Evidence for the involvement of cyclooxygenase activity in the development of cocaine sensitization.

Phospholipase A2 (PLA(2)) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA(2) activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague-Dawley rats were treated for 5 days with cocaine (30 mg/kg) or D-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or D-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA(2) inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5-10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5-10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1-2 mg/kg), piroxicam (0.5-1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5-1 mg/kg), and NS-398 (0.5-1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of D-amphetamine (5 microg/side) or saline coadministered with indomethacin (0.5 microg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for D-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 microg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA.