Human CNR1 blocking peptide

Objective: The endocannabinoid system contributes to the regulation of emotions, stress, memory, and cognition. It has been reported that endocannabinoids cause GABAergic inhibition and dopaminergic increase in the mesolimbic and nigrostriatal systems, thus playing a part in the neurobiology of schizophrenia. In this study, we investigate cannabinoid receptor 1 (CNR1) gene polymorphisms in schizophrenia patients. Methods: CNR1 gene polymorphisms were studied in 66 schizophrenia patients and 65 healthy controls. To obtain genomic DNA, proteinase K digestion and the salt-chloroform method were used. Clinical Global Impression severity scale (CGI-S) and Positive and Negative Syndrome Scale (PANSS) were administered to evaluate the severity of schizophrenia symptoms. CNR1 gene polymorphism was determined by using polymerase chain reaction (PCR), Restriction Fragment Length Polymorphism (RFLP), and Single Strand Conformation Polymorphism (SSCP) methods for the Rs6454674, Rs806368, and Rs1049353 sites. Results: There was no difference in CNR1 gene polymorphisms between schizophrenia patients and control groups (Rs6454674 T/G; p=0.973, Rs806368 T/C; p=0.349, Rs1049353 A/G; p=1.00). However, CGI-S, PANSS total, PANSS positive, PANSS negative and PANSS general psychopathology scores were significantly lower in schizophrenia patients with RS6454674 polymorphism than in those not showing polymorphism. Conclusion: Our results suggest that CNR1 gene polymorphisms may be associated with clinical symptoms and disease severity in schizophrenia patients.

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention.