Neurochemical analysis of the psychotoxicity of methamphetamine and cocaine by microdialysis in the rat brain.

To examine the neurochemical mechanism underlying the development of psychotoxicity by methamphetamine and cocaine, the levels of dopamine, serotonin and their metabolites were determined by in vivo microdialysis in the brains of freely moving rats. Methamphetamine (0.5 mg/kg, s.c.) or cocaine (10 mg/kg, i.p.) was repeatedly administered for 8 to 21 experiment days, and after confirming the development of sensitization to the stimulating effect of the drugs on spontaneous motor activity, a microdialysis probe was implanted into the nucleus accumbens (N.Acc.) or striatum of the brain of the treated rats. Then, each test drug was readministered to the rats and dopamine and DOPAC or serotonin and 5-HIAA concentrations were determined. In the N.Acc. of untreated control rats, methamphetamine increased dopamine to about 4 times the preadministration value along with a decrease of DOPAC. Methamphetamine also increased serotonin to about twice the preadministration value along with no change in 5-HIAA. Cocaine increased dopamine to about 4 times along with a slight decrease in DOPAC. In the treated rats as compared with the untreated rats, the increasing effect of methamphetamine on dopamine in the N.Acc. was enhanced but that of cocaine was not. Also, the serotonin levels were lower than in the untreated rats and 5-HIAA was unchanged. In the striatum of untreated rats, methamphetamine increased dopamine to about 3 times the preadministration value along with a slight decrease in DOPAC. In the treated rats, the increasing effect of methamphetamine on dopamine in the striatum was enhanced, and the DOPAC level was higher than in the treated rats. The present study suggests that the dopamine level at the N.Acc. does not necessarily reflect the sensitization to spontaneous motor activity, and that enhancement of the motor activity does not seem to be the best model for psychotoxic manifestation.