The study of the clinical course of methamphetamine (MAP) psychosis yields insights into the biological aspect of the relapse of the paranoid psychotic state with hallucination in schizophrenia. A series of MAP psychosis studies in Japan conducted over a period of more than four decades revealed three types of clinical courses of MAP psychosis after discontinuation of MAP: transient type, prolonged type, and persistent type. Identification of the latter two indicates a lasting change in the brain that produces and maintains a schizophrenia-like paranoid psychotic state without MAP. The characteristic course seen in the transient type is acute recurrence of the psychotic state after a long remission period, almost identical to the initial episode, due to reuse of MAP or to psychological stressors. Such lasting vulnerability of the brain to schizophrenia-like psychotic symptoms may be caused by a lasting sensitization of the brain to the psychotogenic action of MAP resulting from its chronic abuse. Experimental studies using animals sensitized to MAP-induced stereotypy suggest that lasting enhancement of MAP-induced dopamine release in the striatum and nucleus accumbens is related to the development and expression of brain vulnerability to schizophrenic symptoms.

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Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-beta pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

The present study examined effects of selective antagonists of D-1 and D-2 dopamine receptors on the development of behavioral sensitization produced by repeated methamphetamine (MAP) administration. Male Sprague-Dawley rats were divided into four groups. Each group received a daily injection of saline (control group), 4 mg/kg MAP (MAP group), 1 mg/kg YM-09151-2 plus 4 mg/kg MAP (YM + MAP group) or 0.5 mg/kg SCH 23390 plus 4 mg/kg MAP (SCH + MAP group) for 14 days. During daily injection for 14 days, the MAP group exhibited a progressive augmentation in locomotor and stereotyped behavior, whereas the progression of such behaviors in the YM + MAP and SCH + MAP group was completely prevented. After an abstinence period of 7 days, all groups received a challenge of 2 mg/kg MAP. The MAP challenge reproduced hyperlocomotion and intense stereotyped behavior only in the MAP group. However, neither the YM + MAP group nor the SCH + MAP group showed stereotypy. The manner in which both groups showed only hyperlocomotion was similar to that observed in the control group. These results indicate that both selective D-1 antagonists and selective D-2 antagonists not only reverse MAP-induced motor effects at each injection but also prevent the development of behavioral sensitization induced by repeated MAP administration.

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