Characterization of pre‐ and postsynaptic actions of (—)‐baclofen in the guinea‐pig hippocampus <i>in vitro</i>

Inoue, Masumi; Matsuo, Tatsuya; Ogata, Nobukuni

doi:10.1111/j.1476-5381.1985.tb17378.x

Cited by 74 publications

(31 citation statements)

References 21 publications

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“…There is however some depression of the response to (-)-baclofen by the GABAA receptor antagonist bicuculline. This phenomenon has also been observed in hippocampus (Inoue et al, 1985b;Newberry & Nicoll, 1985) and may be the result of lack of absolute pharmacological selectivity of either agent or the ability of bicuculline to block potassium channels at the concentrations used (Heyer et al, 1982).…”

Section: Discussionmentioning

confidence: 85%

Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Allerton

Boden

Hill

1989

British J Pharmacology

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1 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.

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Section: Discussionmentioning

confidence: 85%

Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Allerton

Boden

Hill

1989

British J Pharmacology

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“…These other channels may include fast inactivating, voltagegated K ϩ channels (289) and small-conductance Ca 2ϩ -activated K ϩ channels (SK channels) (116). Accordingly, the fast inactivating A-type K ϩ -channel blocker 4-aminopyridine inhibits a baclofen-induced current in guinea pig hippocampal neurons (153,243). Moreover, GABA activates Ca 2ϩ -sensitive K ϩ channels (36) and small-conductance K ϩ channels (36, 89) in rat hippocampal neurons.…”

Section: Coupling To Kmentioning

confidence: 99%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

805

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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“…Baclofen causes postsynaptic hyperpolarization in pyramidal neurones (Inoue, Marsuo & Ogata, 1985;Gahwiler & Brown, 1985) via a K+ conductance (Newberry & Nicoll, 1985;Gahwiler & Brown, 1985). This hyperpolarizing action is mediated by G protein activation and is pertussis toxin sensitive (Andrade, Malenka & Nicoll, 1986;Thalmann, 1988;Colmers & Pittman, 1989).…”

Section: Introductionmentioning

confidence: 99%

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

Brooks

Glaum

Miller

et al. 1992

The Journal of Physiology

113

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SUMMARY1. Intracellular and whole-cell patch recordings were made from sixty-seven neurones located in the nucleus tractus solitarii (NTS) in transverse slices of rat brainstem.2. Baclofen at concentrations of 2-20 ftM caused hyperpolarization from normal resting membrane potentials (Vm). This response was associated with a decrease in input resistance (Rm) tested by current pulses in discontinuous current clamp mode when membrane potential was restored to control level by current injection. In single electrode discontinuous voltage clamp mode, baclofen'at these concentrations caused a small (< 50 pA) outward current associated with increased membrane conductance measured by voltage steps from holding potentials (Vh) of -50 or -60 mV. Current-voltage relations at these Vhs and the results of varying Vh between -50 and -110 mV during responses to baclofen gave a reversal potential of -73 mV. The amplitudes of baclofen responses were related to K+ concentration tested by comparing responses in media containing 1-24 mm extracellular K', indicating that postsynaptically baclofen acts via a K+ conductance.3. These effects were still apparent in the presence of tetrodotoxin (which did not abolish all spontaneous synaptic activity) and also in medium containing a combination of C02+, the excitatory amino acid antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the GABAA antagonist bicuculline which blocked synaptic activity.4. The amplitude and frequency of spontaneous postsynaptic potentials (spPSPs) and spontaneous postsynaptic currents (spPSCs) were reduced by baclofen at concentrations (1 /LM or less) which had no effect on membrane potential or holding current in current or voltage clamp recordings respectively.5. The amplitude of evoked excitatory (evEPSPs/evEPSCs) and inhibitory (evIPSPs/evIPSCs) synaptic events elicited by electrical stimulation in the vicinity of the tractus solitarius (TS) was reduced by low concentrations of baclofen (250 nM-1 jM) which did not produce discernible postsynaptic responses.6. In order to examine the effects of baclofen on excitatory synaptic events MS 9797 P. A. BROOKS AND OTHERS without contamination with inhibitory events, stimulation of the TS was carried out in the presence of bicuculline. Conversely to investigate actions on purely inhibitory synaptic responses experiments were carried out with CNQX in the bathing solution. Inhibitory synaptic responses could still be evoked, presumably by stimulation of interneurones in the vicinity of the TS. IPSPs/IPSCs were more sensitive to baclofen than EPSPs/EPSCs.7. The effects of baclofen on membrane potential or holding current and PSP/PSCs were antagonized by 2-hydroxysaclofen (400 /M) confirming that baclofen was acting at y-aminobutyric acid (GABA)B receptors.8. The pre-and postsynaptic depressant effects of baclofen are discussed in relation to the physiological effects of baclofen application in vivo.

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Characterization of pre‐ and postsynaptic actions of (—)‐baclofen in the guinea‐pig hippocampus in vitro

Cited by 74 publications

References 21 publications

Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Molecular Structure and Physiological Functions of GABA_BReceptors

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

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Characterization of pre‐ and postsynaptic actions of (—)‐baclofen in the guinea‐pig hippocampus in vitro

Cited by 74 publications

References 21 publications

Actions of the GABAB agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Actions of the GABAB agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Molecular Structure and Physiological Functions of GABABReceptors

The actions of baclofen on neurones and synaptic transmission in the nucleus tractus solitarii of the rat in vitro.

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Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Molecular Structure and Physiological Functions of GABA_BReceptors