LiCl Pretreatment Ameliorates Adolescent Methamphetamine Exposure-Induced Long-Term Alterations in Behavior and Hippocampal Ultrastructure in Adulthood in Mice

摘要

Background Adolescent methamphetamine exposure causes a broad range of neurobiological deficits in adulthood. Glycogen synthase kinase-3β is involved in various cognitive and behavioral processes associated with methamphetamine exposure. This study aims to investigate the protective effects of the glycogen synthase kinase-3β inhibitor lithium chloride on adolescent methamphetamine exposure-induced long-term alterations in emotion, cognition, behavior, and molecule and hippocampal ultrastructure in adulthood. Methods A behavioral test battery was used to investigate the protective effects of lithium chloride on adolescent methamphetamine exposure-induced long-term emotional, cognitive, and behavioral impairments in mice. Western blotting and immunohistochemistry were used to detect glycogen synthase kinase-3β activity levels in the medial prefrontal cortex and dorsal hippocampus. Electron microscopy was used to analyze changes in synaptic ultrastructure in the dorsal hippocampus. Locomotor sensitization with a methamphetamine (1 mg/kg) challenge was examined 80 days after adolescent methamphetamine exposure. Results Adolescent methamphetamine exposure induced long-term alterations in locomotor activity, novel spatial exploration, and social recognition memory; increases in glycogen synthase kinase-3β activity in dorsal hippocampus; and decreases in excitatory synapse density and postsynaptic density thickness in CA1. These changes were ameliorated by lithium chloride pretreatment. Adolescent methamphetamine exposure-induced working memory deficits in Y-maze spontaneous alternation test and anxiety-like behavior in elevated-plus maze test spontaneously recovered after long-term methamphetamine abstinence. No significant locomotor sensitization was observed after long-term methamphetamine abstinence. Conclusions Hyperactive glycogen synthase kinase-3β contributes to adolescent chronic methamphetamine exposure-induced behavioral and hippocampal impairments in adulthood. Our results suggest glycogen synthase kinase-3β may be a potential target for the treatment of deficits in adulthood associated with adolescent methamphetamine abuse. methamphetamine , adolescent drug exposure , glycogen synthase kinase 3 beta , behavior , hippocampus Significance Statement Current methamphetamine (METH)-related studies tend to focus on adults, ignoring adolescent drug exposure. This study investigated the protective effects of the GSK3β inhibitor lithium chloride (LiCl) on adolescent METH exposure-induced long-term alterations in emotion, cognition, behavior, and hippocampal ultrastructure. Adolescent METH exposure significantly increased GSK3β activity in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHIP), but this effect persisted only in the dHIP in adulthood. Treatment with LiCl before METH administration prevented adolescent METH exposure-induced long-term behavioral alterations, including mild hyperactivity, reduced novel spatial exploration, and impaired social recognition memory as well as GSK3β hyperactivity and ultrastructural alterations in the dHIP in adulthood. Adolescent METH exposure-induced working memory deficits in the Y-maze spontaneous alternation test and anxiety-related behavior in the elevated-plus maze test spontaneously recovered after long-term METH abstinence. Thus, our data suggest GSK3β may be a potential target to improve adolescent METH exposure-induced long-term behavioral and hippocampal impairments.