Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the syntheticcannabinoid compound CP55,940

Chronic exposure to CP55,940 produced a significant down-regulation of cann abinoid receptors in the striatum, cortex, hippocampus, and cerebellum of r at brain. At 24 h after SR141716-precipitated withdrawal, we observed a ten dency to return to basal levels in the striatum and cortex, whereas the spe cific binding remained lower in the hippocampus and cerebellum. When we sur veyed cannabinoid receptor-activated G proteins, in chronic CP55,940-treate d rats the guanosine 5'-O-(3-[S-35]thiotriphosphate) ([S-35]GTP gamma S) bi nding assay revealed a decrease of activated G proteins in the striatum, co rtex, and hippocampus, whereas no significant changes were seen in the cere bellum. At 24 h after the SR141716-precipitated withdrawal, [S-35]GTP gamma S binding increased compared with that of rats chronically exposed to CP55 ,940, attaining the control level except for cerebellum, where we observed a trend to overcome the control amounts. Concerning the cyclic AMP (cAMP) c ascade, which represents the major intracellular signaling pathway activate d by cannabinoid receptors, in the cerebral areas from rats chronically exp osed to CP55,940 we found alteration in neither cAMP levels nor protein kin ase A activity. In the brain regions taken from CP55,940-withdrawn rats, we only observed a significant up-regulation in the cerebellum. Our findings suggest that receptor desensitization and down-regulation are strictly invo lved in the development of cannabinoid tolerance, whereas alterations in th e cAMP cascade in the cerebellum could be relevant in the mediation of the motor component of cannabinoid abstinence.