NONSELECTIVE EFFECTS OF ADENOSINE A(1) RECEPTOR LIGANDS ON ENERGY-METABOLISM AND MACROMOLECULAR BIOSYNTHESIS IN CULTURED CENTRAL NEURONS

To investigate the effects of adenosine A(1) receptor activation on en ergy metabolism and RNA and protein biosynthesis in central neurons, c ultured neurons from the rat forebrain were exposed for 1 hr to 72 hr to various concentrations (10 nM-100 mu M) of the selective A(1) recep tor agonist 2-chloro-N-6-cyclopentyladenosine (CCPA) or the A(1) recep tor antagonist 8-cyclopentyltheophylline (CPT). At all concentrations tested, the adenosinergic compounds did not affect cell viability with in 72 hr of treatment, except for CPT; which reduced viability by 19.7 % when used at the concentration of 100 mu M. Energy metabolism was an alysed by studying the specific uptake of 2-D-[H-3]deoxyglucose ([H-3] 2DG). Rates of RNA and protein biosynthesis were assessed by the measu rement of [H-3]uridine and [H-3]leucine incorporation, respectively. N euronal [H-3]2DG uptake was increased by 16% (P < 0.01) after 8 hr in the presence of 100 mu M CCPA, whereas 100 mu M CPT for 24 hr also inc reased [H-3]2DG; uptake (8%, P < 0.01). At these concentrations, both ligands inhibited [H-3] uridine incorporation after a 3-hr treatment b y 92% and 30%, respectively. CCPA never altered [H-3]leucine incorpora tion when compared to controls, and CPT significantly inhibited protei n synthesis only at 10-100 mu M. Additional experiments to analyse the influence of A(1) ligands on the transport of [H-3]2DG, [H-3]leucine and [H-3]uridine suggested that CCPA and CPT, which interact functiona lly with adenosine receptors by regulating cyclic AMP production in th is model, are able to alter energy metabolism and RNA synthesis in cen tral neurons in a nonspecific manner by interacting with glucose and u ridine transporters. (C) 1998 Elsevier Science Inc.