For many G-protein-coupled receptors (GPCRs), including cannabinoid receptor 1 (CB1R), desensitization has been proposed as a principal mechanism driving initial tolerance to agonists. GPCR desensitization typically requires phosphorylation by a G-protein-coupled receptor kinase (GRK) and interaction of the phosphorylated receptor with an arrestin. In simple model systems, CB1R is desensitized by GRK phosphorylation at two serine residues (S426 and S430). However, the role of these serine residues in tolerance and dependence for cannabinoids in vivo was unclear. Therefore, we generated mice where S426 and S430 were mutated to nonphosphorylatable alanines (S426A/S430A). S426A/S430A mutant mice were more sensitive to acutely administered delta-9-tetrahydrocannabinol (Δ9-THC), have delayed tolerance to Δ9-THC, and showed increased dependence for Δ9-THC. S426A/S430A mutants also showed increased responses to elevated levels of endogenous cannabinoids. CB1R desensitization in the periaqueductal gray and spinal ...

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Δ9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Δ9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Δ9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Δ9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.

〔Objective.〕 In progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), phosphorylated tau accumulates in both nerve cells and glial cells. In PSP and CBD, the pathological tau contains only four repeat tau. In this study, we examined the difference of the tau protein isoforms of PSP and CBD between white matter and cortex. 〔Methods.〕 Sarcosyl-insoluble fraction was extracted from white matter and cortex in four cases of PSP and two of CBD following the protocol (Goedert et al, Neuron 1989 3(4):519-26). Insoluble tau was subjected to the western blot with a phosphorylation-dependent anti-tau antibody AT8 . 〔Results and discussion〕The pattern of the three bands of 64, 68 and 72KDa in PSP and CBD was different between cerebral cortex and white matter. When the relative amounts of these bands were compared between white matter and cortex, in white matter, 68KDa band was prominent when compared to 72KDa band (P<0.05). In cortex, tau deposits are both neruronal and glial, whereas in white matt...

Consumption of cannabis during pregnancy and the lactation period is a rising public health concern ([Scheyer et al., 2019][1]). Exposure to synthetic or plant-derived cannabinoids via lactation disrupts the development of GABAergic neurons in the prefrontal cortex (PFC) and alters early-life behaviors ([Scheyer et al., 2020b][2]). Recently, additional data revealed that Δ9-tetrahydrocannabinol (THC) perinatal exposure via lactation causes lasting behavioral and neuronal consequences ([Scheyer et al., 2020a][3]). Here, the long-term effects in adult offspring of maternal exposure to the synthetic cannabinoid agonist WIN 55,12,2 are reported. The data demonstrate that rats exposed during lactation to WIN display social and motivational deficits at adulthood. These behavioral changes were paralleled by a specific loss of endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC and nucleus accumbens (NAc), while other forms of synaptic plasticity remained intact. Thus, similarly to THC, perinatal WI...

Anandamide, an endogenous ligand for brain cannabinoid CB1 receptors, produces many behavioral effects similar to those of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB1 receptor antagonist rimonabant ([SR141716][1]). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB1 receptor...

Rates of cannabis use among adolescents are high, and are increasing concurrent with changes in the legal status of marijuana and societal attitudes regarding its use. Recreational cannabis use is understudied, especially in the adolescent period when neural maturation may make users particularly vulnerable to the effects of Δ-9-tetrahydrocannabinol (THC) on brain structure. In the current study, we used voxel-based morphometry to compare gray matter volume (GMV) in forty-six 14-year-old human adolescents (males and females) with just one or two instances of cannabis use and carefully matched THC-naive controls. We identified extensive regions in the bilateral medial temporal lobes as well as the bilateral posterior cingulate, lingual gyri, and cerebellum that showed greater GMV in the cannabis users. Analysis of longitudinal data confirmed that GMV differences were unlikely to precede cannabis use. GMV in the temporal regions was associated with contemporaneous performance on the Perceptual Reasoning Inde...

Carotid body denervation (CBD) in newborn rats produces high mortality and, in survivors, weight loss and severe breathing abnormalities. To gain insight into the recovery of physiologic functions in newborn Sprague-Dawley rats that survived CBD or sham-denervation (SHAM) at 6 different postnatal (PN) age-groups (PN 2-3, PN 4, PN 7-8, PN 12-13, PN 15 and PN 20-21), we studied the animals before and after surgery for 3-4 weeks in a plethysmograph during eupnea and tested the response to hypoxia (FIO2: 0.12) at 2 and 22 days after surgery. We found that CBD rats had an initial significant (P&lt;0.05) decrease in weight gain at all ages except PN 20-21 (P=0.41) but resumed normal growth after a few days or a few weeks (PN12-13 and 15 or PN2-3, PN 4 and PN 7-8, respectively), while SHAM rats did not show any changes in weight gain. There was a greater inhibition of breathing during hypoxia in CBD rats 2 days after denervation than in SHAM. However, CBD and SHAM rats had similar responses to hypoxia 22 days aft...

Zebra finches learn a complex song during a developmental sensitive period through a process of sensorimotor integration and auditory feedback, which shares features with language development in humans. Chronic treatment with the synthetic cannabinoid f...

Interruption of chronic cannabinoid administration, produces a withdrawal syndrome, which is characterized by a number of functional alterations at the level of the ventrotegmental area (VTA). In the present study, we investigated the effects of chronic administration and withdrawal from two structurally different cannabinoid agonists: Delta9-Tetrahydrocannabinol (THC) and CP 55940 (CP) on the morphological properties of immuno-labelled Tyrosine Hydroxylase (TH)-positive neurons of the rat VTA. Withdrawal was induced by removing CP treatment and by administration of the cannabinoid antagonist SR 141716A (SR). Rats were treated for 6,5 days with either THC or CP and then assigned to one of following groups: 1) Control (chronically treated with saline). 2) Chronically treated with THC + SR. 3) Chronically treated with CP. 4) Chronically treated with CP + SR. 5) Chronically treated with CP + 24 hours drug free. 6) Chronic saline + SR. Histological analysis was performed with a confocal laser scanning microsco...

The rat Prefrontal Cortex (PFC) receives a major inhibitory input from mesocortical dopaminergic system. Electrical stimulation of the Ventral Tegmental Area (VTA) produces a marked phasic inhibition of the electrical activity of most PFC neurons. Evidence suggests that cannabinoids may act as modulators of dopaminergic neuronal system. In the present study we utilized extracellular recordings in anaesthetized rats in order to determine whether the psychoactive constituent of marijuana Delta9-tetrahydrocannabinol (Delta9-THC), the synthetic cannabinoid agonist WIN55212,2 (WIN) and the antagonist SR141617A modulate the activity of neurons in the PFC and influence the inhibitory response induced by VTA stimulation. Electrical stimulation of VTA induced a marked inhibition, lasting 149.6±5.5 msec, of the spontaneous activity of PFC neurons. Acute administration of Delta9-THC (1mg/kg, i.v.) or WIN (0.5 mg/kg i.v.) reversed the electrically evoked inhibition of the majority of PFC neurons (73.3%, n=15). These e...