Effects of baclofen on medial vestibular nucleus neurones in guinea-pig brainstem slices (original) (raw)
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Actions of (−)-baclofen on rat dorsal horn neurons
Brain Research, 1991
The actions of a y-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae l-IV) were examined by using intraceUular recordings in spinal cord slice from young rats. in addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to l0 ~M) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca 2+, 10 mM Mg 2+-or a TI'X-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions, Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca 2+-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABA~ receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.
British Journal of Pharmacology, 1989
The electrophysiological actions of the GABAB agonist, (-)-baclofen, on deep dorsal horn neurones were studied using an in vitro preparation of the spinal cord of 9-16 day old rat. 2 On all neurones tested, (-)-baclofen (100nM-30.uM) had a hyperpolarizing action which was associated with a reduction in apparent membrane input resistance. The increase in membrane conductance was dose-dependent and had a Hill coefficient of 1.0. 3 The (-)-baclofen-activated hyperpolarization persisted in the presence of bicuculline (50 gM) and Mg2+ (20mM). 4 The reversal potential of the hyperpolarizing event was estimated at 102 mV and was made less negative by increasing the external concentration of potassium ions. 5 Over the same concentration range, (-baclofen also depressed the polysynaptic composite excitatory postsynaptic potentials (e.p.s.ps) evoked in these neurones by electrical stimulation of the dorsal root entry zone. 6 The potassium channel blockers caesium, applied intracellularly, and barium, applied extracellularly, depressed the postsynaptic response to baclofen but not its effect on e.p.s.ps. 7 We propose that (-baclofen has more than one mechanism of action in spinal dorsal horn: a postsynaptic action mediated via an increase in potassium conductance and a presynaptic action that is not associated with potassium channels and may be mediated via calcium channels. Since previous studies have demonstrated little effect of (-)-baclofen on transmitter release in spinal cord, it is possible that the postsynaptic hyperpolarizing action of (-)-baclofen may account for its clinical potency as an anti-spastic agent.
Mechanism of action of baclofen in rat dorsal motor nucleus of the vagus
AJP Gastrointestinal and Liver Physiology
Using whole cell patch-clamp recordings, we investigated the effects of the GABA(B) receptor agonist baclofen in thin slices of rat brain stem containing identified gastric- or intestinal-projecting dorsal motor nucleus of the vagus (DMV) neurons. Perfusion with baclofen (0.1-100 microM) induced a concentration-dependent outward current (EC(50), 3 microM) in 54% of DMV neurons with no apparent differences between gastric- and intestinal-projecting neurons. The outward current was attenuated by pretreatment with the selective GABA(B) antagonists saclofen and 2-hydroxysaclofen, but not by the synaptic blocker TTX, indicating a direct effect at GABA(B) receptors on DMV neurons. Using the selective ion channel blockers barium, nifedipine, and apamin, we showed that the outward current was due to effects on potassium and calcium currents as well as calcium-dependent potassium currents. The calcium-mediated components of the outward current were more prominent in intestinal-projecting neu...
The Journal of physiology, 1992
1. Intracellular microelectrode recordings were used to study the cellular location, pharmacology, and mechanism of action of gamma-aminobutyric acidB (GABAB) receptors on pyramidal cells and presynaptic axonal endings in area CA3 of organotypic hippocampal slice cultures. 2. Baclofen (bath applied at 10 microM) caused a 10-15 mV hyperpolarization of CA3 cells and a 75-100% decrease in the amplitude of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Baclofen reduced the amplitude of monosynaptic IPSPs elicited in the presence of excitatory amino acid receptor antagonists, as well as the amplitude of EPSPs elicited after blocking GABAA receptors and reducing subsequent epileptic bursts with excitatory amino acid receptor antagonists. These data indicate that GABAB receptors are located on both excitatory and inhibitory presynaptic elements. 3. The GABAB receptor antagonist CGP 35 348 blocked the postsynaptic action of baclofen, the late IPSP, and the reduction of...
Complex effects of baclofen on synaptic transmission of the frog optic tectum in vitro
Neuroscience Letters, 1988
In the frog optic tectum in vitro, low concentrations of the GABAB agonist (-)-baclofen reversibly depressed field potentials evoked by optic nerve stimulation. This effect, which was dose-dependent and stereo-specific, differed from the potent facilitatory action of bath-applied GABA. A transient enhancement in field potential amplitude often preceded the more consistently observed depression. Both phases of the baelofen response were insensitive to the GABAA antagonist picrotoxin. Since the effects of baclofen and GABA were different, it is suggested that GABA~ receptors were unlikely to mediate the action of GABA on synaptic transmission in the optic tectum. We have recently described an unusual potentiating effect of GABA on monosynaptic excitatory transmission in the frog optic tectum [16]. Since this action of GABA was insensitive to bicuculline, a selective GABAA antagonist [15], it was proposed that GABAA receptors were not involved in this phenomenon. It was further considered that GABAB receptors [3, 9] were unlikely to mediate this response on the basis of its antagonism by picrotoxin and its mimicry by low concentrations of muscimol. Nonetheless, the issue of GABAB receptors had not been directly investigated by using the potent and specific GABAB agonist baclofen [2]. The present study was therefore initiated to clarify it baclofen would mimic the effect of GABA on synaptic transmission in the frog optic tectum. Experiments were carried out on the isolated forebrain of frogs (Rana temporaria) according to the method previously reported [16, 17]. Briefly, tissues were continuously superfused in vitro with Ringer solution of the following composition (mM): NaCI 111, KCI 2.5, NaHCO3 17, NaH2PO4"2H20 0.1, CaC12 2.5, glucose 4 (gassed with 95 % 02 5 % CO2). The temperature in the tissue chamber was 7°C. Following electrical stimulation of the contralateral optic nerve (0.08 Hz; 1.2 ms; supra
Experimental Brain Research, 1995
Inhibitory amino acids are considered as major transmitters in the vestibular system. Using intracellular recordings in slices, we applied gamma-aminobutyric acid (GABA) and muscimol (a specific agonist of the GABA A receptor) to the two main types of medial vestibular nucleus neurones (A and B MVNn). In either a high Mg2+/low Ca 2+ solution, or a solution containing tetrodotoxin, all MVNn were hyperpolarized by GABA and muscimol. This indicates that both types of MVNn are endowed with postsynaptic, hyperpolarising GABA A receptors. In a normal medium, about half of A and B MVNn were, in contrast, depolarised by GABA and muscimol, whereas the remaining cells were hyperpolarised. These results could be due to a modulation by GABA and muscimol of a tonic GABA release in the slice. Such a release was, indeed, suggested by results showing the depolarising effect of either tetrodotoxin (TTX) or bicuculline, when applied alone. The cells that were depolarised by GABA or muscimol in control conditions were always hyperpolarised in the presence of TTX. Our data therefore suggest that GABA acting at GABA A receptors in the medial vestibular nucleus can play a role either through a postsynaptic hyperpolarising action or indirectly by inhibiting a tonic GABA release, probably resuiting from the spontaneous activity of local inhibitory interneurones. A GABAergic regulation of these interneurones could be important in processes of vestibular habituation and/or adaptation.
Effects of baclofen on synaptically-induced cell firing in the rat hippocampal slice
British Journal of Pharmacology, 1983
The effects of baclofen on the synaptically-induced firing of pyramidal and granule cell populations were tested in the rat hippocampal slice. Population spikes were evoked by stimulating excitatory pathways in the presence and absence of bath-applied drug. 2 (±)-Baclofen (20 iM) completely blocked the firing of CAl or CA3 hippocampal pyramidal cells subsequent to stimulation of projections that originate in area CA3. In contrast, the firing of dentate granule cells evoked by stimulation of the perforant path fibres was depressed by only 46% and baclofen did not affect the monosynaptic firing of CA3 pyramidal cells evoked by mossy fibre stimulation. These results are consistent with the effects of baclofen on the corresponding extracellularly-recorded excitatory postsynaptic potentials (e.p.s.ps). 3 The Schaffer collateral-commissural population spike in area CAl was depressed by (-)baclofen (EC5o = 2.8 pM), GABA (EC5o = 2.2 mM) and 3-aminopropanesulphonic acid (3-APS) (EC5o = 0.34 mM). (-)-Baclofen was 180 times as potent as (+)-baclofen. 4 Bicuculline methiodide (100 pm) did not reverse the depressant action of (-)-baclofen. GABAinduced depressions were antagonized to only a small degree, whilst the effect of 3-APS was readily reversed. Raising the concentration of bicuculline from 100 jIM to 500 JM did not further reverse the action of GABA. 5 The effects of (-)-baclofen and 3-APS on the relationship between extracellular e.p.s.p. and population spike were tested by stimulation of the Schaffer collateral-commissural fibres in area CA1. (-)-Baclofen shifted the 'input/output' curve to the right at a concentration of 1 JAM, but less or not at all at 3 jAM. In contrast, increasing the concentration of 3-APS shifted this curve farther to the right. 6 These results are consistent with the hypothesis that baclofen and GABA can depress neuronal firing by interacting with a bicuculline-insensitive receptor. In the CAl area, activation of these receptors mainly depresses transmitter release from terminals of projections from area CA3, but also reduces pyramidal cell excitability.
Baclofen antagonism by 2-hydroxy-saclofen in the cat spinal cord
Neuroscience Letters, 1988
When administered microelectrophoretically, a sulphonic acid derivative of baclofen, 3-amino-2-(4chlorophenyl)-2-hydroxy-propylsulphonic acid, reversibly reduced the presynaptic reduction by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in low threshold primary afferent fibres of the cat as well as the postsynaptic depression by (-)-baciofen of the firing of these neurones. This compound, 2-hydroxy-saclofen, may be useful in assessing the physiological significance of central baclofen receptors.
Experimental Brain Research, 1985
Intravenous baclofen (1–6.25 mg kg-1) substantially reduced the monosynaptic excitation of neurones in the intermediate nucleus of the cat spinal cord by impulses in group I extensor muscle primary afferent fibres, but had little or no effect on excitation by stimulating fibres of the ipsilateral dorsolateral funiculus or the contralateral red nucleus. Relatively low concentrations of baclofen thus appear not to influence the release of excitatory transmitter from the terminals of rubrospinal, corticospinal and long descending propriospinal fibres, in contrast to the reduction of the release of primary afferent transmitters.