EFFECTS OF COMBINATIONS OF METHYLXANTHINES AND ADENOSINE-ANALOGS ON LOCOMOTOR-ACTIVITY IN CONTROL AND CHRONIC CAFFEINE-TREATED MICE

Chronic caffeine ingestion (CCl) by male NIH Swiss strain mice results in a prolonged reduction in locomotor activity and alterations in res ponse to caffeine, other xanthines, and adenosine analogs. Caffeine, t he A1 selective 8-cyclopentyltheophylline (CPT), and the A2-selective 3,7-dimethyl-1-propargylxanthine (DMPX) remain stimulatory and the bel l-shaped locomotor dose-response curves are left-shifted after CCI. Th e depressant effects of methylxanthines that are potent phosphodiester ase inhibitors remain after CCI. After CCI, mice became more sensitive to depressant effects of A1, mixed A1/A2, and A2 agonists. In the pre sence of caffeine the A1-selective agonist N6-cyclohexyladenosine (CHA ), the mixed A1/A2 agonist 5'-N-ethylcarboxamidoadenosine and the A2-s elective agonist ylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (A PEC) all have dose-response curves, appearing to consist of initial de pressant effects, then stimulatory effects, and finally pronounced dep ressant effects. The phasic character is reduced or absent after CCI. Synergistic depressant effects of combinations of CHA and APEC also ap pear reduced after CCI. (C) 1993 Wiley-Liss, Inc.