Chronic and intermittent morphine treatment differently regulates opioid and dopamine systems: a role in locomotor sensitization

Abstract

Behavioral sensitization induced by repeated morphine administrations may depend on patterns of administration. However, neurobiological mechanisms involved in this sensitization are largely unknown. We compared the effects of intermittent (20 mg/kg, once daily for 7 days) and chronic (escalating doses from 5 to 40 mg/kg, three times a day for 5 days) morphine treatments in mice on locomotor activity. We also quantified, by autoradiography, mu opioid receptor (MOR) in ventral tegmental area (VTA), dopamine D1 (D1R) and D2 (D2R) receptors in striatum. Whereas the intermittent treatment led to a long-term sensitization to locomotor effects of morphine [until withdrawal day (WD) 14], the chronic treatment induced a tolerance (WD1) followed by a transient sensitization (WD14). Binding studies demonstrated a decrease of MOR in VTA at WD1 for the chronic treatment. In contrast, striatal D1R level was decreased at WD1, and increased at WD14 for the chronic treatment. For the D2R, we observed a decrease from WD1 to WD14 for the intermittent treatment and an increase at WD1 followed by a decrease at WD14 for the chronic treatment. These results demonstrate that chronic and intermittent morphine treatments could induce different behavioral adaptations that could be explained in part by distinct changes occurring in dopamine and opioid systems.