Cross-sensitization between caffeine- and l-dopa-induced behaviors in hemiparkinsonian mice

Adenosine A2A receptor (A2AR) antagonists, including the non-specific adenosine antagonist caffeine, have been proposed as a novel, non-dopaminergic treatment strategy for Parkinson's disease (PD). However, the long-term interaction between caffeine and l-dopa treatment in PD models has not been characterized. We examined the interaction between caffeine and l-dopa following a repeated treatment paradigm in hemiparkinsonian mice. In contrast to the progressively sensitized rotational behavior induced by daily l-dopa (2.0 mg/kg) treatment, tolerance for the rotational response to daily caffeine (2.5 or 10 mg/kg) treatment tended to develop over several weeks. However, after a subsequent two-week washout, challenge with same drug demonstrated an extinction of the sensitized l-dopa-induced rotation, but a sensitization of the caffeine-induced rotation. In a cross-challenge paradigm, daily treatment of mice with l-dopa (compared to daily saline) produced a three-fold enhancement in the rotational response to a subsequent re-challenge with caffeine. Similarly, daily treatment of mice with caffeine produced a six-fold enhancement in the rotational response to a subsequent re-challenge with l-dopa. Furthermore, daily co-administration of caffeine plus l-dopa produced enhanced rotational behavior, compared to caffeine or l-dopa alone, indicating an additive or synergistic interaction between caffeine and l-dopa during repeated treatment. Cross-sensitization between caffeine and l-dopa following repeated treatment and their positive interaction during chronic co-adminstration in hemiparkinsonian mice suggest that repeated exposure to caffeine may alter l-dopa responses in PD.