ALKYLXANTHINE ADENOSINE ANTAGONISTS AND EPILEPTIFORM ACTIVITY IN RAT HIPPOCAMPAL SLICES IN-VITRO

Citation
Ajr. Chesi et Tw. Stone, ALKYLXANTHINE ADENOSINE ANTAGONISTS AND EPILEPTIFORM ACTIVITY IN RAT HIPPOCAMPAL SLICES IN-VITRO, Experimental Brain Research, 113(2), 1997, pp. 303-310
Citations number
66
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
00144819
Volume
113
Issue
2
Year of publication
1997
Pages
303 - 310
Database
ISI
SICI code
0014-4819(1997)113:2<303:AAAAEA>2.0.ZU;2-4
Abstract
Despite its potent proconvulsant effects in vitro, the adenosine Al re ceptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) does not induce seizures when administered in vivo. This contrasts with the eff ects of less selective adenosine antagonists such as theophylline or c yclopentlytheophylline, and led us to reexamine the nature of DPCPX-in duced epileptiform activity. In the present study, we report that proc onvulsant effects of bath-applied DPCPX in rat hippocampal slices are only observed after a preceding stimulus such as NMDA receptor activat ion or brief tetanic stimulation. While this may be due to the absence of a basal ''purinergic tone'' the relatively high interstitial conce ntrations of adenosine present in the slice suggest that access of the drug to Al receptors may instead be prevented by tightly coupled endo genous adenosine, with the ternary adenosine-Al receptor-G protein com plex stabilised in the high-affinity conformation by a coupling cofact or. This implies that a substantial percentage of adenosine Al recepto rs are inactive under physiological conditions, but that access of ade nosine Al receptor antagonists may be facilitated under pathological c onditions. Once induced, DPCPX-evoked spiking persists for long period s of time. A ''kindling'' effect of Al receptor blockade is unlikely, since persistent spiking is not usually observed with less selective A l antagonists even after prolonged application. Alternatively, endogen ous adenosine released during increased neuronal activity may activate A2 receptors during selective Al blockade. The most important factor determining the duration of DPCPX-induced spiking, however, may be a p ersistence of the drug in the tissue and subsequent access to the Al r eceptor via a membrane-delineated pathway, since DPCPX-induced spiking could be shown to decrease markedly after a transient superfusion of theophylline. This hypothesis, which implies that the apparent affinit y of adenosine antagonists for the Al receptor is in part a function o f their membrane partitioning coefficient, is supported by a close cor relation between alkylxanthine logP values obtained from the literatur e and their K-i value at Al receptors, but not at the enzyme phosphodi esterase, whose xanthine binding site is presented to the cytosol. The implications for the therapeutic value of purinergic drugs are discus sed.