Cocaine kindling in mice. Responses to N-methyl-D,L-aspartate (NMDLA) and L-arginine.

Previous studies proposed the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in the development of sensitization to the convulsive effect of cocaine (cocaine kindling). The present study was undertaken to determine, first, if cocaine kindling is associated with enhanced sensitivity of the NMDA receptor to the convulsive response of N-methyl-D,L-aspartate (NMDLA), and second, whether in vivo modulation of nitric oxide synthase (NOS) function regulates the development of cocaine kindling. The following results were observed: 1. Cocaine-kindled animals were significantly more susceptible to the convulsive effect of the NMDA receptor agonist NMDLA than saline controls; 2. Pretreatment with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg; ip) blocked the development of cocaine kindling; 3. The protective effect of L-NAME was partially reversed with the coadministration of the NOS substrate, L-arginine (300 mg/kg; ip), but not D-arginine; and 4. L-Arginine (300 mg/kg; ip), but not D-arginine, amplified the development of cocaine kindling. Taken together, these findings suggest that supersensitivity of the NMDA receptor and activation of NOS may underlie the development of cocaine kindling.