Effects of baclofen on synaptically‐induced cell firing in the rat hippocampal slice

Abstract

1The 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 activates voltage‐dependent and 4‐aminopyridine sensitive K+ conductance in guinea‐pig hippocampal pyramidal cells maintained in vitro

“…Baclofen appears to have an additional property of inducing a change in the excitability of the neuronal membrane in addition to its well-known presynaptic action (e.g. Bowery et al, 1980;Davies, 1981;Ault & Nadler, 1983). The finding that the effect of baclofen was persistent in the Ca+-free medium further confirms its postsynaptic nature.…”

“…The GABAB site is resistant to bicuculline, whereas the GABAA site is bicuculline-sensitive. A number of studies on both the peripheral (Bowery et al, 1981) and central (Davies, 1981;Ault & Nadler, 1983) nervous systems indicate that GABAB sites are present on nerve terminals and when activated result in diminished transmitter release 'Correspondence.…”

Quantitative evaluation of the potencies of GABA‐receptor agonists and antagonists using the rat hippocampal slice preparation

“…When several concentrations of antagonist were studied on the same slice, recovery from the inhibitory response to the agonist was obtained in the presence of the antagonist and then the antagonist concentration raised and a further 15 min allowed for equilibration. Following the observations of Ault & Nadler (1983), that bicuculline reduced the stimulus intensity required to produce a maximal response, we took care to ensure that the population spikes remained submaximal in the presence of the antagonists. Therefore, we did not change the stimulus intensity between the control and the antagonist runs.…”

Adenosine inhibits epileptiform activity arising in hippocampal area CA3

“…Baclofen, like adenosine, suppresses the firing of CAl pyramids by reducing transmitter release from terminals of Schaffer collateral-commissural fibres (Lanthorn & Cotman, 1981;Ault & Nadler, 1982;Olpe et al, 1982) and depressing cell excitability (Ault & Nadler, 1983b;Newberry & Nicoll, 1984;Inoue et al, 1985).…”