Agonist efficacy and receptor efficiency in heterozygous CB1 knockout mice: relationship of reduced CB1 receptor density to G‐protein activation

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Abstract
Heterozygous CB1 receptor knockout mice were used to examine the effect of reduced CB1 receptor density on G‐protein activation in membranes prepared from four brain regions: cerebellum, hippocampus, striatum/globus pallidus (striatum/GP) and cingulate cortex. Results showed that CB1 receptor levels were approximately 50% lower in heterozygous mice in all regions examined. However, maximal stimulation of [35S]guanosine‐5′‐(γ‐O‐thio) triphosphate ([35S]GTPγS) binding by the high efficacy agonist WIN 55,212–2 was reduced by only 20–25% in most brain regions, with the exception of striatum/GP where the decrease in stimulation was as predicted (approximately 50%). Furthermore, although the efficacies of the cannabinoid partial agonists, methanandamide and Δ9‐tetrahydrocannabinol, were similarly lower in heterozygous mice, their relative efficacies compared with WIN 55,212–2 were generally unchanged. Saturation analysis of net WIN 55,212–2‐stimulated [35S]GTPγS binding showed that decreased stimulation by WIN 55,212–2 in striatum/GP of heterozygous mice was caused by a decrease in the apparent affinity of net‐stimulated [35S]GTPγS binding. The apparent maximal number of binding sites (Bmax) values of net WIN 55,212–2‐stimulated [35S]GTPγS binding were unchanged in cerebellum and striatum/GP of heterozygous mice, but decreased in cingulate cortex, with a similar trend in hippocampus. Moreover, in every region except cingulate cortex, the maximal number of net‐stimulated [35S]GTPγS binding sites per receptor was significantly increased in heterozygous mice. These results indicate region‐dependent increases in the apparent efficiency of CB1 receptor‐mediated G‐protein activation in heterozygous CB1 knockout mice.

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