Blockade of the orexin 1 receptors in the nucleus accumbens' shell reversed the reduction effect of olanzapine on motivation for positive reinforcers.

Effort-based choice of high reward requires one to decide how much effort to expend for a certain amount of reward. Orexin is a crucial neuropeptide in the physiological aspect especially a variety of affective and cognitive processes. The nucleus accumbens (NAc) is a region of the neural system that serves effort-related high reward choices andthe Orexin 1 receptor (OX1R) is distributed extensively throughout the nucleus accumbens shell (AcbS). Olanzapine (OLZ), a typical antipsychotic drug, has a high affinity to D2 as an antagonist, and also partial agonistic-like action at D2 receptors has been reported. We examined the interaction of OLZ with the orexinergic receptor 1 in AcbS on effort- related high reward choice when two goal arms were different in the amount of accessible reward. The animals had to pass the barrier for receiving a high reward in one arm (HRA) or obtain a low reward in the other arm without any cost. Before surgery, all animals were selecting the HRA on almost every trial.During test days, the rats received local injections of either DMSO 20% /0.5 µl, as vehicle or SB334867 (30, 100, 300 nM/0.5 µl), as selective OX1R antagonist, within the AcbS. Other group received OLZ (32 µM/0.5 µl DMSO20%) / vehicle alone or 5 min after administration of SB334867 (300 nM/0.5 µl). The results showed that administration of OLZ in the AcbS alters rat's preference for high reward. On the other hand, blocked of the OX1R (300 nM/0.5 µl) in this region could reverse the effect of OLZ, however, administration of the OX1R antagonists alone in the AcbS led to decreasing rat's preference for high reward. This result indicates that the orexin-1 antagonist might affect some effects of antipsychotic drugs.

Orexin 1 receptors in the anterior cingulate and orbitofrontal cortex regulate cost and benefit decision-making.

Orexin neurons are discretely localized within the lateral hypothalamus and have widespread projections into all areas of the brain. In addition, several lines of evidence specify that orexins may also participate in the regulation of a variety of affective and cognitive processes. The Orexin-1 receptor (OX1r) is distributed extensively throughout the prefrontal cortex (PFC). Delay-based decision- making is mediated largely by the orbitofrontal cortex (OFC) while effort- based decision-making is controlled by the anterior cingulated cortex (ACC). Hence, in the present study, a series of experiments were conducted to clarify the role of OX1r in the mPFC (ACC and/or OFC) in cost and benefit decision-making. The rats were trained in a delay and/or effort-based form of cost-benefit T-maze decision-making task. Two goal arms were different in the amount of accessible reward and cost. Before surgery, all animals were selecting the high reward arm and pay the cost on almost every trial. During the test days, the rats received local injections of either DMSO 20% /0.5 µl, as a vehicle, or SB334867 (3, 30 and 300 nM/0.5 µl), as a selective OX1r antagonist, within the ACC and/or OFC. The results of this study showed that the bilateral microinjection of SB334867 into ACC and/or OFC changed the preference to a low reward arm with no cost, indicating the role of OX1 receptors in cost and benefit decision- making. From these results, it can be implied that OX1 receptors in the mPFC play a crucial role for allowing the animal to evaluate and pay the cost to acquire greater rewards.

Effects of High-dose Vitamin E Supplementation on Markers of Cardiometabolic Risk and Oxidative Stress in Patients with Diabetic Nephropathy: a Randomized Double-blinded Controlled Trial.

INTRODUCTION: Patients with diabetic nephropathy (DN) may benefit from vitamin E's antilipid and antioxidant activities. This study aimed to evaluate the effects of high-dose vitamin E supplementation on markers of cardiometabolic risk and oxidative stress in patients with DN. MATERIALS AND METHODS: This randomized controlled trial was carried out on 54 patients with DN that were randomly divided into 2 groups to receive vitamin E supplement (800 IU/d) or placebo for 12 weeks. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine markers of cardiometabolic risk and oxidative stress. RESULTS: Vitamin E supplementation, compared with the placebo, resulted in a significant reduction in serum total cholesterol (-14.3 ± 29.9 mg/dL versus -0.8 ± 13.1 mg/L, P = .03), low-density lipoprotein cholesterol (-16.4 ± 28.5 mg/dL versus 0.1 ± 17.2 mg/L, P = .01), and ratio of total cholesterol to high-density lipoprotein cholesterol ratio (-0.5 ± 0.7 versus 0.1 ± 0.5, P = .001), and a significant elevation in vitamin E levels (39.7 ± 12.4 nmol/mL versus -0.5 ± 1.3 nmol/mL, P < .001) and high-density lipoprotein cholesterol levels (1.4 ± 3.7 versus -2.1 ± 5.1 mg/L, P = .006). It also resulted in a significant elevation in plasma glutathione levels. CONCLUSIONS: Our study demonstrated that high-dose vitamin E supplementation for 12 weeks had favorable effects on lipid profile and glutathione levels of patients with DN, except for triglycerides, very low-density lipoprotein cholesterol, nitric oxide, and total antioxidant capacity levels.

Effects of Coenzyme Q10 Supplementation on Gene Expressions Related to Insulin, Lipid, and Inflammation Pathways in Patients With Diabetic Nephropathy.

INTRODUCTION: Data on the effects of coenzyme Q10 (CQ10) on gene expression related to insulin, lipid, and inflammation in patients with diabetic nephropathy (DN) are scarce. This study aimed to determine the effects of CQ10 supplementation on gene expression related to insulin, lipid, and inflammation pathways in patients with DN. MATERIALS AND METHODS: Forty patients with DN, aged 40 to 85 years old, were randomly assigned into 2 groups to receive either 100 mg/d of CQ10 supplements (n = 20) or placebo (n = 20), for 12 weeks. Gene expression related to signaling pathway of insulin, lipid, and inflammation were determined in blood samples using a reverse transcriptase polymerase chain reaction method. RESULTS: Quantitative results of reverse transcriptase polymerase chain reaction demonstrated that compared with the placebo, CQ10 administration upregulated gene expression of peroxisome proliferator-activated receptor-γ (P = .02) in peripheral blood mononuclear cells of the patients with DN. In addition, compared with the placebo, CQ10 supplementation downregulated gene expression of interleukin-1 (P = .003) and tumor necrosis factor-α (P = .02). No significant effects were observed on gene expression of oxidized low-density lipoprotein, lipoprotein(a), glucose transporter-1, transforming growth factor-ß in the CQ10 group. CONCLUSIONS: Overall, CQ10 supplementation for 12 weeks in DN patients significantly improved gene expression of peroxisome proliferator-activated receptor-γ, interleukin-1, and tumor necrosis factor-α.