Methamphetamine (METH) is a highly addictive psychostimulant. Cannabidiol (CBD) is an exogenous cannabinoid without psychostimulating activity, which has potential therapeutic effects on opioid addiction. However, it is unclear whether CBD has therapeutic effects on METH-induced motivational effects. The present study examines whether CBD has a protective effect on METH-induced conditioned place preference (CPP) in rats by regulating the Sigma1R and AKT-GSK3β-CREB signaling pathway. Seventy rats were equally and randomly divided into seven groups. The rat CPP model was established via the intraperitoneal injection (IP) of 2 mg/kg of METH. Next, the intraperitoneal injection of 10, 20, 40, and 80 mg/kg CBD was performed 1 h prior to the injection of saline or METH. The protein expression levels of Sigma1R, AKT, p-AKT, GSK-3β, p-GSK-3β, CREB, and p-CREB in the rats’ prefrontal cortex, nucleus accumbens, and hippocampus and ventral tegmental were detected using western blot analysis. CBD was found to inhibit METH-induced CPP in a dose-dependent fashion. The expression levels of Sigma1R, p-AKT, p-GSK3β, and p-CREB increased significantly in the METH-induced CPP model. Treatment involving different doses of CBD caused differential inhibitory responses in the cellular protein abundance of Sigma1R, p-AKT, p-GSK3β, and p-CREB across various brain regions. The present study found that METH can induce CPP in rats. When a pretreatment of CBD is applied, the CBD can weaken CPP in METH-induced rats by regulating the SigmaR1/AKT/GSK-3β/CREB signaling pathway. The results of this study indicate that CBD has a potential therapeutic effect on METH-induced rewarding effects.

Probiotics hold great potential for treating metabolic diseases such as obesity. Given the complex and multifactorial nature of these diseases, research on probiotic combination with multiple targets has become popular. Here, we choose four obesity-related targets to perform high-throughput screening, including pancreatic lipase activity, bile salt hydrolase activity, glucagon-like peptide-1 secretion and adipocyte differentiation. Then, we obtained 649 multi-strain combinations with the requirement that each must cover all these targets in principle. After in vitro co-culture and in vivo co-colonization experiments, only four (<0.7%) combinations were selected as symbiotic probiotic communities (SPCs). Next, genome-scale metabolic model analysis revealed that these SPCs showed lower metabolic resource overlap and higher metabolic interaction potential involving amino acid metabolism (Ammonium, L−Lysine, etc.) and energy metabolism (Phosphate, etc.). Further animal experiments demonstrated that all SPCs exhibited a good safety profile and excellent effects in improving obesity and associated glucose metabolism disruptions and depression-like behaviors in high-fat-diet-fed mice. This anti-obesity improvement was achieved through reduced cholesterol level, fat accumulation and inhibited adipocyte differentiation. Taken together, our study provides a new perspective for designing multi-strain combinations, which may facilitate greater therapeutic effect on obesity and other complex diseases in the future.

Many individuals infected with human immunodeficiency virus (HIV) are also afflicted with HIV-associated neurocognitive disorders (HANDs). Methamphetamine (METH) abuse puts HIV-1 patients at risk for HANDs because METH and HIV-1 proteins, such as trans-activator of transcription (Tat), can synergistically damage the blood–brain barrier (BBB). However, the underlying mechanism of METH- and HIV-Tat-induced BBB damage remains unclear. In this study, male adult tree shrews and human brain capillary endothelial cells were treated with HIV-Tat, METH, and gastrodin. We used western blotting to examine the expressions of glucose transporters (GLUT1 and GLUT3), tight junctions, and junctional adhesion molecule A (JAMA) and to evaluate the damage and detect Evans blue (EB) and fluorescein sodium in the brain to assess BBB permeability to study the effect of METH and the HIV-1 Tat protein on BBB function in vitro and in vivo. The results showed that the group treated with Tat and METH experienced a significant change at the ultrastructural level of the tree shrew cerebral cortex, decreased protein levels of occluding, claudin-5, Zonula occludens 1 (ZO1), and JAMA in vitro and in vivo, and increased levels of EB and fluorescein sodium in the tree shrew cerebral cortex. The protein levels of GLUT1 and GLUT3 was downregulated in patients with Tat- and METH-induced BBB damage. Pretreatment with gastrodin significantly increased the levels of EB and fluorescein sodium in the tree shrew cerebral cortex and increased the expressions of occluding, ZO1, JAMA, and GLUT1 and GLUT. These results indicate that gastrodin may offer a potential therapeutic option for patients with HANDs.