There exist clinical characteristics of methamphetamine (MAP) psychosis in the Japanese population. MAP psychosis involves paranoid-hallucinatory states indistinguishable from paranoid schizophrenia, with residual volitional disturbances (e.g., loss of spontaneity and idleness). Paranoid-hallucinatory states persist after the pharmacological effects of MAP have worn off and readily reappear upon a reinjection of MAP. Individuals with a history of MAP psychosis further undergo spontaneous recurrence of their paranoid-hallucinatory states in response to stress. The development of MAP psychosis might therefore be related to persisting brain damage or changes in brain metabolism induced by repeated MAP use, and thus studies of the clinical course and neurological basis of MAP psychosis could provide insights into the pathophysiology of schizophrenia. Accordingly, psychiatrists have studied the clinical characteristics of MAP psychosis and examined the neurobiological basis of MAP-induced behavioral sensitization, using animals. MAP-induced behavioral sensitization might well be related to dopamine supersensitivity; however, the contribution of presynaptic autoreceptors remains controversial, and other hypotheses should be considered. Recently, the process that triggers spontaneous recurrence of MAP psychosis (flashbacks) and corresponding peripheral neurotransmitter functions has been studied. Stress sensitization associated with noradrenergic hyperactivity, involving increased dopamine release, appears to be crucial in the development of flashbacks. Overall, MAP-induced susceptibility to paranoid-hallucinatory states and to abnormal behavior (e.g., stereotyped behavior) in animals is examined as a model for predicting relapses of paranoid schizophrenia. Further extensive studies on the neurobiological and molecular mechanisms of this susceptibility are required.

A number of consistent clinical observations provide direction for the hypothesis that pathological sensitization of neuronal systems may be an important factor for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and schizophrenia. First, psychotic symptoms can be produced in normal subjects by stimulants. Secondly, a large portion of schizophrenic patients exhibit exacerbation of psychotic symptoms in response to stimulants at doses which would not be psychotogenic in normal subjects. Lastly, the ability of stress to precipitate the onset and relapse of schizophrenia is well documented. In this regard, acute responses to stimulants provide useful information for relapse prediction of schizophrenia and substance abuse. This paper addresses the nature and role of pathological sensitization in relapse of stimulant-and phencyclidine-induced psychosis and schizophrenia, and its relation to pathophysiology of schizophrenia.

In this study, we examined the relationship between increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes, and susceptibility to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (i.e., flashbacks). The subjects were 81 physically healthy females. Plasma monoamine metabolite levels were assayed in: 19 flashbackers, of whom 11 experienced a single flashback and 8 exhibited subsequent flashbacks; 20 non-flashbackers with a history of MAP psychosis; 8 subjects with persistent MAP psychosis; and 23 MAP users and 11 non-user controls. All 19 flashbackers had undergone frightening and stressful experiences during previous MAP use. Mild psychosocial stressors then triggered their flashbacks. During flashbacks, plasma norepinephrine levels increased, with a small increase in plasma levels of 3-methoxytyramine, which is an index of dopamine release. Among the 19 flashbackers, the 8 with subsequent episodes had increased NE levels and slightly increased 3-methoxytyramine levels, while the 11 with a single episode displayed small increases in norepinephrine and 3-methoxytyramine levels. Thus, noradrenergic hyperactivity and increased dopamine release in response to mild psychosocial stressors may be responsible for the development of flashbacks. Robust noradrenergic hyperactivity with slightly increased DA release in response to mild stress may induce susceptibility to subsequent flashbacks. Flashbacks and schizophrenia may share the pathophysiology of susceptibility to recurrence of paranoid-hallucinatory states such as stress sensitization, and also noradrenergic hyperactivity and enhanced DA release. Thus, flashbacks may provide an appropriate model of susceptibility to paranoid-hallucinatory states of schizophrenia. The model psychosis is a potential tool for validating basic neurobiological concepts thought to be related to the schizophrenia. A better understanding of the neurobiological mechanisms of susceptibility to recurrence could provide useful information in the development of strategies for preventing relapse.

These results suggest that strong 5-HT2A antagonists such as risperidone, but not dopamine D2 antagonists, counteract lethality due to 5-HT syndrome, and that not only does enhancement of 5-HT activity occur in the 5-HT syndrome, but NA activity also increases.

We examined the influence of electroconvulsive seizure (ECS) and imipramine (IMI) treatment on the transcription and translation of cyclic nucleotide phosphodiesterase type IV (PDE IV) isozymes in the rat brain. Our in situ hybridization studies revealed an increase of PDE IV-B mRNA level in various brain regions after acute ECS. However, the increase of PDE IV activity was produced not by acute but by chronic ECS treatment in the frontal cortex. Increased PDE V-B mRNA expression in frontal but not in hippocampal subfields was induced also after chronic ECS treatment. Although an increase in PDE V-A mRNA expression of the dentate gyrus in the hippocampus was observed, no change of PDE IV activity was produced in the hippocampus by acute or chronic ECS treatment. These results suggest that the repeated increases of PDE lV-B mRNA expression are attributable to the increase of PDE IV translation. Increased PDE IV-B transcription and PDE IV translation in the frontal cortex were also produced after chronic Ml treatment. This is the first report demonstrating an expressional regulation of Drosophila melanogaster dunce (dnc) gene homologue PDE IV isozymes in the brain. Although no pathophysiological conditions with reduced PDE IV activity in the nervous system are known except for a learning deficit in the mutant fly dnc -, our results suggest possible treatments to cope with reduced PDE IV activity. Key Words: Cyclic nucleotide phosphodiesterase type IV-Rolipram -Electroconvulsive seizure-Imipramine-In situ hybridization-Enzyme activity.