Behavioral consequences of methamphetamine-induced neurotoxicity in mice: relevance to the psychopathology of methamphetamine addiction.

Methamphetamine (METH) is a major drug of abuse in the United States. A high dose of METH given to mice and rats causes long-lasting depletion of tyrosine hydroxylase activity, dopamine (DA), and DA-transporter (DAT) binding sites in the striatum. In human METH-abusers, a marked decrease of the DAT in the caudate putamen was observed. Despite intensive investigations of the mechanism associated with METH-induced neurotoxicity, the behavioral consequences of this phenomenon are not clear. We used the mouse model of METH-induced neurotoxicity to investigate the response of the animals to the psychomotor-stimulating effect of METH and the rewarding effect of the drug. Mice pre-exposed to a neurotoxic dose of METH developed a marked sensitization to the psychomotor-stimulating effect of METH, which lasted for more than two months. The rewarding effect of METH was determined by the conditioned place preference (CPP) paradigm. Mice pre-exposed to the neurotoxic dose of METH showed reduced sensitivity to the rewarding effect of METH compared with control animals. While CPP was maintained for three months in the control group, the conditioned response in the METH pre-exposed animals lasted only a few days. These findings indicate that METH neurotoxicity is associated with opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse. Sensitization is pertinent to compulsive drug-seeking behavior that is accompanied by desensitization to the rewarding effect of METH.