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First published on April 26, 2006; DOI: 10.1124/mol.106.023309

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Received for publication February 8, 2006.
Revised March 30, 2006.
Accepted for publication April 26, 2006.

Pregabalin Reduces the Release of Synaptic Vesicles from Cultured Hippocampal Neurons

Kristina D. Micheva 1*, Charles P. Taylor 2, Stephen J Smith 1

1 Stanford University School of Medicine 2 Department of CNS Biology, Pfizer Global R & D

* Address correspondence to: E-mail: kmicheva{at}stanford.edu

Abstract

Pregabalin (S-[+]-3-isobutylGABA or (S)-3-(aminomethyl)-5-methylhexanoic acid, LyricaTM) is an anticonvulsant and analgesic medication that is both structurally and pharmacologically related to gabapentin (NeurontinTM). Previous studies have shown that pregabalin reduces the release of neurotransmitters in several in vitro preparations, although the molecular details of these effects are less clear. The present study was performed using living cultured rat hippocampal neurons with the synaptic vesicle fluorescent dye probe, FM4-64, to determine details of the action of pregabalin to reduce neurotransmitter release. Our results indicate that pregabalin treatment, at concentrations that are therapeutically relevant, slightly but significantly reduces the emptying of neurotransmitter vesicles from presynaptic sites in living neurons. Dye release is reduced in both glutamic acid decarboxylase (GAD) immunoreactive and GAD-negative (presumed glutamatergic) synaptic terminals. Furthermore, both calcium-dependent release and hyperosmotic (calcium-independent) dye release are reduced by pregabalin. The effects of pregabalin on dye release are masked in the presence of L-isoleucine, consistent with the fact that both of these compounds have a high binding affinity to the calcium channel {alpha}2-{delta} protein. The effect of pregabalin is not apparent in the presence of an N-methyl-d-aspartate antagonist (AP5), suggesting that pregabalin action depends on NMDA receptor activation. Finally, the action of pregabalin on dye release is most apparent before and early during a train of electrical stimuli when vesicle release preferentially involves the readily-releasable pool.


Key words: Fluorescence techniques, Exocytosis


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