1 |
DIET-RELATED CHANGES IN SENSITIVITY TO THE PHARMACOLOGICAL EFFECTS OF DELTA-9-TETRAHYDROCANNABINOLWright, Mayo 05 May 2009 (has links)
Recent evidence suggests that sustained consumption of a high-fat diet is associated with reduced CB1 receptor expression in some brain areas. Many of the neuromodulatory functions of endogenous cannabinoids are mediated by the CB1 receptor. The CB1 receptor also mediates the behavioral and physiological effects of delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of marijuana. While high-fat diets are associated with region-specific changes in CB1 receptor expression, it is not clear whether such changes are behaviorally relevant. To that end, separate groups of male and female rats were placed on either a high-fat diet or a standard diet. Cannabinoid function was determined in a triad of measures (e.g., hypothermia, gross locomotion, time on bar apparatus) at postnatal day 30 (PD30), PD44, PD68 and PD114. These age points respectively correspond to rodent models of early adolescence, late adolescence, early adulthood and full maturity in humans. Male rats were also tested at PD37 and PD61. Subsequently, the antinociceptive properties of delta-9-THC and the effect of delta-9-THC on food intake were also measured. After 38 days, female rats maintained on a high-fat diet were significantly less sensitive to the psychomotor effects of delta-9-THC than were the female rats maintained on the control diet. These diet-related differences persisted into full maturity. Female rats maintained on a high-fat diet were also less sensitive to changes in food intake caused by delta-9-THC than were female rats maintained on the control diet. In contrast, the hypothermic effects of delta-9-THC were not differentially affected by the type of diet consumed. Likewise, female rats maintained on a high-fat diet exhibited tail-flick latencies that were indistinguishable from those of female rats maintained on the control diet. With two minor exceptions, and in sharp contrast to female rats, sensitivity to the pharmacological effects of delta-9-THC was not differentially affected by the type of diet in male rats. In short, female rats maintained on a high-fat diet appeared to be cross-tolerant to the psychomotor and hyperphagic effects of delta-9-THC while male rats maintained on a high-fat diet exhibited responses to delta-9-THC that were virtually indistinguishable from control animals.
|
2 |
Cannabinoid Effects on NFkappaB Function in Microglial-Like Cells: Dual Mode of ActionGriffin-Thomas, LaToya 09 April 2009 (has links)
Cannabinoids have been shown to modulate the immune system in vitro and in animal models. A major area of interest is how cannabinoids impact the brain. A whole variety of neuropathies or brain disorders, such as AIDS dementia, Parkinson’s disease, Multiple Sclerosis and Alzheimer’s disease, are associated with a hyperinflammatory response within the brain. Microglia, the resident macrophages of the brain, are the major cell type responsible for the persistent elicitation of pro-inflammatory cytokines (IL-1a, IL-1b, IL-6, TNFa) and other mediators. In vitro experiments have demonstrated that the partial exogenous cannabinoid agonist delta-9-tetrahydrocannabinol (D9-THC) and the potent synthetic exogenous cannabinoid agonist CP55940 down-regulate the robust production of pro-inflammatory cytokines elicited in response to bacterial lipopolysaccharide (LPS) at the mRNA level. These observations suggest that cannabinoids, devoid of psychotropic properties, have the potential to betherapeutic agents. These highly lipophilic compounds can pass through the blood brain barrier and act through specific cannabinoid receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 and CB2 are expressed in the brain and the periphery, respectively, and may serve as molecular targets for ablating chronic brain inflammation. Electrophoretic mobility shift assays (EMSA) were used to assess the effects of D9-THC and CP55940 on the LPS-induced binding interactions of the universal transcription factor NFkB to its cognate promoter binding site in BV-2 microglial-like cells. EMSA analyses demonstrated that the D9-THC and CP55940 down-regulated LPS-induced NFkB binding in BV-2 cells in a biphasic manner. Furthermore, reporter activity assays determined that D9-THC and CP55940 attenuated LPS-induced, NFkB transcriptional activity in the same biphasic manner. We then determined the specificity in which cannabinoids inhibit NFkB function. Real-Time RT-PCR analysis demonstrated that BV-2 cells did not express CB1 mRNA, but they do express CB2 mRNA when untreated and stimulated with IFN-g or LPS. We performed specificity studies using CB1 and CB2 selective agonists and antagonists with our reporter activity assays. The CB1-selective agonist ACEA did not affect NFkB transcriptional activity but the CB2-selective agonist O-2137 exerted a significant decrease in activity. Furthermore, the CB1 antagonist SR141716A could not reverse the inhibitory effects of CP55490 but those effects were blocked by the CB2 antagonist SR144528. Lastly, we determined the site of action in which cannabinoids inhibit NFkB function by assessing the effects of D9-THC and CP55940 on NFkB’s inhibitor protein IkBa. IkBa retains NFkB in the cytoplasm until stimulus-induced cell activation. Neither cannabinoid compound was able to inhibit the phosphorylation of IkBa, which initiates its degradation. However both cannabinoids inhibited the complete degradation of IkBa. Western immunoblot analysis also demonstrated that comparable levels of endogenous and phosphorylated p65, the transactivation subunit of the NFkB protein (p65/p50), were detected in the nucleus of LPS-stimulated BV-2 cells pre-treated with or without D9-THC. These results suggest that, in addition to inhibiting the proteolytic degradation of IkBa, there is also a mechanism of action in the nucleus that prevents the proper binding and subsequent transcriptional activity of NFkB. Collectively, these results suggest that cannabinoids suppress pro-inflammatory cytokine gene expression at the transcriptional level, but it is likely that there is more than one signal transduction pathway involved in the cannabinoid-mediated inhibition of NFkB function.
|
3 |
Bedeutung des Cytochrom-P450-2C9- und -3A5-Genpolymorphismus für Pharmakokinetik, Wirkungen und Nebenwirkungen von Delta-9-Tetrahydrocannabinol bei gesunden Probanden und Probandinnen / Relevance of genetic polymorphisms in Cytochrom-P450-2C9- and -3A5 for pharmacokinetics, effects and adverse effects of Delta-9-Tetrahydrocannabinol in healthy male and female volunteersPfeil, Johannes 02 January 2009 (has links)
No description available.
|
Page generated in 0.0198 seconds