Search

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression which might be due to a reduction in DNA methylation at gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

This summary is a project of the Institute for Community Engaged Scholarship (ICES) at the University of Guelph, with project partners: the Catalyst Centre, SPARK Program at the University of Guelph, and Knowledge Mobilization Unit at York University. This project is part of the Pan-Canadian Research Impact Network. http://csahs.uoguelph.ca/pps/Clear_Research The naturally occurring cannabinoid 2AG suppressed vomiting in shrews by attaching to the CB1 receptor. 2AG, along with its metabolite, AA, also suppressed nausea-induced conditioned gaping in rats, but this effect was largely independent of CB1 (or CB2) receptors. Project support by Agri-Food and Rural Link, Mobilizing Agri-food and Rural Research Knowledge. A program of the OMAFRA-U of G Partnership. http://www.uoguelph.ca/research/omafra/partnership/KTT_and_IP.shtml

This summary is a project of the Institute for Community Engaged Scholarship (ICES) at the University of Guelph, with project partners: the Catalyst Centre, SPARK Program at the University of Guelph, and Knowledge Mobilization Unit at York University. This project is part of the Pan-Canadian Research Impact Network. http://csahs.uoguelph.ca/pps/Clear_Research Cannabidiol suppressed drug-induced vomiting in shrews and nausea-associated behaviours in rats. This effect was reversed, however, if the rodents were also given chemicals that blocked serotonin receptors in a part of the brainstem. Cannabidiol may help naturally produced serotonin activate these receptors more effectively. Project support by Agri-Food and Rural Link, Mobilizing Agri-food and Rural Research Knowledge. A program of the OMAFRA-U of G Partnership. http://www.uoguelph.ca/research/omafra/ partnership/KTT_and_IP.shtml

Dopaminergic and cannabinoid receptors are localized in the outflow nuclei of the basal ganglia. We have investigated the possible interrelation of these receptors in the regulation of motor activity in male rats. To this end we have first studied the behavioural effects of the highly potent cannabinoid receptor agonist (-)11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210, 20 micrograms mg) after chronic stimulation of dopamine D1 and D2 receptors. The catalepsy induced by the synthetic cannabinoid, measured as the descent latency in the bar test, was enhanced in male rats chronically treated with the dopamine D1 receptor agonist SKF38393 (8 mg kg-1, twice a day during 21 days). However, animals exposed to the dopamine D2 agonist quinpirole (1 mg kg-1 daily during 21 days) displayed the same degree of catalepsy as those exposed to HU-210 alone. Although a possible involvement of D2 receptors cannot be excluded, this finding suggests a predominant role for dopamine D1 receptors in the regulation of the cataleptic response to cannabinoids. The possible cross-talk between dopamine D1 and cannabinoid receptors is further supported by the decreased responsiveness to the acute behavioural effects of SKF38393 (8 mg kg-1) observed in animals chronically exposed to HU-210 (20 micrograms kg-1 daily during 14 days).

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure.Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment.Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.

The occurrence of the novel proposed endocannabinoid, noladin ether (2- arachidonyl glyceryl ether, 2-AGE) in various rat organs and brain regions, and its inactivation by intact C6 glioma cells, were studied. 2- AGE was measured by isotope dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry, with a detection limit of 100 fmol. A compound with the same mass and chromatographic/chemical properties as 2-AGE was found in whole brain, with the highest amounts in the thalamus and hippocampus. Synthetic [(3)H]2-AGE was inactivated by intact rat C6 glioma cells by a time- and temperature-dependent process consisting of cellular uptake and partial incorporation into phospholipids. Further data suggested that 2-AGE is taken up by cells via the anandamide/2-arachidonoyl glycerol (2-AG) membrane transporter(s), and biosynthesized in a different way as compared to 2-AG.

1. (-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2. CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca(2+) concentrations in cells over-expressing human VR1; (b) [(14)C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [(14)C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC(50)=3.2 - 3.5 microM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 - 70% of the effect obtained with ionomycin (4 microM). CBD (10 microM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. 4. (+)-5'-DMH-CBD and (+)-7-hydroxy-5'-DMH-CBD inhibited [(14)C]-AEA uptake (IC(50)=10.0 and 7.0 microM); the (-)-enantiomers were slightly less active (IC(50)=14.0 and 12.5 microM). 5. CBD and (+)-CBD were also active (IC(50)=22.0 and 17.0 microM). CBD (IC(50)=27.5 microM), (+)-CBD (IC(50)=63.5 microM) and (-)-7-hydroxy-CBD (IC(50)=34 microM), but not the other analogues (IC(50)100 microM), weakly inhibited [(14)C]-AEA hydrolysis. 6. Only the (+)-isomers exhibited high affinity for CB(1) and/or CB(2) cannabinoid receptors. 7. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB(1) and CB(2) receptors, (-)-5'-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.

Potential metabolites of (-)-3,4-trans-tetrahydrocannabinol (THC) with a carboxylic acid function in the side chain were synthesized as their methyl esters in the delta1(6)-series. The chromatographic and mass-spectrometric properties of the five side-chain homologues were examined and utilized to facilitate the isolation and the identification of the corresponding monocarboxylic acid metabolites of delta1(6)-THC in the mouse, guinea pig, and rabbit formed after ip administration. The metabolites were identified by gas chromatography and mass fragmentography. In mouse liver delta1(6)-THC-7-oic acid and 3'',4'',5''-trisnor delta1(6)-THC-2''-oic acid were identified as metabolites. In guinea pig liver these acids occurred together with 4'',5''-bisnor-delta1(6)-THC-3''-oic acid and 5''-nor-delta1(6)-THC-4''-oic acid. Rabbit liver contained delta1(6)-THC-7-oic acid, 2'',3'',4'',5''-tetranor-delta1(6)-THC-1''-oic acid and 4'',5''-bisnor-delta1(6)-THC-3''-oic acid. Further, the structure of three dicarboxylic acid metabolites of delta1(6)-THC in rabbit kidney were determined by mass spectrometry and proton magnetic resonance spectroscopy.

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.