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

Background: Adolescent methamphetamine (METH) exposure causes a broad range of neurobiological deficits in adulthood. Glycogen synthase kinase-3β (GSK3β) is involved in various cognitive and behavioral processes associated with METH exposure. This study aims to investigate the protective effects of the GSK3β inhibitor lithium chloride (LiCl) on adolescent METH exposure-induced long-term alterations in emotion, cognition, behavior, molecule and hippocampal ultrastructure in adulthood.

Methods: A behavioral test battery was used to investigate the protective effects of LiCl on adolescent METH exposure-induced long-term emotional, cognitive and behavioral impairments in mice. Western blotting and immunohistochemistry were used to detect GSK3β activity levels in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHIP). Electron microscopy was used to analyze changes in synaptic ultrastructure in the dHIP. Locomotor sensitization with a METH (1 mg/kg) challenge was examined 80 days after adolescent METH exposure.

Results: Adolescent METH exposure induced long-term alterations in locomotor activity, novel spatial exploration and social recognition memory; increases in GSK3β activity in dHIP; and decreases in excitatory synapse density and postsynaptic density thickness in CA1. These changes were ameliorated by LiCl pretreatment. Adolescent METH 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 METH abstinence. No significant locomotor sensitization was observed after long-term METH abstinence.

Conclusions: Hyperactive GSK3β contributes to adolescent chronic METH exposure-induced behavioral and hippocampal impairments in adulthood. Our results suggest GSK3β may be a potential target for the treatment of deficits in adulthood associated with adolescent METH abuse.