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Vol. 60, Issue 1, 155-163, July 2001
Department of Pharmacology and Toxicology, Medical College of
Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
(C.S.B., G.G., B.R.M.); and Istituto per la Chimica di Molecole di
Interesse Biologico, Consiglio Nazionale delle Ricerche, Arco Felice
(NA), Italy (V.D.M.)
The purpose of these studies was to support the hypothesis that an
undiscovered cannabinoid receptor exists in brain.
[35S]GTP
S binding was stimulated by anandamide and
WIN55212-2 in brain membranes from both CB1+/+
and CB1
/ mice. In contrast, a wide variety
of other compounds that are known to activate CB1
receptors, including CP55940, HU-210, and 
9-tetrahydrocannabinol, failed to stimulate
[35S]GTPS binding in CB1/
membranes. In CB1/ membranes, SR141716A
affected both basal and anandamide- or WIN55212-2-induced stimulation
of [35S]GTPS binding only at concentrations greater
than 1 µM. In CB1+/+ membranes, SR141716A
inhibited only 84% of anandamide and 67% of WIN55212-2 stimulated
[35S]GTPS binding with an affinity appropriate for
mediation by CB1 receptors
(KB 
0.5 nM). The remaining
stimulation seemed to be inhibited with lower potency
(IC50 5 µM) similar to that seen in
CB1/ membranes or in the absence of
agonist. Further experiments determined that the effects of anandamide
and WIN55212-2 were not additive, but that the effect of µ opioid,
adenosine A1, and cannabinoid ligands were additive. Finally, assays of
different central nervous system (CNS) regions demonstrated significant
activity of cannabinoids in CB1/ membranes
from brain stem, cortex, hippocampus, diencephalon, midbrain, and
spinal cord, but not basal ganglia or cerebellum. Moreover, some of
these same CNS regions also showed significant binding of
[3H]WIN55212-2, but not [3H]CP55940. Thus
anandamide and WIN55212-2 seemed to be active in
CB1/ mouse brain membranes via a common G
protein-coupled receptor with a distinct CNS distribution, implying the
existence of an unknown cannabinoid receptor subtype in brain.
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