Behavioral sensitization and relative hyperresponsiveness of striatal and limbic dopaminergic neurons after repeated methamphetamine treatment.

Rats were used in a study of the effects of repeated methamphetamine treatment on stereotyped behavior and striatal and limbic dopamine metabolism in response to challenge with the drug or other dopamine agonists. Repeated administration of d-methamphetamine (6 mg/kg per day for 3-14 days) produced long-term behavioral sensitization (augmented response to a challenge injection) not only to the compound (at 44-89 days after drug withdrawal) but also to apomorphine and nomifensine. Even a single injection of d-methamphetamine (6 mg/kg) enhanced the behavioral response to the drug. A challenge dose of d-methamphetamine (2 mg/kg) markedly increased dopamine turnover (lower dopamine and higher 3,4-dihydroxyphenylacetic acid levels, higher ratios of 3,4-dihydroxyphenylacetic acid over dopamine) in the striatum and mesolimbic area of the sensitized animals on day 15 of withdrawal from treatment repeated for 14 days with the drug (6 mg/kg per day). These findings demonstrate that behavioral sensitization induced by methamphetamine is accompanied by increased central dopaminergic transmission.