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Posttraumatic stress disorder (PTSD), a psychiatric disorder caused by stressful events, is characterized by long-lasting fear memory. The nucleus accumbens shell (NAcS) is a key brain region that regulates fear-associated behavior. Small-conductance calcium-activated potassium channels (SK channels) play a key role in regulating the excitability of NAcS medium spiny neurons (MSNs) but their mechanisms of action in fear freezing are unclear. We established an animal model of traumatic memory using conditioned fear freezing paradigm, and investigated the alterations in SK channels of NAc MSNs subsequent to fear conditioning in mice. We then utilized an adeno-associated virus (AAV) transfection system to overexpress the SK3 subunit and explore the function of the NAcS MSNs SK3 channel in conditioned fear freezing. Fear conditioning activated NAcS MSNs with enhanced excitability and reduced the SK channel-mediated medium after-hyperpolarization (mAHP) amplitude. The expression of NAcS SK3 were also reduced time-dependently. The overexpression of NAcS SK3 impaired conditioned fear consolidation without affecting conditioned fear expression, and blocked fear conditioning-induced alterations in NAcS MSNs excitability and mAHP amplitude. Additionally, the amplitudes of mEPSC, AMPAR/NMDAR ratio, and membrane surface GluA1/A2 expression in NAcS MSNs was increased by fear conditioning and returned to normal levels upon SK3 overexpression, indicating that fear conditioning-induced decrease of SK3 expression caused postsynaptic excitation by facilitating AMPAR transmission to the membrane. These findings show that the NAcS MSNs SK3 channel plays a critical role in conditioned fear consolidation and that it may influence PTSD pathogenesis, making it a potential therapeutic target against PTSD. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent studies found that non‐coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug‐induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine‐conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR‐876‐5p in the acquisition of opioids‐associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self‐administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre‐miR‐876, transfection of LV‐lncLingo2 into HEK293 cells significantly upregulated miR‐876 expression and the changes of mature miR‐876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR‐876‐5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual‐luciferase assay confirmed that miR‐876‐5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training‐induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium‐activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR‐876‐5p in NAcC, hence modulating the development of opioid‐associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction. [ABSTRACT FROM AUTHOR]

A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541–5p and miR-6934–3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541–5p and miR-6934–3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541–5p and miR-6934–3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence. [Display omitted] [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is one of the most prevalently used illegal psychostimulants in many countries. Continuous exposure to METH leads to behavioral sensitization in animals, which can be used as a behavioral model with many mechanisms in common with relapse in humans. Molecular hydrogen has recently gained attention for its potential as a novel healthcare product with preventive and therapeutic applicability to a wide range of pathological conditions. However, it remains unclear whether and, if so, how hydrogen regulates METH-induced behavioral abnormalities. In the present study, we investigated the roles of molecular hydrogen on the acquisition and transfer of METH-induced behavioral sensitization and the accompanying changes in ERK phosphorylation and ΔFosB activation in the nucleus accumbens (NAc) of mice. To this end, male C57BL/6 mice received METH (0.1, 0.5 and 1.0 mg/kg, i.p.) injections for 7 days followed by a METH challenge (0.1, 0.5 and 1.0 mg/kg, i.p.) after a 7-day transfer period. Molecular hydrogen, delivered through a hydrogen-rich saline (HRS) injection (10 mL/kg, i.p., 3-h interval), was administered during the acquisition and transfer periods. We found that HRS administration was able to inhibit the acquisition and transfer of 0.1 and 0.5 mg/kg METH-induced behavioral sensitization to a certain extent, thereby attenuating the expression of behavioral sensitization. The HRS injections alone did not induce any obvious changes in locomotor activity in mice. Intriguingly, the increases in pERK and ΔFosB in the NAc, which accompanied the METH-induced behavioral sensitization, were also attenuated by the HRS treatments. Due to the anti-oxidative function of molecular hydrogen, the HRS injections reduced METH-induced reactive oxygen species and malondialdehyde generation in the NAc. These results suggest that molecular hydrogen serves as an anti-oxidative agent with potentially therapeutic applicability to the treatment of METH addicts. • Molecular hydrogen has previously been found to prevent morphine-withdrawal-induced negative affective states. • Molecular hydrogen was able to attenuate behavioral sensitization to a certain extent. • Molecular hydrogen was also shown to attenuate METH-induced accompanying increases of pERK and ΔFosB in NAc. • Molecular hydrogen may serve as an anti-oxidative agent with therapeutic potential in METH addiction. [ABSTRACT FROM AUTHOR]