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• The study represented the pioneering investigation into the association between CNR1 polymorphisms and susceptibility to TD, as well as cognitive function, in the Chinese population. • CNR1 gene polymorphisms were associated with the severity of involuntary movements and cognitive impairments in TD patients. • CNR1 polymorphisms were associated with the severity of involuntary movements in TD patients, particularly affecting limb-truncal movements. • CNR1 rs806368 and rs806370 polymorphisms may play a role in TD susceptibility. Tardive dyskinesia (TD) is a medically induced movement disorder that occurs as a result of long-term use of antipsychotic medications, commonly seen in patients with schizophrenia (SCZ). The study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of the CNR1 gene, TD and cognitive impairments in a Chinese population with SCZ. A total of 216 SCZ patients were recruited. The participants were divided into TD and without TD (WTD) groups using the Schooler-Kane International Diagnostic Criteria. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) scale. Hardy-Weinberg equilibrium tests, chained disequilibrium analyses and haplotype analyses were performed using SHE-sis software. To explore the main effects of TD diagnosis, genotype and cognitive function, as well as interaction effects, analysis of covariance (ANCOVA) was employed. The prevalence of TD was approximately 27.3%. Significant differences were observed in the rs806368 CT genotype and rs806370 TC genotype within the hypercongenic pattern between the male TD and WTD groups (OR = 2.508, 95% CI: 1.055–5.961, p = 0.037; OR = 2.552, 95% CI: 1.073–6.069, p = 0.034). Among TD patients, those carrying the rs806368 CC genotype exhibited higher limb trunk scores (p < 0.05). Moreover, there was a statistically significant difference in visuospatial/construction between the TD and WTD groups (p = 0.04), and a borderline significant difference in visuospatial/construction when considering the interaction between TD diagnosis and genotype at the rs806368 locus (p = 0.05). CNR1 rs806368 and rs806370 polymorphisms may play a role in TD susceptibility. Additionally, CNR1 gene polymorphisms were associated with the severity of involuntary movements and cognitive impairments in TD patients. [ABSTRACT FROM AUTHOR]

The endocannabinoid system regulates neurite outgrowth and neurogenesis during development of the central nervous system. Cannabinoid receptor 1 (CB1R) is expressed in neurons, including the somata and fibers, that innervate the endometrial ectopic cyst in rats. Here, we investigated the contribution of CB1R and its downstream signaling to the innervation of endometrial ectopic growth. We found that intrathecal injection of a CB1R agonist enhanced both the density of protein gene product (PGP) 9.5-immunoreactive sprouted nerve fibers and the protein level of PGP 9.5 of the ectopic cyst, and the CB1R antagonist induced opposite effects. The CB1R agonist increased the expression of phosphorylated extracellular signal-regulated kinase (pERK) and c-Jun N -terminal kinase (pJNK), but not pp38, in dorsal root ganglion (DRG), whereas the CB1R antagonist only decreased the expression of pERK. In cultured DRG neurons, CB1R agonists dose-dependently increased neurite elongation. The mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) and JNK inhibitors, but not the p38 inhibitor, attenuated CB1R agonist-induced neurite elongation. The inhibitions of CB1R and its downstream ERK and JNK signaling pathways may alleviate the sprouted innervation that has been involved in ENDO-associated pain. This finding may provide a new therapeutic target for patients with endometriosis. [ABSTRACT FROM AUTHOR]

Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in different parts of the brain and functions as a neurotransmitter and neuromodulator. In the central nervous system (CNS), SST inhibits Ca 2+ influx and regulates neuronal excitability in the hippocampus, the brain region which plays a major role in seizure, as well as cognitive and memory function. Much like SST, cannabinoid receptor 1 (CB1 receptor) is also widely distributed in the CNS, associated with memory function ad exerts inhibitory effects on seizure. It is unknown whether overlapping functional activities of SST and CB1 receptor are also associated with coexpression in the hippocampus. In the present study, we determined the colocalization between SST and CB1 receptor in adult rat brain hippocampus. In the CNS, the majority of SST positive interneurons coexpress neuronal nitric oxide synthase (nNOS). Accordingly, colocalization studies were also performed to determine whether nNOS positive neurons display comparable colocalization with CB1 receptor. The findings suggested that SST and nNOS are expressed in most interneurons whereas CB1 receptor is present in both interneurons and projection neurons in hippocampal regions. The distinct neuronal populations either expressing CB1 receptor, SST and nNOS alone or colocalization were observed in a region specific manner. Taken together, the observations described here anticipate the possibility of crosstalk between somatostatin subtypes and CB1 receptor in regulation of physiological activities in the hippocampus. [ABSTRACT FROM AUTHOR]

Orexin receptor 1 (OX 1 R) signaling is implicated in cannabinoid receptor 1 (CB 1 R) modulation of feeding. Further, our studies established the dependence of the central CB 1 R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. Here, we tested the novel hypothesis that brainstem orexin-A/OX 1 R signaling plays a pivotal role in the central CB 1 R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB 1 R, OX 1 R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB 1 R following intracisternal (i.c.) WIN55,212-2 (15 μg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB 1 R-mediated pressor response because (i) selective blockade of central CB 1 R (AM251, 30 μg/rat; i.c.) abrogated WIN55,212-2-evoked increases in RVLM orexin-A level, (ii) the selective OX 1 R antagonist SB-408124 (10 nmol/rat; i.c.) attenuated orexin-A (3 nmol/rat; i.c.) or WIN55,212-2 (15 μg/rat; i.c.)-evoked pressor response while selective CB 1 R blockade (AM251) had no effect on orexin-A (3 nmol/rat; i.c.)-evoked pressor response, (iii) direct CB 1 R activation in the RVLM (WIN55,212-2; 0.1 μg/rat) increased RVLM orexin-A and BP. Finally, SB-408124 attenuated WIN55,212-2-evoked increases in RVLM nNOS and ERK1/2 phosphorylation and BP. Our findings suggest that orexin-A/OX 1 R dependent activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism for the central CB 1 R-mediated pressor response in conscious rats. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a life-threatening neurological disorder. It is important to discover new drugs to control SE without the development of pharmacoresistance. Focus on the cannabinoid receptor and cannabinoid-related compounds might be a good option. Cannabinoid receptor 1 (CB1) and orexin receptor 1 (OX1) both belong to the GPCR superfamily and display “cross-talk” interactions, however, there has been no study of the effect of OX1/CB1 in epilepsy. Therefore, we investigated the potential long-term effects of SE on CB1 and OX1 expression in rat hippocampus, aiming to elucidate whether they are involved in the causative mechanism of epilepsy and whether they might form a heterodimer. In this study, SE was induced with kainic acid, and results of immunohistochemistry and RT-PCR both showed that the expression of CB1 in the hippocampus increased after SE and was significantly higher compared to controls especially 1 week post-SE. However we did not find any significant difference in the expression of OX1 between the SE group and the controls at any time. Under immunofluorescence staining, we observed an overlapping distribution of CB1 and OX1 in the hippocampus. The increased expression of CB1 in the hippocampus indicates that CB1 may play an important role in the underlying mechanism of SE, but the effect of OX1 was not obvious. The overlapping distribution of CB1 and OX1 in the hippocampus indicates that they may form a heterodimer to exert their effect in epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: Relapse is a major clinical problem and remains a major challenge in the treatment of drug addiction. There is strong evidence that the endocannabinoid system of the nucleus accumben core (NAcc) is involved in drug-seeking behavior, as well as in the mechanisms that underlie relapse to drug use. To reveal the mechanism that underlies this finding, we examined the expression pattern of the cannabinoid receptor 1 (CB1-R) in the NAcc of SD rats that had been undergoing morphine withdrawal (MW) for 1 day, 3 days and 3 weeks (acute, latent and chronic phases, respectively). Morphine exposure induced conditioned place preference (CPP) in rats. Significant increase of CB1-R expression in NAcc was observed in animals in the 1 day, 3 days and 3 weeks morphine withdrawal compare to the control group. Immunofluorescence labeling showed axonal fibers or terminals by fluorescence microscope observation. Immunoelectron microscopy detection showed silver-gold particles located in the presynaptic membranes that mainly give rise to symmetrical synapses. Quantitative electron microscopy showed an increase in number of CB1-R-positive terminals in the morphine withdrawal groups and the number of immunogold particles was significantly increased at these inhibitory terminals. We also confirmed that infusions of the CB1-R antagonist rimonabant into the NAcc attenuated the CPP during morphine withdrawal. Our present data have thus indicated that increasing pattern of CB1-R expression in the NAcc during above morphine withdrawal phases, which might underlie the relapse associated drug seeking behavior after morphine withdrawal. [Copyright &y& Elsevier]

Abstract: In stroke, a common cause of neurological disability in adults is that the myelin sheaths are lost through the injury or death of mature oligodendrocytes, and the failure of remyelination may be often due to insufficient proliferation and differentiation of oligodendroglial progenitors. In the current study, we used middle cerebral artery occlusion (MCAO) to induced transient focal cerebral ischemia, and found that WIN55, 212-2 augmented actively proliferating oligodendrocytes measured by CC1 immunoreactive cells within the peri-infarct areas. To establish whether these effects were associated with changes in myelin formation, we analyzed the expression of myelin basic protein (MBP) and myelin ultrastructure. We found that WIN55, 212-2 showed more extensive remyelination than vehicle at 14 days post injection (dpi). The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway may be involved in OPCs differentiation. To determine the regulatory effect of WIN55, 212-2 post-treatment on phospho-ERK 1/2 (p-ERK 1/2) after ischemia/reperfusion, Western blot analysis was performed. We found that WIN55, 212-2 regulated the phosphorylation level of the ERK 1/2 to promote OPCs survival and differentiation. Notably, cannabinoid receptor 1 is coupled to the activation of the ERK cascade. Following rimonabant combined treatment, the effect of WIN55, 212-2 on regulating the phosphorylation level of the ERK 1/2 was reversed, and the effect of accelerated myelin formation was partially inhibited. Together, we first found that WIN55, 212-2 promoted OPCs differentiation and remyelination through regulation of the level of the p-ERK 1/2 via cannabinoid receptor 1. [Copyright &y& Elsevier]

Abstract: Post-ictal depression of consciousness occurs after generalized convulsive seizures, and includes analgesia, lasting for hours after electrically or chemically induced seizures in animals. The brain sites and mechanisms, mediating post-ictal analgesia, are unclear. The ventrolateral periaqueductal gray (PAG) is an important neuronal network site for mediating analgesia and also in generalized seizures, particularly in genetically epilepsy-prone rats (GEPRs). Endocannabinoids are implicated in mediating analgesia in several brain sites, including the PAG, and generalized seizures result in endocannabinoid release. This study evaluated if post-ictal analgesia occurs in GEPRs, following audiogenic seizures (AGS), and whether this analgesia involves endocannabinoid actions in PAG. Analgesia was evaluated, using thermal stimulation to evoke nociception, measuring changes in paw withdrawal latencies (PWLs) induced by AGS. Endocannabinoid involvement in post-ictal analgesia in GEPRs was evaluated, using focal bilateral microinjection of a cannabinoid (CB1) receptor antagonist (AM251) into PAG. AGS induced a significant increase in PWLs, lasting for ≥120min. Microinjection of AM251 (100 and 200, but not 50 pmol/side) into PAG significantly decreased post-ictal analgesia in GEPRs. Endocannabinoids are also known to activate transient receptor potential vanilloid (TRPV1) receptors, but PAG microinjection of a TRPV1 receptor antagonist (capsazepine) did not affect post-ictal analgesia in GEPRs. These results indicate that AGS in GEPRs induce post-ictal analgesia, which is the first observation of this phenomenon in a genetic epilepsy model. These findings suggest an important role of PAG in post-ictal analgesia. The results also suggest that CB1 receptors in PAG are critical for mediating post-ictal analgesia in GEPRs. [Copyright &y& Elsevier]