| Abstract: | Background: Methamphetamine abuse and addiction can lead to impaired cognition and psychosis, and there is no effective treatment for methamphetamine-induced mental illnesses. In this study, we tested whether repeated electroconvulsive shock (ECS) treatment has a therapeutic effect on methamphetamine-induced abnormal behavior in mice. Methods: To test the effects of ECS on methamphetamine-induced psychosis, ICR mice were randomly assigned to administration with either chronic methamphetamine or saline injection, and then both groups underwent post-treatment with either six once-daily ECS treatments or parallel sham controls. Prepulse inhibition (PPI), the novel object recognition test (NORT) and behavioral sensitization were performed for behavioral evalu-ation between the groups. To test the effects of ECS on methamphetamine addiction, methamphetamine-induced conditioned place preference (CPP) was examined after ECS and drug-primed reinstatement in the other set of experiments. Results: Analysis of PPI scores revealed a main effect of prepulse stimuli (three-way ANOVA; F (2,72) =186.5, p < 0.001), methamphetamine pretreatment (F (1,36) =5.1, p=0.03) and a significant methamphetamine × prepulse stimuli interaction (F (2,72) =3.4, p=0.039). The use of post hoc comparisons showed that the PPI scores of the MAP + Sham group were significantly reduced (vs. MAP + ECS: p=0.036, vs. SAL + ECS: p=0.023, vs. SAL + Sham: p=0.024), while there were no significant differences in PPI among the three other groups. The PPI results suggest that chronic repeated methamphetamine administration could induce PPI disruption in this paradigm, and the disruption could be ameliorated by ECS. In the NORT training session, the mice spent nearly the same time exploring the two identical objects, and the exploratory preferences of the four groups were similar. In the retention session, preferred exploration of the new object was found among all tested groups of mice, and ANOVA showed that both methamphetamine and ECS had the main effects of exploratory preferences (methamphetamine, F (1,36) =33.4, p < 0.001; ECS, F (1,36) =9.39, p=0.004]. The preference index of the MAP + Sham group was significantly lower than that of the other three groups (post hoc comparison, p < 0.01). The results of NORT suggest that long-term administration of methamphetamine could lead to cognitive impairment, which could be improved by ECS treatment. Methamphetamine-induced behavioral sensitization was established in this paradigm and intervention with ECS at the dose tested did not reverse it in the drug-pre-exposed animals. In the CPP study, the ECS-treated animals achieved extinction of place preference, but relapsed after a low-dose reinstatement of methamphetamine. Discussion: The results of each part of our study are in line with the dopamine hypothesis of psychosis as well as the clinical responses commonly seen in patients receiving ECT: better responses for psychotic symptoms, poor responses for addiction and relapse prevention. To our knowledge, this is the first study combining methamphetamine pretreatment and ECS post-treatment with several behavioral phenotyping assays. We tested the possible therapeutic effects of ECT and generated an animal model dealing with development, recovery or relapse pertaining to psychosis and addiction. It appears that this animal model suitably reflects the effect of ECT on psychotic symptoms in clinical situations, and provides an elegant approach to researching new targets for the development of drugs. |
