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 microM) 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 microM) and theophylline (60 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Elphick
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MRC Unit, Radcliffe Infirmary, Oxford, UK.
Taghavi
Z
Z
Powell
T
T
Godfrey
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PP
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D011941:Receptors, Adrenergic / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000241:Adenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D002110:Caffeine; D002220:Carbamazepine; D003000:Clonidine; D000242:Cyclic AMP; D010660:Phenylisopropyladenosine; D011687:Purines; D011941:Receptors, Adrenergic; D013449:Sulfonamides; D013806:Theophylline; D014970:Xanthines; C052023:N-(2-(dimethylamino)ethyl)-N-methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C051360:1,3-dipropyl-8-cyclopentylxanthine