Synaptic Neurotransmission Depression in Ventral Tegmental Dopamine Neurons and Cannabinoid-Associated Addictive Learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction

Synergistic bimetallic Ru–Pt catalysts for the low-temperature aqueous phase reforming of ethanol

Aqueous phase reforming (APR) of ethanol has been studied over a series of Ru and Pt catalysts supported on carbon and titania, with different metal loadings and particle sizes. This study proposed that, on both metals, ethanol is first dehydrogenated to acetaldehyde, which subsequently undergoes CC cleavage followed by different paths, depending on the catalyst used. For instance, although monometallic Pt has high selectivity toward H2 via dehydrogenation, it has a low efficiency for CC cleavage, lowering the overall H2 yield. Large Ru particles produce CH4 through methanation, which is undesirable because it consumes H2. Small Ru particles have lower activity but higher selectivity toward H2 rather than CH4. On these small particles, CO blocks low-coordination sites, inhibiting methanation. The combination of the two metals in bimetallic Ru–Pt catalysts results in improved performance, benefiting from the desirable properties of each Ru and Pt, without the negative effects of either

Curcumin Inhibits srebp-2 Expression in Activated Hepatic Stellate Cells in Vitro by Reducing the Activity of Specificity Protein-1

Elevated levels of cholesterol/low-density lipoprotein (LDL) are a risk factor for the development of nonalcoholic steatohepatitis and its associated hepatic fibrosis. However, underlying mechanisms remain elusive. We previously reported that curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)-γ and stimulated its activity, leading to the inhibition of the activation of hepatic stellate cells (HSCs), the major effector cells during hepatic fibrogenesis. We recently showed that curcumin suppressed gene expression of LDL receptor in activated HSCs in vitro by repressing gene expression of the transcription factor sterol regulatory element binding protein-2 (SREBP-2), leading to the reduction in the level of intracellular cholesterol in HSCs and to the attenuation of the stimulatory effects of LDL on HSCs activation. The current study aimed at exploring molecular mechanisms by which curcumin inhibits srebp-2 expression in HSCs. Promoter deletion assays, mutagenesis assays, and EMSAs localize a specificity protein-1 (SP-1) binding GC-box in the srebp-2 promoter, which is responsible for enhancing the promoter activity and responding to curcumin in HSCs. Curcumin suppresses gene expression of SP-1 and reduces its trans-activation activity, which are mediated by the activation of PPARγ. The inhibitory effect of curcumin on SP-1 binding to the GC-box is confirmed by chromatin immuno-precipitation. In summary, our results demonstrate that curcumin inhibits srebp-2 expression in cultured HSCs by activating PPARγ and reducing the SP-1 activity, leading to the repression of ldlr expression. These results provide novel insights into molecular mechanisms by which curcumin inhibits LDL-induced HSC activation

NMDAR mediates cannabinoid-facilitated LTD induction in the VTA.

<p>(A) CPPG and 4CPG together failed to affect LFS-induced LTD in chronic HU210-treated rats. (B) AP-5 blocked LFS-induced VTA LTD in chronic HU210-treated rats. (C) Ro25-6981 and ifenprodil blocked LFS-induced VTA LTD in chronic HU210-treated rats. (D) NVP-AAM077 failed to affect LFS-induced LTD in chronic HU210-treated rats. (E) Summary of LTD induction and blockade. ** <i>p</i><0.01 versus baseline.</p