One-way Cross-sensitization and Cross-tolerance to Seizure Activity from Cocaine to Lidocaine

The present study examined the effects of daily treatment with a subconvulsant dose (50 mg/kg) of cocaine or lidocaine on susceptibility to seizures induced by cross-injections of the same dose of the other local anesthetic, and to seizures induced by pentylenetetrazol (PTZ) or N-methyl-DL-aspartate (NMDLA) in ddY mice. Repeated administration of 50 mg/kg cocaine caused the development of sensitization to cocaine-induced seizures during an initial 3 or 4 days, followed by the development of tolerance on days 4-6. The same dose of lidocaine, however, produced little or no seizure activity following repeated administration. In contrast, when injected 24 hr after 2-4 days of cocaine treatment, 50 mg/kg lidocaine produced severe seizures. Interestingly, this cross-sensitization from cocaine to lidocaine diminished upon further cocaine treatment. In contrast, treatment with lidocaine for 2-6 days had no effect on subsequent changes in seizure susceptibility following repeated cocaine injections. Neither treatment with cocaine nor lidocaine for 2 or 5 days influenced susceptibility to seizures induced by a challenge injection of PTZ (50 mg/kg, i.p.) or NMDLA (300 mg/kg, i.p.) 24 hr after treatment. HPLC analyses revealed that the cocaine treatment paradigm used in these studies increased the levels of the polyamines, putrescine and spermidine, in mouse brain, while lidocaine treatment had no effect on cerebral polyamine levels. These results suggest that there are differences in the neural mechanisms underlying the convulsant properties of cocaine and lidocaine in ddY mice.