CHRONIC CARBAMAZEPINE DOWN-REGULATES ADENOSINE-A2 RECEPTORS - STUDIES WITH THE PUTATIVE SELECTIVE ADENOSINE ANTAGONISTS PD115,199 AND PD116,948

Carbamazepine (CBZ), an anticonvulsant with psychotropic and anti-pain properties, has been reported to displace ligands at adenosine binding sites. This paper describes biochemical and behavioural studies in rodents comparing CBZ to the adenosine agonists l-phenylisopropyl-adenosine (l-PIA) and N-ethylcarboxamido-adenosine (NECA), the new antagonists PD116,948 and PD115,199 which are also relatively A1 and A2 specific respectively, and the mixed antagonists theophylline and caffeine, attempting to determine functional correlates of the binding studies. Changes in cAMP synthesis and behavioural syndromes produced by the drugs, alone and in combination, were monitored. Classification of the observed effects in terms of A1 and A2 activity was complex, probably due to functional interactions between A1 and A2 subtypes. Nevertheless, it was found that chronic CBZ administration (0.25% in food for 3 days, followed by 0.5% for 11 days) produced a pattern of interaction identical to that of PD115,199 (10-100 mg/kg IP). Thus, both treatments attenuated the behavioural syndrome produced by l-PIA (0.1 or 0.5 mg/kg SC), but did not affect that produced by NECA (0.03 mg/kg SC). CBZ mildly increased hypoactivity after clonidine (0.2 mg/kg IP) which was used as a control. By contrast, the A1 antagonist PD116,948 (0.1-10 mg/kg IP) antagonised both behavioural syndromes. Similarly in the biochemical experiments both chronic CBZ and PD115,199 (10-100 μM) reduced stimulation of cAMP synthesis by l-PIA (confirming that this is mediated by A2 receptors), while only basal cAMP synthesis was affected by PD116,948 (10 μM) and theophylline (60 μM). Acute CBZ did not alter l-PIA stimulated cAMP synthesis at concentrations up to 100 μM (i.e. within the therapeutic plasma concentration). Chronic CBZ did not alter motor activity stimulated by caffeine (5 mg/kg IP). These results suggest that PD155,199 and PD116,948 may be useful in defining the functions of adenosine receptor subtypes, and that chronic CBZ appears to functionally down-regulate A2 receptors. © 1990 Springer-Verlag.