Clinically, it has been reported that atopic dermatitis (AD) has been linked with negative emotional problems such as depression and anxiety, thereby reducing the quality of life, but little is known about the molecular mechanism that underlies AD-associated emotional impairments. We sought to determine whether AD could induce anxiety- and depressive-like symptoms in mice and to identify pertinent signaling changes in brain reward circuitry. AD-like lesions were induced by the repeated intradermal application of MC903 into the cheek of the mouse. We assessed dermatitis severity with scratching behavior, histopathological changes, anxiety- and depressive-like behaviors using the elevated plus maze, open field and tail suspension tests, and serum corticosterone levels. In the nucleus accumbens (NAc), dorsal striatum (DS) and ventral tegmental area (VTA), protein levels of dopamine- and plasticity-related signaling molecules were determined by Western immunoblotting assay. Intradermal administration of MC903 into mouse cheek provoked a strong hind limb scratching behavior as well as the robust skin inflammation with epidermal thickening. MC903-treated mice also displayed markedly increased anxiety- and depressive-like behaviors, along with elevated serum corticosterone levels. Under these conditions, enhanced cAMP response element binding protein (CREB) and dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) phosphorylation, significantly higher brain-derived neurotrophic factor (BDNF) and ΔFosB, but reduced tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) protein expression were found in the NAc, DS and VTA. Striatal BDNF, phospho-DARPP32 and phospho-CREB levels were significantly associated with the levels of depressive-like behavior in these mice. Taken together, these findings demonstrate that AD-like skin lesion elicits anxiety- and depressive-like phenotypes that are associated with neuroplasticity-related changes in reward circuitry, providing a better understanding of AD-associated emotional impairments.

Post-traumatic stress disorder (PTSD) is a psychiatric disease that can form following exposure to a traumatic event. Acupuncture has been proposed as a beneficial treatment for PTSD, but the underlying mechanisms remain unclear. The present study investigated whether acupuncture improves depression- and anxiety-like behaviors induced using a single prolonged stress (SPS) as a PTSD rat model. In addition, we investigated whether the effects were mediated by increased mTOR activity and its downstream signaling components, which contribute to protein synthesis required for synaptic plasticity in the hippocampus. We found that acupuncture at HT8 significantly alleviated both depression- and anxiety-like behaviors induced by SPS in rats, as assessed by the forced swimming, elevated plus maze, and open field tests; this alleviation was blocked by rapamycin. The effects of acupuncture were equivalent to those exerted by fluoxetine. Acupuncture regulated protein translation in the mTOR signaling pathway and enhanced the activation of synaptic proteins, PSD95, Syn1, and GluR1 in the hippocampus. These results suggest that acupuncture exerts antidepressant and anxiolytic effects on PTSD-related symptoms by increasing protein synthesis required for synaptic plasticity via the mTOR pathway in the hippocampus. Acupuncture may be a promising treatment for patients with PTSD and play a role as an alternative PTSD treatment.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons in the lateral hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, indicating the involvements of many physiological functions, but the role in pain has yet to be determined. In this study, we found that pMCH^−/−mice showed lower baseline pain thresholds to mechanical and thermal stimuli than did pMCH^+/+mice, and the time to reach the maximum hyperalgesic response was also significantly earlier in both inflammatory and neuropathic pain. To examine its pharmacological properties, MCH was administered intranasally into mice, and results indicated that MCH treatment significantly increased mechanical and thermal pain thresholds in both pain models. Antagonist challenges with naltrexone (opioid receptor antagonist) and AM251 (cannabinoid 1 receptor antagonist) reversed the analgesic effects of MCH in both pain models, suggesting the involvement of opioid and cannabinoid systems. MCH treatment also increased the expression and activation of CB1R in the medial prefrontal cortex and dorsolateral- and ventrolateral periaqueductal grey. The MCH1R antagonist abolished the effects induced by MCH. This is the first study to suggest novel analgesic actions of MCH, which holds great promise for the application of MCH in the therapy of pain-related diseases.

Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( l -dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l -dopa and antidyskinetic effects caused by l -dopa as well. The effects of KD5040 and l -dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by l -dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum. KD5040 synergistically improved the motor function when low-dose l -dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose l -dopa. KD5040 lowered the effective dose of l -dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of l -dopa and alleviate its adverse effects in patients with PD.