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
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.