evoked synaptic responses in mitral/tufted and juxtaglomerular cells and 2) the amplitude and frequency of spontaneous, but not miniature, excitatory postsynaptic currents in juxtaglomerular cells. Taken together, these findings are consistent with the hypothesis that activation of D2 receptors presynaptically inhibits ON terminals. DA and D2 agonists had no effect in D2 receptor knockout mice, suggesting that D2 receptors are the only type of DA receptors that affect signal transmission from the ON to the rodent olfactory bulb.


Subject(s)
Nerve Endings/physiology , Olfactory Nerve/physiology , Olfactory Receptor Neurons/physiology , Receptors, Dopamine D2/physiology , Receptors, Presynaptic/physiology , Animals , Electrophysiology , Excitatory Postsynaptic Potentials/physiology , Extracellular Space/physiology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Olfactory Bulb/cytology , Olfactory Bulb/physiology , Patch-Clamp Techniques , Rats , Receptors, Dopamine D2/genetics , Synaptic Transmission/physiology
8.
J Neurophysiol ; 86(5): 2173-82, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11698509

ABSTRACT

The main olfactory bulb receives a significant modulatory noradrenergic input from the locus coeruleus. Previous in vivo and in vitro studies showed that norepinephrine (NE) inputs increase the sensitivity of mitral cells to weak olfactory inputs. The cellular basis for this action of NE is not understood. The goal of this study was to investigate the effect of NE and noradrenergic agonists on the excitability of mitral cells, the main output cells of the olfactory bulb, using whole cell patch-clamp recording in vitro. The noradrenergic agonists, phenylephrine (PE, 10 microM), isoproterenol (Isop, 10 microM), and clonidine (3 microM), were used to test for the functional presence of alpha1-, beta-, and alpha2-receptors, respectively, on mitral cells. None of these agonists affected olfactory nerve (ON)-evoked field potentials recorded in the glomerular layer, or ON-evoked postsynaptic currents recorded in mitral cells. In whole cell voltage-clamp recordings, NE (30 microM) induced an inward current (54 +/- 7 pA, n = 16) with an EC(50) of 4.7 microM. Both PE and Isop also produced inward currents (22 +/- 4 pA, n = 19, and 29 +/- 9 pA, n = 8, respectively), while clonidine produced no effect (n = 6). In the presence of TTX (1 microM), and blockers of excitatory and inhibitory fast synaptic transmission [gabazine 5 microM, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) 10 microM, and (+/-)-2-amino-5-phosphonopentanoic acid (APV) 50 microM], the inward current induced by PE persisted (EC(50) = 9 microM), whereas that of Isop was absent. The effect of PE was also observed in the presence of the Ca(2+) channel blockers, cadmium (100 microM) and nickel (100 microM). The inward current caused by PE was blocked when the interior of the cell was perfused with the nonhydrolyzable GDP analogue, GDPbetaS, indicating that the alpha1 effect is mediated by G-protein coupling. The current-voltage relationship in the absence and presence of PE indicated that the current induced by PE decreased near the equilibrium potential for potassium ions. In current-clamp recordings from bistable mitral cells, PE shifted the membrane potential from the downstate (-52 mV) toward the upstate (-40 mV), and significantly increased spike generation in response to perithreshold ON input. These findings indicate that NE excites mitral cells directly via alpha1 receptors, an effect that may underlie, at least in part, increased mitral cell responses to weak ON input during locus coeruleus activation in vivo.


Subject(s)
Norepinephrine/metabolism , Olfactory Bulb/physiology , Receptors, Adrenergic, alpha-1/physiology , Adrenergic alpha-Agonists/pharmacology , Animals , Evoked Potentials/physiology , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Membrane Potentials/drug effects , Membrane Potentials/physiology , Neurons/drug effects , Neurons/physiology , Olfactory Bulb/cytology , Olfactory Bulb/drug effects , Olfactory Nerve/physiology , Rats , Rats, Sprague-Dawley
9.
J Neurophysiol ; 83(2): 766-76, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10669492

ABSTRACT

Moxonidine is an antihypertensive drug that lowers sympathetic vasomotor tone by stimulating either alpha2-adrenergic (alpha2-AR) or imidazoline I1 receptors within the rostral ventrolateral medulla (RVL). In this study, we investigated the effects of moxonidine (10 microM) on RVL neurons in brain stem slices of neonatal rats. We recorded mainly from retrogradely labeled RVL bulbospinal neurons (putative presympathetic neurons) except for some extracellular recordings. Prazosin was used to block alpha1-adrenoceptors. Moxonidine inhibited the extracellularly recorded discharges of all spontaneously active RVL neurons tested (bulbospinal and unidentified). This effect was reversed or blocked by the selective alpha2-AR antagonist SKF 86466 (10 microM). In contrast, the I1 imidazoline ligand AGN 192403 (10 microM) had no effect on the spontaneous activity. In whole cell recordings (holding potential -70 mV), moxonidine produced a small and variable outward current (mean 7 pA). This current was observed in both tyrosine hydroxylase-immunoreactive and other bulbospinal neurons and was blocked by SKF 86466. Excitatory postsynaptic currents (EPSCs) evoked by focal electrical stimulation were isolated by incubation with gabazine and strychnine, and inhibitory postsynaptic currents (IPSCs) were isolated with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moxonidine reduced the amplitude of the evoked EPSCs (EC(50) = 1 microM; 53% inhibition at 10 microM) but not their decay time constant (5.6 ms). The effect of moxonidine on EPSCs persisted in barium (300 microM) and was reduced approximately 80% by SKF 86466. Moxonidine also reduced the amplitude of evoked IPSCs by 63%. In conclusion, moxonidine inhibits putative RVL presympathetic neurons both presynaptically and postsynaptically. All observed effects in the present study are consistent with an alpha2-AR agonist activity of moxonidine.


Subject(s)
Adrenergic alpha-2 Receptor Agonists , Antihypertensive Agents/pharmacology , Imidazoles/pharmacology , Medulla Oblongata/physiology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Adrenergic alpha-Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Animals , Antihypertensive Agents/metabolism , Baclofen/pharmacology , Barium/pharmacology , Benzazepines/pharmacology , Bridged Bicyclo Compounds/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , Glycine Agents/pharmacology , Heptanes/pharmacology , Imidazoles/metabolism , Imidazoline Receptors , In Vitro Techniques , Kinetics , Ligands , Medulla Oblongata/chemistry , Neurons/chemistry , Neurons/drug effects , Neurons/physiology , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Drug/metabolism , Strychnine/pharmacology
10.
Am J Physiol ; 277(3): H1069-80, 1999 09.
Article in English | MEDLINE | ID: mdl-10484430

ABSTRACT

The rostral ventrolateral medulla (RVLM) controls sympathetic tone via excitatory bulbospinal neurons. It is also the main target of alpha2-adrenoceptor (alpha2-AR) agonists used for treatment of hypertension. In this study, we examined the synaptic mechanisms by which alpha2-AR agonists may inhibit the activity of RVLM bulbospinal neurons. We recorded selectively from RVLM bulbospinal neurons in brain stem slices of neonate rats (P5-P21) using the patch-clamp technique (holding potential -70 mV). alpha2-ARs were activated by norepinephrine (NE, 30 microM) in the presence of the alpha1-adrenoceptor blocker prazosin. NE induced modest outward currents (5-28 pA) in 70% of the cells that were blocked by barium and by the alpha2-AR antagonist 2-methoxyidazoxan. The magnitude of this current was not correlated with the tyrosine hydroxylase immunoreactivity of the neurons. Mono- and oligosynaptic excitatory postsynaptic currents (EPSCs) or monosynaptic inhibitory postsynaptic currents (IPSCs) were evoked by focal electrical stimulation. In all cells, NE decreased the amplitude of the evoked EPSCs in the absence or presence of barium (49 and 70%) and decreased the amplitude of the evoked IPSCs (64 and 59%). The effect of NE on EPSC amplitude was blocked by 2-methoxyidazoxan. Focal stimulation produced a 1- to 2-s EPSC afterdischarge (probably due to activation of interneurons) that was 53% inhibited by NE. In the presence of tetrodotoxin, NE decreased the frequency of miniature EPSCs by 74%. In short, alpha2-AR stimulation produces weak postsynaptic responses in RVLM bulbospinal neurons and powerful presynaptic inhibition of both glutamatergic and GABAergic inputs. Thus the inhibition of RVL bulbospinal neurons by alpha2-AR agonists in vivo results from a combination of postsynaptic inhibition, disfacilitation, and disinhibition.


Subject(s)
Medulla Oblongata/physiology , Receptors, Adrenergic, alpha-2/physiology , Synapses/physiology , Animals , Brain Stem/physiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Synaptic Transmission/physiology
11.
J Neurophysiol ; 80(4): 2003-14, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9772256

ABSTRACT

The effects of methionine-enkephalin (ME) on visualized bulbospinal neurons of the rostral ventrolateral medulla (RVL) were characterized in thin slices at 32 degrees C using the whole cell patch-clamp technique. Thirty-five percent of the recorded neurons were found to be tyrosine hydroxylase immunoreactive (C1 neurons). In voltage-clamp recordings, ME (3 microM) induced an outward current in 66% of RVL bulbospinal neurons. A similar percentage of C1 and non-C1 neurons were opioid sensitive. The current induced by ME was inwardly rectifying, reversed close to the potassium equilibrium potential, and was blocked by barium. Most spontaneous postsynaptic currents recorded in these neurons were tetrodotoxin (TTX)-resistant miniature postsynaptic currents (mPSCs). Approximately, 75% of mPSCs had rapid kinetics (decay time = 4.7 ms) and were glutamatergic [miniature excitatory postsynaptic currents (mEPSCs)] because they were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM). The remaining mPSCs had much slower kinetics (decay time = 19.6 ms) and were GABAergic [miniature inhibitory postsynaptic currents (mIPSCs)] as they were blocked by gabazine (3 microM) but not by strychnine (3-10 microM). ME decreased the frequency of mEPSCs and mIPSCs by 69 and 43%, respectively. The inhibitory effects of ME were mimicked by the selective mu-opioid receptor agonist endomorphin-1 (EM, 3 microM) and were blocked by naloxone (1 microM). In the absence of TTX, excitatory PSCs evoked by focal electrical stimulation were isolated by application of gabazine and strychnine. EM reduced the amplitude of the evoked EPSCs by 41% without changing their decay time. We conclude that opioids inhibit the majority of RVL C1 and non-C1 bulbospinal neurons by activating a potassium conductance postsynaptically and by decreasing the presynaptic release of glutamate. These cellular mechanisms could explain the depressive cardiovascular effects and the sympathoinhibition produced by opioid transmitters in the RVL, in particular during hypotensive hemorrhage.


Subject(s)
Enkephalin, Methionine/pharmacology , Medulla Oblongata/drug effects , Neural Inhibition/physiology , Presynaptic Terminals/physiology , Spinal Cord/drug effects , Synapses/physiology , Animals , Electric Conductivity , Excitatory Postsynaptic Potentials/drug effects , Medulla Oblongata/cytology , Medulla Oblongata/physiology , Narcotics/pharmacology , Neurons/drug effects , Neurons/physiology , Potassium/physiology , Presynaptic Terminals/drug effects , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/physiology , Synapses/drug effects
12.
Brain Res ; 753(1): 120-7, 1997 Apr 04.
Article in English | MEDLINE | ID: mdl-9125438

ABSTRACT

Mesencephalic trigeminal neurons are primary sensory neurons which have cell somata located within the brain stem. In spite of the presence of synaptic terminals on and around the cell somata, applications of a variety of neurotransmitter substances in earlier studies have failed to demonstrate responses. Using intracellular recording in a brain slice preparation, we have observed prominent depolarizations and decreases in input resistance in response to applications of gamma-aminobutyric acid (GABA) in most recorded mesencephalic trigeminal neurons. Those cells failing to respond were located deeply within the slice, and the low responsiveness was shown to be related to uptake of GABA in the slice. The responses were direct, since they remained during perfusion with a low calcium, high magnesium solution that blocks synaptic transmission. The responses were mimicked by the GABA(A) receptor agonist isoguvacine, and blocked by GABA(A) receptor antagonists. The GABA(B) receptor agonist baclofen evoked no changes in membrane potential or input resistance in neurons exhibiting depolarizations with GABA application. Tests of neuronal excitability during GABA applications indicated that the excitatory effects of the depolarization prevail over the depressant effects of the increase in membrane conductance. In situ hybridization histochemistry indicated that the GABA(A) receptors in Me5 cells are comprised of alpha2, beta2 and gamma2 subunits.


Subject(s)
Neurons, Afferent/drug effects , Trigeminal Nuclei/drug effects , gamma-Aminobutyric Acid/pharmacology , Animals , Female , In Situ Hybridization , In Vitro Techniques , Male , Membrane Potentials/drug effects , Rats , Rats, Wistar , Trigeminal Nuclei/cytology
13.
Neuroscience ; 77(1): 199-217, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9044387

ABSTRACT

Noradrenaline and adrenergic agonists were tested on pacemaker-like and silent neurons of the rat rostral ventrolateral medulla using intracellular recording in coronal brainstem slices as well as in punches containing only the rostral ventrolateral medullary region. Noradrenaline (1-100 microM) depolarized or increased the frequency of discharge of all cells tested in a dose-dependent manner. The noradrenaline-induced depolarization was associated with an apparent increase in cell input resistance at low concentrations and a decrease or no significant change at higher concentrations. Moreover, it was voltage dependent and its amplitude decreased with membrane potential hyperpolarization. Noradrenaline caused a dose-related increase in the frequency and amplitude of spontaneous inhibitory postsynaptic potentials. The alpha 1-adrenoceptor antagonist prazosin (0.5 microM) abolished the noradrenaline depolarizing response as well as-the noradrenaline-evoked increase in synaptic activity and unmasked an underlying noradrenaline dose-dependent hyperpolarizing response associated with a decrease in cell input resistance and sensitive to the alpha 2-adrenoceptor/antagonist yohimbine (0.5 microM). The alpha 1-adrenoceptor agonist phenylephrine (10 microM) mimicked the noradrenaline depolarizing response associated with an increase in membrane resistance as well as the noradrenaline-induced increase in synaptic activity. The alpha 2-adrenoceptor agonists UK-14,304 (1-3 microM) and clonidine (10-30 microM) produced only a small hyperpolarizing response, whereas the beta-adrenoceptor agonist isoproterenol (10-30 microM) had no effect. Baseline spontaneous postsynaptic potentials were abolished by strychnine (1 microM), bicuculline (30 microM) or both. However, only the strychnine-sensitive postsynaptic potentials had their frequency increased by noradrenaline or phenylephrine and they usually occurred with a regular pattern. Tetrodotoxin (1 microM) eliminated 80-95% of baseline spontaneous postsynaptic potentials and prevented the increase in synaptic activity evoked by noradrenaline and phenylephrine. Similar results were obtained in rostral ventrolateral medulla neurons impaled in both coronal slices and punches of the rostral ventrolateral medulla. It is concluded that noradrenaline could play an important inhibitory role in the rostral ventrolateral medulla via at least two mechanisms: an alpha 2-adrenoceptor-mediated hyperpolarization and an enhancement of inhibitory synaptic transmission through activation of alpha 1-adrenoceptors located on the somatic membrane of glycinergic interneurons. Some of these interneurons exhibit a regular discharge similar to the pacemaker-like neurons and might, at least in part, constitute a central inhibitory link in the baroreceptor-vasomotor reflex pathway.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Biological Clocks/drug effects , Interneurons/drug effects , Medulla Oblongata/cytology , Norepinephrine/pharmacology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Adrenergic beta-Agonists/pharmacology , Animals , Bicuculline/pharmacology , Biological Clocks/physiology , Brimonidine Tartrate , Dose-Response Relationship, Drug , Electric Stimulation , Electrophysiology , Excitatory Amino Acid Antagonists/pharmacology , GABA Antagonists/pharmacology , Glycine Agents/pharmacology , Interneurons/physiology , Ion Channel Gating/physiology , Isoproterenol/pharmacology , Medulla Oblongata/physiology , Prazosin/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Wistar , Strychnine/pharmacology , Synaptic Transmission/drug effects , Tetrodotoxin/pharmacology , Yohimbine/pharmacology
14.
Neuroscience ; 74(2): 403-14, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8865192

ABSTRACT

The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK3 receptors.


Subject(s)
Adrenergic Fibers/physiology , Brain/drug effects , Locus Coeruleus/drug effects , Peptide Fragments/pharmacology , Receptors, Neurokinin-3/drug effects , Substance P/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Gerbillinae , Guinea Pigs , Microdialysis , Neuropeptides/pharmacology , Norepinephrine/pharmacology , Piperidines/pharmacology , Prazosin/pharmacology , Substance P/pharmacology
15.
Brain Res ; 709(2): 173-83, 1996 Feb 19.
Article in English | MEDLINE | ID: mdl-8833753

ABSTRACT

Rostro-ventrolateral medulla (RVL) neurons were recorded using conventional intracellular recording techniques in brain slices maintained in vitro at 32 degrees C and classified into 3 major groups. The first group included neurons having endogenous pacemaker-like (PL) activity with regular firing frequency (mean 8 Hz) and a linear current-voltage relationship (I-V). The second group of neurons were slowly and irregularly firing (IF) or quiescent, presenting membrane potential oscillations and their I-V usually displayed an inward rectification. These neurons had a relatively longer action potential duration. The third group included silent neurons (S) with no apparent membrane oscillations and they differed from the first two groups by having relatively shorter action potential duration and amplitude and lower cell input resistance. When recorded with KCl-filled electrodes, the majority of silent neurons displayed a time-dependent inward rectification. With KAc-filled electrodes, irregular slow hyperpolarizing and depolarizing spontaneous potentials could be recorded primarily on PL and IF neurons, respectively. Moreover, fast spontaneous inhibitory postsynaptic potentials (PSPs) were detected in about 15% of PL and S neurons. They generally exhibited a regular pattern and were depolarizing when KCl-filled electrodes were used for recording. The amplitude of these inhibitory PSPS was reversibly reduced by the GABA A antagonists bicuculline, SR 95531 and picrotoxin. With KAc-filled electrodes, pressure-applied GABA (20 mM) evoked complex responses. In PL neurons, it consisted of a fast hyperpolarization followed by a slower depolarization that were both sensitive to SR 95531 and picrotoxin. The response was terminated by a long-lasting hyperpolarization that was reduced, but not abolished, by the GABA B antagonist CGP 35348. In IF and S neurons, GABA application usually produced a fast followed by a slow monophasic hyperpolarization and depolarization, respectively. The fast component of these responses was sensitive to the GABA A antagonists. Pressure application of isoguvacine (10 mM) always induced monophasic responses in all types of neurons recorded. Baclofen (1-30 mu M) reduced the firing frequency and hyperpolarized PL and IF neurons, an effect that was antagonized by CGP 35348 (50-100 mu M); however, it had little effect on silent neurons. It is concluded that RVL neurons have heterogeneous electrophysiological characteristics. Their predominant synaptic input and GABA responsiveness might be additional criteria to identify the excitatory and inhibitory elements in the RVL circuitry. All neuronal types seem to have functional GABA A and GABA B receptors; however, only a subpopulation is under tonic inhibitory control in vitro, probably from local GABAergic pacemaker interneurons. Our results further emphasize the role of GABA as an important neurotransmitter in the RVL network.


Subject(s)
Medulla Oblongata/drug effects , Medulla Oblongata/physiology , Neurons/drug effects , Neurons/physiology , gamma-Aminobutyric Acid/pharmacology , Animals , Baclofen/pharmacology , Bicuculline/pharmacology , Brain Stem , Electrophysiology , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , GABA-A Receptor Antagonists , GABA-B Receptor Antagonists , Heart Conduction System/cytology , Heart Conduction System/physiology , In Vitro Techniques , Medulla Oblongata/cytology , Organophosphorus Compounds/pharmacology , Picrotoxin/pharmacology , Pyridazines/pharmacology , Rats , Rats, Wistar , Synapses/physiology
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