The effects of chronic caffeine administration on both adenosine and benzodiazepine receptors were studied in mouse brain membranes. Animals were fed on a diet enriched with caffeine (600 mg/kg diet) for 15 days and sacrificed 2, 4, 8 and 15 days after withdrawal. Compared with controls fed on a regular diet, animals receiving a caffeine-enriched diet showed an increase in the number of brain adenosine receptors labeled with [3H]-DPX in both the cerebellum and forebrain regions. This up-regulation was still significant 15 days after withdrawal in the cerebellum but not in the forebrain, where the number of adenosine receptors returned to control levels within 8 days following withdrawal. Benzodiazepine receptors labeled by [3H]-B-CCE were not influenced by chronic caffeine diet or withdrawal.