Chronic effects of xanthines on levels of central receptors in mice

1. Chronic ingestion of caffeine causes a significant increase in levels of A(1)-adenosine, nicotinic and muscarinic receptors, serotonergic receptors , GABA(A) receptors and L-type calcium channels in cerebral cortical membra nes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of ca ffeine except that levels of L-type channels were unchanged. Chronic theobr omine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A(1)-adenosine receptors. A combination of chroni c caffeine and IBMX had the same effects on receptors as caffeine alone. Ch ronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A(2A)-a ntagonist, caused only an increase in levels of A(1)-adenosine receptors. P entoxyfylline, an adenosine-uptake inhibitor inactive at adenosine receptor s, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caff eine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IB MX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A(1) and A(2A)-adeno sine receptors is necessary for the full spectrum of biochemical changes el icited by chronic ingestion of xanthines, such as caffeine, theophylline, a nd paraxanthine.