The Contribution of cocoa additive to cigarette smoking addiction

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Page 186 of 207 RIVM report 650270002 Anandamide In vivo Lipopolysaccharide (LPS) increases the levels of the endogenous cannabinoid anandamide level in rat macrophages. LPS enhances the levels of anandamide (fourfold over controls) also in human lymphocytes. LPS inhibits the activity of the anandamide -degrading enzyme fatty acid amide hydrolase (FAAH) in these cells, by downregulating the gene expression at transcriptional level (41) (the anandamide dose was not mentioned in the abstract). In the absence of indomethacin, anandamide did not contract the guinea-pig bronchus at concentrations up to 100 µM. In the presence of indomethacin (10 µM), anandamide induced concentration-related contractions with a potency (pEC50 (negatively log of EC50)) value of 5.18 ± 0.11. The vanilloid receptor antagonist, capsazepine (10 µm), significantly attenuated the contractile effect of anandamide. The response to 100 pM anandamide being 40.53 ± 7.04% in the presence of vehicle and 1.57 ± 8.93% in the presence of 10 µM capsazepine. The contractile actions of anandamide was markedly enhanced by the peptidase inhibitor thiorphan. The lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid (etya) and 5,8,11 eicosatriynoic acid (eti) reduced the effect of 100 µM anandamide from 34.7 ± 1.9% (vehicle) to 7.7 ± 5% (etya, 10 pM) and from 41.85 ± 4.25% (n=6) (vehicle) to 10.31 ± 3.54 (n=6) (eti, 20 µM) (19). The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH)-catalysed hydrolysis of [H- 3]-anandamide ([H-3]-AEA) has been investigated. Palmitoylethanolamide and homologues with chain lengths from 12 - 18 carbon atoms inhibited rat 3 Hanandamide metabolism with pec(50) values of around 5. Homologues with chain lengths less than or equal to eight carbon atoms gave
RIVM report 650270002 Page 187 of 207 Anandamide Critical assessment Chemical No data available for assessment. In vivo The anandamide level is affected either by inhibition of the anandamide degrading enzym or by inhibition of the anandamide transport through the cellmembrane. Conclusion Chemical No data available for conclusion. In vivo The anandamide level is affected either by inhibition of the anandamide degrading enzyme or by inhibition of the anandamide transport through the cellmembrane. DEPENDENCY Cannabinoids have a long history of consumption for recreational and medical reasons. In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana.Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system (13). There is evidence that cannabinoids cause tolerance and physical dependence in humans and animals. The question is whether the endogenous ligand for the cannabinoid receptor, anandamide, induces also behavioral tolerance and physical dependence in rats. Rats were injected with anandamide (20 mg/kg i.v.) daily for 2 weeks. To assess tolerance, on days 1, 8 and 15 of treatment, rats were observed and behavior was tested. Two common methods were employed to assess physical dependence: interruption of anandamide dosing and vehicle substitution or administration of a cannabinoid CB1 receptor antagonist (3 mg/kg i.v.). Full or partial tolerance developed to the classical behavioral effects elicited by the cannabinoids: hypothermia, catalepsy, hypomotility, decrease in stereotypic activity (rearing and grooming) and hindlimb splaying. No tolerance to anandamide was observed for reduced defecation. An abstinence syndrome appeared after abrupt cessation of cannabinoid intake and after withdrawal precipitated by CB1 receptor antagonist; the withdrawal signs were scratching, licking and biting, eating of feces, ptosis, arched back, wet dog shakes, head shakes, myoclonic spasms, writhing, forepaw fluttering, teeth chattering and piloerection. These findings indicate that the endogenous cannabinoid ligand, administered exogenously, induces both tolerance and physical dependence in rats (44). However, other studies (45, 46) indicate that anandamide has no addictive properties. The recent discovery of anandamide, an endogenous ligand for cannabinoid receptors, and the synthesis of SR141716A, a cannabinoid antagonist selective for
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