Effects of Combinations of Methylxanthines and Adenosine Analogs on Locomotor Activity in Control and Chronic Caffeine-Treated Mice.

Chronic caffeine ingestion (CCI) by male NIH Swiss strain mice results in a prolonged reduction in locomotor activity and alterations in response to caffeine, other xanthines, and adenosine analogs. Caffeine, the A1 selective 8-cyclopentyltheophylline (CPT), and the A2-selective 3,7-dimethyl-1-propargylxanthine (DMPX) remain stimulatory and the bell-shaped locomotor dose-response curves are left-shifted after CCI. The depressant effects of methylxanthines that are potent phosphodiesterase inhibitors remain after CCI. After CCI, mice became more sensitive to depressant effects of A1, mixed A1/A2, and A2 agonists. In the presence of caffeine the A1-selective agonist N6-cyclohexyladenosine (CHA), the mixed A1/A2 agonist 5'-N-ethylcarboxamidoadenosine and the A2-selective agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (APEC) all have dose-response curves, appearing to consist of initial depressant effects, then stimulatory effects, and finally pronounced depressant effects. The phasic character is reduced or absent after CCI. Synergistic depressant effects of combinations of CHA and APEC also appear reduced after CCI.