The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicleinjected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0·5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.Cannabinoid system: CB 1 receptors: Food intake: Nutritional value: WIN 55,212-2: AM 251: Serotonin: Acetic acid 5-hydroxy-indol: c-fos Expression Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. The endogenous cannabinoid system is involved in mechanisms that regulate energy metabolism, and interacts with many other signalling systems that play an important role in metabolic regulation (1) . The cannabinoid type 1 (CB 1 ) receptor has been strongly implicated in the regulation of food intake (2) . CB 1 receptors are present in the brain and in the periphery. In the brain, CB 1 receptors have been identified in pathways responsible for reward and energy balance (3 -5) , whereas in the periphery, CB 1 receptors have been identified in the gut (6 -8) , as well as in hepatocytes (9) and adipocytes (3,10) . CB 1 receptor agonists such as D 9 -tetrahydrocannabinol, together with the endocannabinoids, anandamide and 2-arachidonoylglycerol, increase food intake in both man and animals (11) . The enhancement of food intake can also be induced by other cannabinoid CB 1 receptor agonists such as WIN 55, . This action is blocked or reversed by the selective CB 1 receptor antagonist SR 141716A (13) and by the structurally and pharmacologically similar compound AM 251 (14,15) .Since the nutritive utilization of any foodstuff can be significantly affected by the amount of food consumed, we undertook the study of food intake regulation at the central and peripheral level using the CB 1 receptor agonist WIN 55,212-2 and the CB 1 inverse agonist AM 251 administered at different doses by means of intracerebroventricular (icv) or ...

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The control of appetite and satiety is extremely complex and involves a balance between neurotransmitters and neuropeptides to stimulate and/or inhibit feeding behaviour. The effect of cannabinoids on food intake is well established, but little is known about the mechanism of action underlying their activity. In the present report, the effect of pharmacological manipulation of the cannabinoid receptor on the expression of hypothalamic neuropeptides is investigated. We used an immunohistochemical approach to examine the effect of intracerebroventricular administration of the cannabinoid receptor agonist WIN55,212-2 and the inverse agonist AM251 on neuropeptide Y (NPY) and the b-endorphin (b-end) neuronal hypothalamic systems. Double immunohistochemistry (c-fos/b-end) was used to assess the number of b-end neurons activated by the cannabinoid agonist. The present results showed that 1 mg WIN 55,212-2 increases b-end immunoreactivity within the arcuate nucleus while no significant changes were noted in the NPY-immunoreactive nerve fibres network in comparison to the control group. Injection of 1 mg AM251 decreases both NPY and b-end immunoreactivity within the arcuate nucleus. The number of b-end neurons exhibiting c-fos increased significantly in WIN 55,212-2 compared with the control group. These results suggest that cannabinoids affect the expression of hypothalamic neuropeptides, notably the NPY and b-end systems, which may have implications in the orexigenic action of cannabinoids.