CHRONIC ADENOSINE A(1) RECEPTOR AGONIST AND ANTAGONIST - EFFECT ON RECEPTOR DENSITY AND N-METHYL-D-ASPARTATE INDUCED SEIZURES IN MICE

The effect of chronic administration of the adenosine A(1) receptor ag onist N-6-cyclopentyladenosine (CPA) and the adenosine A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) on N-methyl-D-aspartate (NMD A)-evoked seizures was studied in C57BL/6 mice (20/ group). Animals we re injected i.p. for 9 days with either 1.0 mg/kg CPA or 1.0 mg/kg CPX followed by 2 injection-free days (the washout period) and subsequent administration of a single dose of 60 mg/kg NMDA. As in our previous study, this dose of NMDA caused clonic/tonic seizures resulting in hig h (60%) mortality within 3 h after injection of the drug. Despite insi gnificant changes in seizure latency, chronic pretreatment with CPA in creased the incidence of clonic tonic episodes and end-point mortality . Conversely, chronic exposure to CPX completely eliminated clonic/ton ic episodes, significantly increased average survival time, and reduce d end-point mortality (P < 0.05). The results indicate that chronic tr eatment with adenosine A(1) receptor antagonist may protect against NM DA-evoked seizures to the same degree as previously observed following a single, acute exposure to CPA. Since the density of adenosine recep tor binding sites was unchanged after chronic treatment with either CP X or CPA, it is likely that the mechanism behind the observed protecti on may rest at the level of second messenger systems coupled to adenos ine A(1) receptors.