Basolateral Amygdala Serotonin 2C Receptor Regulates Emotional Disorder-Related Symptoms Induced by Chronic Methamphetamine Administration

Abstract

Globally, methamphetamine (MA) is the second most abused drug, with psychotic symptoms being one of the most common adverse effects. Emotional disorders induced by MA abuse have been widely reported both in human and animal models; however, the mechanisms underlying such disorders have not yet been fully elucidated. In this study, a chronic MA administration mouse model was utilized to elucidate the serotonergic pathway involved in MA-induced emotional disorders. After 4 weeks of MA administration, the animals exhibited significantly increased depressive and anxious symptoms. Molecular and morphological evidence showed that chronic MA administration reduced the expression of the 5-hydroxytryptamine (5-HT) rate-limiting enzyme, tryptophan hydroxylase 2, in the dorsal raphe and the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid in the basolateral amygdala (BLA) nuclei. Alterations in both 5-HT and 5-HT receptor levels occurred simultaneously in BLA; quantitative polymerase chain reaction, western blotting, and fluorescence analysis revealed that the expression of the 5-HT2C receptor (5-HT2CR) increased. Neuropharmacology and virus-mediated silencing strategies confirmed that targeting 5-HT2CR reversed the depressive and anxious behaviors induced by chronic MA administration. In the BLA, 5-HT2CR-positive cells co-localized with GABAergic interneurons. The inactivation of 5-HT2CR ameliorated impaired GABAergic inhibition and decreased BLA activation. Thus, herein, for the first time, we report that the abnormal regulation of 5-HT2CR is involved in the manifestation of emotional disorder-like symptoms induced by chronic MA use. Our study suggests that 5-HT2CR in the BLA is a promising clinical target for the treatment of MA-induced emotional disorders.

Running ameliorates methamphetamine-associated cognitive impairment by regulating hippocampal neurogenesis through the GSK3β/β-catenin pathway

“…METH is not only highly addictive but also strongly neurotoxic, and its neurotoxic properties are dose dependent, eventually causing cognitive impairment, anxiety, depression and etc [26][27][28][29] . The dose and frequency of METH lead to occur different degrees of neuropsychiatric disorders, and the duration of the disorders varies [30][31][32][33] . Accumulating evidence indicates that repeated METH administration impairs object recognition, spatial working memory and fear memory, and some memory impairments can persist for about 28 d after drug withdrawal 30,34,35 .…”

Regulation and bioinformatic analysis of circ_0015891/miR-129-1-3p axis in methamphetamine-induced dopaminergic apoptosis

“…Proteins related to METH responses serotonin pathway is also thought to be involved in METH-induced behavioral changes. Targeting 5-HT 2C R can reverse depressive and anxiety behaviors induced by chronic METH administration ( 42 ). Another study evaluated the role of dopamine receptors (D1R and D2R) in METH-induced presynaptic and postsynaptic damage including dopaminergic apoptosis and DA-terminal marker depletion, and found that inhibition of either of the two receptors effectively reduced presynaptic and postsynaptic damage induced by METH ( 43 ).…”

Aerobic Exercise Improves Methamphetamine-Induced Olfactory Dysfunction Through α-Synuclein Intervention in Male Mice

“…85–23, revised 1985) and supervised by the Animal Ethics Committee of The Third Affiliated Hospital of Sun Yat-sen University. The chronic administration route and dosage (10 mg/kg i. p. daily, National Institute Control of Pharmaceutical and Biological Products, Beijing, China) of Meth were chosen based on our previous chronic toxicity study ( Wang et al, 2021a ). Behavioral experiments were performed 1 week after the last Meth administration or 4 weeks after the virus injection.…”