Antagonist of N-methyl-D-aspartate receptors partially prevent the development of cocaine sensitization

Behavioral sensitization to cocaine was tested for in rats pretreated with MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, or D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene), a competitive NMDA antagonist. A 5-day regimen of once-daily cocaine (15 mg/kg) injections yielded sensitization to cocaine (15 mg/kg)-induced behavioral activation. Cocaine sensitization was partially prevented by MK-801 (0.25 mg/kg) or D-CPPene (20 mg/kg) pretreatment. These results differ from previous reports that NMDA receptor antagonists completely prevented the development of stimulant sensitization. While raising questions about methodological differences among laboratories studying this issue, our findings suggest that sensitization may involve mechanisms dependent on NMDA-receptor function as well as NMDA receptor-independent mechanisms.