Treadmill exercise training inhibits morphine CPP by reversing morphine effects on GABA neurotransmission in D2-MSNs of the accumbens-pallidal pathway in male mice.

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.

The different cell-specific mechanisms of voluntary exercise and forced exercise in the nucleus accumbens.

Physical inactivity is a global epidemic. People who take the initiative to exercise will feel pleasure during the exercise process and stick with it for a long time, while people who passively ask for exercise will feel pain and cannot stick with it. However, the neural mechanisms underlying voluntary and forced exercise remain unclear. Here, we report that voluntary running increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC) but decreased membrane excitability in D1R-MSNs, whereas D2R-MSNs did not change in mEPSC and membrane excitability. Forced running increased the frequency of mEPSC and membrane excitability in D2R-MSNs, but D1R-MSNs did not change, which may be the mechanism by which forced exercise has a non-rewarding effect. These findings provide new insights into how voluntary and forced exercise mediate reward and non-reward effects.

Chronic restraint stress-induced depression-like behavior is mediated by upregulation of melanopsin expression in C57BL/6 mice retina.

BACKGROUND: Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin. METHODS: Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs. RESULTS: The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid. CONCLUSIONS: CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice.

CD59 prevents human complement-mediated injuries in isolated guinea pig hearts.

OBJECTIVE: To assess complement-mediated myocardial injury on isolated guinea pig working hearts and cardioprotective effects of CD59. METHODS: Using a modified Langendorff apparatus, isolated guinea-pig working hearts were perfused with a modified Krebs Henseleit buffer containing 3% heat-inactivated human plasma and zymosan (IPZ) (control) (n = 10), 3% normal human plasma and zymosan (NPZ) (n = 10), or 3% normal human plasma and zymosan and 1.5 microg/ml CD59 (NPZC) (n = 10), respectively. Epicardial electrocardiogram (ECG), cardiac output (CO), coronary arterial flow (CF), maximum left ventricular developed pressure (LVP(max)), maximum left ventricular developed pressure increase rate (+ dp/dt(max)), maximum left ventricular developed pressure decrease rate (- dp/dt(max)) and heart rate (HR) were recorded at 0, 15, 30, 45 and 60 min of treatment. After the experiment, immunohistochemical examination was performed to detect the presence of C3a or C5b-9 in the myocardium of the isolated hearts. RESULTS: Compared the IPZ group, hearts treated with NPZ showed a slight depression on ST segments of epicardial ECG at 15 min, a significant elevation between 30 min to 60 min, a decrease in CF, CO, LVP(max), + dp/dt(max) and - dp/dt(max), and an increase in HR at 15 min. The observed alterations in CF, CO, LVP(max), + dp/dt(max) and - dp/dt(max) remained decreased, while the HR remained increased until the end of the protocol. The all above parameters of hearts treated with NPZC were similar to the control group (IPZ) at any given time. Immunohistochemical examination showed positive signals of C3a and C5b-9 in the myocardium of hearts treated with NPZ. C3a was positive in NPZC, and C3a and C5b-9 were negative in IPZ. CONCLUSIONS: Activated human complements directly damage isolated guinea pig working hearts, and CD59 offers a significant protection against the injuries.