Neurobiological and Molecular Bases of Methamphetamine-Induced Behavioral Sensitization and Spontaneous Recurrence of Methamphetamine Psychosis, and its Implication in Schizophrenia

Spontaneous recurrence of methamphetamine-or amphetamine-induced paranoid hallucinatory psychosis (i.e., flashbacks) occasionally occurs in response to non-specific mild stress in drug-free patients with a history of methamphetamine- or amphetamine-induced psychosis. Stress sensitization associated with noradrenergic hyperactivity and increased dopamine release may be related to this flashbacks. Stressful frightening experiences as well as fear-related paranoid- hallucinatory states during methamphetamine use may be related to these stress sensitization. Robust noradrenergic hyperactivity with increased dopamine release may predicts subsequent flashback episodes. Schizophrenia-like symptoms (e.g., passivity phenomena, Gedankenlautwerden, and thought disorder such as circumstantiality and egorrhea symptoms) appear to develop related to dopaminergic hyperactivity. One of the dopamine receptor-encoding genes DRD2, TaqIA A1/A1 type, with which reduced density of the D2 receptor is associated, reduces to the risk of development of flashbacks. Stress sensitization has been proposed as a key step in the progression from vulnerability to an overt paranoidhallucinatory states, so that schizophrenia and flashbacks due to previous methamphetamine psychosis shares common underlying mechanisms of stress sensitization. Compared to flashbacks due to previous methamphetamine psychosis, psychedelic drug flashbacks are the recurrence of a perception learned while an individual is experiencing high anxiety levels, and thus recur in anxiety-related situations. Anxiety or fear during drug use is an important factor in the development of flashbacks due to previous methamphetamine psychosis and also psychedelic drug flashbacks. Dopaminergic and glutamatergic neural circuits including the striatum, nucleus accumbens and prefrontal cortex play an important role in the development of psychostimulant-induced long-lasting behavioral sensitization. Immediate early genes expression in the particular brain regions affected by the psychostimulants is involved in this process. Furthermore, recent advances in molecular analysis could shed light on the fundamental mechanism involved, by identifying specific participating molecules such as delta FosB, NAC1, G-protein b1 subunit and methamphetamine-responsive transcript 1b.