[Modification of the behavioral effects of drugs after repeated administration--special reference to the reverse tolerance of amphetamines]

Abstract

It has been well-known that a chronic abuse of amphetamines induces schizophrenia-like psychotic symptoms, namely amphetamine psychosis. When amphetamines are repeatedly administered to rodents, a reverse tolerance (behavioral sensitization) to the ambulation-increasing and/or stereotypy-producing effect is observed. The process of the reverse tolerance is affected by various factors. A clear reverse tolerance is produced when optimal doses of the drug (2 mg/kg, s.c. for mice, and 0.5-1 mg/kg, s.c., for rats) is administered at intervals of longer than 1 day rather than a shorter interval. Furthermore, the animal has to be put into a freely mobile situation during the presence of the acute drug effect. A cross reverse tolerance is observed between certain types of drugs that show an ambulation-increasing effect, although the potencies are different among the drugs. A reverse tolerance to the stereotypy (in particular sniffing and head-bobbing)-producing effect is also observed when comparatively higher doses of methamphetamine are repeatedly administered. The process is qualitatively identical with the reverse tolerance to the ambulation-increasing effect produced by the repeated administration of comparatively smaller doses. The reverse-tolerance, once established, to both ambulation-increasing and stereotypy-producing effects is almost irreversible even with various treatments such as repeated post-treatment with antipsychotics. The characteristics of reverse tolerance to methamphetamine in animals might be closely correlated to the amphetamine psychosis in humans. It is also necessary to search for a method that effectively reduces the established reverse tolerance to amphetamines.