Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines

Abstract

1. The potencies of caffeine and related methylxanthines as adenosine antagonists were assessed with respect to three apparent subtypes of adenosine receptors in rat brain preparations: (i) the A1-adenosine receptor which binds with a very high affinity the ligand [3H]cyclohexyladenosine (KD, 1 n M) in rat brain membranes; (ii) a ubiquitous low-affinity A2-adenosine receptor which activates cyclic AMP accumulation in rat brain slices-this A2-adenosine system exhibits an EC50 for 2-chloroadenosine of about 20 μM; and (iii) a relatively high-affinity A2-adenosine receptor which activates adenylate cyclase in rat striatal membranes-this A2-adenosine system exhibits an EC50 for 2-chloroadenosine of about 0.5 μM and is present in striatal but not in cerebral cortical membranes. 2. The rank order of potency for methylxanthines versus binding of 1 n M [3H]cyclohexyladenosine in membranes from eight rat brain regions is theophylline (IC50, 20-30 μM) > paraxanthine (IC50, 40-65 μM) > caffeine (IC50, 90-110 μM) > theobromine (IC50, 210-280 μM). There thus appears to be little difference in A1-receptors in different brain regions in terms of interaction with these methylxanthines. 1-Methylxanthine is more potent than caffeine in rat cerebral cortical membranes, while 3-methylxanthine and 7-methylxanthine are less potent than caffeine. 3. The rank order of potency for methylxanthines versus activation of cyclic AMP accumulation by 50 μM 2-chloroadenosine in rat striatal slices is theophylline (IC50, 60 μM) > paraxanthine (IC50, 90 μM) > caffeine (IC50, 120 μM) » theobromine (IC50, > 1000 μM). Similar potencies pertain in cerebral cortical slices. 4. The rank order of potency of methylxanthines versus activation of adenylate cyclase by 1 μM 2-chloroadenosine in rat striatal membranes is theophylline (IC50, 20 μM) > paraxanthine (IC50, 40 μM) > caffeine (IC50, 80 μM) » theobromine (IC50, > 1000 μM). 5. Caffeine and other methylxanthines, thus, antagonize effectively both A1- and A2-adenosine receptors in brain perparations. Theobromine appears less effective versus A2-receptors than versus A1-receptors. Caffeine exhibits a Ki value of about 50 μM at the very high-affinity A1-binding sites, a Ki value of about 30 μM at the low-affinity A2-adenosine site in brain slices, and a Ki value of about 27 μM at the high-affinity A2-adenosine site in striatal membranes. The functional significance of antagonism of such adenosine receptors by caffeine in situ will depend both on the local levels of adenosine and on the affinity for adenosine for the receptor, since antagonism by xanthines is competitive in nature. In addition, the functional significance of xanthine action will depend on the degree of inhibition of adenosine input which is required to alter the output signal. For a stimulatory input to adenylate cyclase via an A2-adenosine receptor, profound antagonism by methylxanthines is probably required to alter the cyclic AMP-mediated output signal, while for inhibitory input to adenylate cyclase via an A1-adenosine receptor, presumably a lesser degree of antagonism by methylxanthines may be required to alter the cyclic AMP-mediated output signal. © 1983 Plenum Publishing Corporation.