Elsevier

Neuroscience

Volume 75, Issue 2, 25 October 1996, Pages 573-585
Neuroscience

Effects of a centrally active benzoylpiperidine drug on α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor kinetics

https://doi.org/10.1016/0306-4522(96)00263-1Get rights and content

Abstract

A newly developed benzoylpiperidine drug that increases the size of fast, excitatory synaptic responses was examined for its effects on the kinetic properties of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid-type glutamate receptors. When long pulses of glutamate were applied to excised hippocampal patches of the rat, the compound [1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20] caused an approximately 15-fold reduction in the rate at which responses desensitized and a similar size increase in steady-state currents. In experiments using 1-ms glutamate pulses, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 prolonged response deactivation by a factor of about four and greatly reduced the depression in the second response when two consecutive glutamate pulses were given. Two types of equilibrium binding assays indicated that 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 causes a measurable increase in the affinity of α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors; the ec50 values for this effect were similar to those obtained in excised patch studies. The actions of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 on physiology and ligand binding could be adequately reproduced in a receptor model by slowing the rate of desensitization and increasing the affinity of the sensitized states.

The biochemical and physiological effects of benzoylpiperidine compounds were qualitatively different from those obtained with cyclothiazide, although both types of drug increased α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptor-mediated synaptic responses. Moreover, interactions between the drugs were at most only partially competitive; α-amino-3-hydroxy-5-methyl-4-isoxalepropionic acid receptors may thus have multiple modulatory sites with distinct drug preferences and different effects on receptor kinetics.

Section snippets

Patch-clamp recordings

Physiological studies were carried out with outside-out patches excised from pyramidal neurons of fields CA1 and CA3 of cultured hippocampal slices. The slice cultures were prepared from 10–13-day-old Sprague–Dawley rats and grown for two to four weeks on cellulose membrane inserts[28](Millipore CM; Millipore, Bedford, MA, U.S.A.) (see details in del Cerro et al.[7]); as previously reported, this preparation exhibits various physiological features which are characteristic of adult tissue,

Effect of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine-20 on glutamate-induced inward currents

Glutamate pulses of long duration were applied to outside-out patches excised from cultured hippocampal slices using a fast-switch system that alternately delivers a flow of background or glutamate containing medium;[4]solution exchange time was less than 1 ms according to junction potential measurements. A series of recordings in which a step pulse of 1 mM l-glutamate was applied for periods of several hundred milliseconds is shown in Fig. 1. In agreement with results of previous studies,[4]

Discussion

The drug used in the present studies (BDP-20) is one of a family of benzoylpiperidine compounds that have been shown to increase the size and duration of AMPA receptor-mediated synaptic responses in hippocampal slices.9, 26, 27Certain of these analogues are known to cross the blood–brain barrier and to enhance both hippocampal excitatory postsynaptic potentials and the induction of LTP in intact animals.[26]As expected from these results, BDP-20 has pronounced effects on glutamate-elicited

Conclusions

It remains an important question whether AMPA receptor drugs can be grouped into separate families with distinct effects on receptor kinetics, and whether such functional differences arise from the presence of multiple types of sites, either on different receptor subunits or within each subunit. It has been demonstrated that cyclothiazide shows a preference for certain splice variants of the major AMPA receptor subunits.[21]Similar studies are in progress with different subgroups of BDP type

Acknowledgements

This research was supported by grant 92-J-0307 from the AFOSR, by the RSA award MH-00358 from NIMH, and by a grant from Cortex Pharmaceuticals, Inc. The authors wish to thank Dean Chang for his assistance in preparing and maintaining hippocampal organotypic slice cultures and Jackie Porter and Marla Lay for their excellent secretarial assistance.

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