Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brainderived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.
Our study illustrates that the Bayesian approach represents the better choice in NIPAT data interpretation. Further, the adoption of more informative markers (e.g., tri-allelic SNPs, tetra-allelic SNPs, and micro-haplotypes) or deeper sequencing is recommended for the improvement of the testing efficiency.
Methamphetamine (MA), an extremely addictive synthetic stimulant, has quickly spread to become the most frequently used illicit drug in China. People with a history of chronic and heavy MA use have a high possibility of exhibiting schizophrenia-like psychotic symptoms, mainly delusions of reference, auditory hallucinations and cognitive deficits. These emerging findings suggest MA use increases aggression and violence and that there is a correlation between MA use and violence. However, it is unclear how to assess the capacity of criminal responsibility in “MA-induced” psychosis and how to set clear boundaries between schizophrenia and MA-induced psychosis when only limited and inconsistent evidence is available. Furthermore, a final persuasive differential diagnostic method based on improved understanding of schizophrenia and MA-induced psychotic disorders has yet to be developed. This paper will evaluate the epidemiology, social harm, and forensic psychiatric assessment of MA users, propose a future direction for the differential diagnosis between MA-induced psychotic disorders and schizophrenia, and put forward some practical solutions to assess the capacity of criminal responsibility of defendants with drug-induced psychotic disorder.
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