Beside cytotoxic mechanisms impacting on neurons, amyloid beta (A beta)-induced astroglial activation is operative in Alzheimer's disease brain, suggesting that persistent inflammatory response may have a role in the illness and that positive results may be achieved by curbing the astroglial reaction. Because the role of the endocannabinoid system could represent a promising field of research, the present study conducted in vitro and in vivo experiments to assess this system. C6 rat astroglioma cells were challenged with 1 microg/ml A beta 1-42 in the presence or absence of selective agonists and antagonists of cannabinoid (CB)1 and CB2 receptors. Furthermore, rats were inoculated into the frontal cortex with 30 ng of A beta 1-42 and were i.p. administered with 5 mg/kg of the same substances. Immunohistochemical and biochemical findings revealed that selective agonism at CB1 and antagonism at CB2 receptors was able to blunt A beta-induced reactive astrogliosis with subsequent overexpression of glial fibrillary acidic protein and S100B protein. Moreover, A beta provoked down-regulation of CB1 receptors together with a reduction of anandamide concentration, whereas CB2 receptors were up-regulated and 2-arachidonoyl glycerol concentration was increased. Finally, to our knowledge, the current study is the first showing that interactions at cannabinoid receptors result in a dual regulation of A beta-induced reactive astrogliosis. The data support the assumption that compounds able to selectively block CB2 receptors may have therapeutic potential in controlling A beta-related pathology, due to their beneficial effects devoid of psychotropic consequences.