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Levodopa is the most commonly prescribed drug for Parkinson's disease (PD). Although levodopa improves PD symptoms in the initial stages of the disease, its long-term use is limited by the development of side effects, including abnormal involuntary movements (dyskinesias) and psychiatric complications. The endocannabinoid system is emerging as an important modulator of basal ganglia functions and its pharmacologic manipulation represents a promising therapy to alleviate levodopa-induced dyskinesias. Rats with 6-OHDA lesions that are chronically treated with levodopa develop increasingly severe axial, limb, locomotor and oro-facial abnormal involuntary movements (AIMs). Administration of the cannabinoid agonist WIN 55,212-2 attenuated levodopa-induced axial, limb and oral AIMs dose-dependently via a CB(1)-mediated mechanism, whereas it had no effect on locomotive AIMs. By contrast, systemic administration of URB597, a potent FAAH inhibitor, did not affect AIMs scoring despite its ability to increase anandamide concentration throughout the basal ganglia. Unlike WIN, anandamide can also bind and activate transient receptor potential vanilloid type-1 (TRPV1) receptors, which have been implicated in the modulation of dopamine transmission in the basal ganglia. Interestingly, URB597 significantly decreased all AIMs subtypes only if co-administered with the TRPV1 antagonist capsazepine. Our data indicate that pharmacological blockade of TRPV1 receptors unmasks the anti-dyskinetic effects of FAAH inhibitors and that CB(1) and TRPV1 receptors play opposite roles in levodopa-induced dyskinesias.  相似文献
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PURPOSE: The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes. METHODS: N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions. RESULTS: The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index. CONCLUSIONS: N-palmitoylethanolamide, an endogenous compound with antiinflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.  相似文献
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Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin.  相似文献
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Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Δ9-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia. The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Δ9-THC versus AEA. Tolerance to Δ9-THC, but not AEA, involves a decrease in the release of dynorphin A. Our preclinical studies indicate that Δ9-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.  相似文献
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Despite recent data suggesting that the endocannabinoid transmission is a component of the brain reward system and plays a role in dependence/withdrawal to different habit-forming drugs, only a few studies have examined changes in endocannabinoid ligands and/or receptors in brain regions related to reinforcement processes after a chronic exposure to these drugs. Recently, we carried out a comparative analysis of the changes in cannabinoid CB(1) receptor density in several rat brain regions caused by chronic exposure to some of the most powerful habit-forming drugs. In the present study, we have extended this objective by examining changes in the brain contents of arachidonoylethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), the endogenous ligands for cannabinoid receptors, in animals chronically exposed to cocaine, nicotine or ethanol. Results were as follows. Cocaine was the drug exhibiting the minor number of effects, with only a small, but significant, decrease in the content of 2-AG in the limbic forebrain. In contrast, chronic alcohol exposure caused a decrease in the contents of both AEA and 2-AG in the midbrain, while it increased AEA content in the limbic forebrain. This latter effect was also observed after chronic nicotine exposure together with an increase in AEA and 2-AG contents in the brainstem. In contrast, the hippocampus, the striatum and the cerebral cortex exhibited a decrease in AEA and/or 2-AG contents after chronic nicotine exposure. We also tested the effect of chronic nicotine on brain CB(1) receptors, which had not been investigated before, and found an almost complete lack of changes in mRNA levels or binding capacity for these receptors. In summary, our results, in concordance with previous data on CB(1) receptors, indicate that the three drugs tested here produce different changes in endocannabinoid transmission. Only in the case of alcohol and nicotine, we observed a common increase in AEA contents in the limbic forebrain. This observation is important considering that this region is a key area for the reinforcing properties of habit-forming drugs, which might support the involvement of endocannabinoid transmission in some specific events of the reward system activated by these drugs.  相似文献
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Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the most active endocannabinoids at brain (CB1) cannabinoid receptors. CD1 mice lacking the CB1 receptors ("knockout" [KO] mutants) were compared with wildtype (WT) littermates for their ability to degrade AEA through an AEA membrane transporter (AMT) and an AEA hydrolase (fatty acid amide hydrolase, FAAH). The age dependence of AMT and FAAH activity were investigated in 1- or 4-month-old WT and KO animals, and found to increase with age in KO, but not WT, mice and to be higher in the hippocampus than in the cortex of all animals. AEA and 2-AG were detected in nmol/mg protein (microm) concentrations in both regions, though the hippocampus showed approximately twice the amount found in the cortex. In the same regions, 2-AG failed to change across groups, while AEA was significantly decreased (approximately 30%) in hippocampus, but not in cortex, of old KO mice, when compared with young KO or age-matched WT animals. In the open-field test under bright light and in the lit-dark exploration model of anxiety, young KO mice, compared with old KO, exhibited a mild anxiety-related behaviour. In contrast, neither the increase in memory performance assessed by the object recognition test, nor the reduction of morphine withdrawal symptoms, showed age dependence in CB1 KO mice. These results suggest that invalidation of the CB1 receptor gene is associated with age-dependent adaptive changes of endocannabinoid metabolism which appear to correlate with the waning of the anxiety-like behaviour exhibited by young CB1 KO mice.  相似文献
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Activation of postsynaptic group 1 metabotropic glutamate receptors (mGluRs) by the agonist DHPG causes a long-term depression (DHPG-LTD) of excitatory transmission in the CA1 region of the hippocampus, as well as causing the release of endocannabinoids from pyramidal cells. As cannabinoid agonists cause a presynaptic inhibition at these synapses and DHPG-LTD is thought to be expressed, at least in part, by a presynaptic mechanism, we examined the possibility that endocannabinoids mediated DHPG-LTD. We find that antagonists of cannabinoid receptors reduce the acute depression induced by DHPG, but have no effect on the lasting depression. Furthermore, both the acute and the lasting effects of DHPG were unaffected in the CB1 knockout mouse. These findings suggest that endocannabinoids, acting on a non-CB1 cannabinoid receptor, contribute to the acute depression but not to DHPG-LTD. Presumably some other retrograde signalling mechanism is responsible for DHPG-LTD.  相似文献
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