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Volume 17, Number 14,
Issue of July 15, 1997
pp. 5327-5333
Copyright ©1997 Society for Neuroscience
Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2
Receptors Augments cAMP Accumulation in Striatal Neurons: Evidence for
a Gs Linkage to the CB1 Receptor
Received Jan. 29, 1997; revised April 14, 1997; accepted May 6, 1997.
Michelle Glass and
Christian C. Felder
Laboratory of Cellular and Molecular Regulation, National Institute
of Mental Health, Bethesda, Maryland 20892-4090
Cannabinoids act at the CB1 receptor to inhibit adenylate cyclase
activity via a pertussis toxin-sensitive G-protein. Within the
striatum, CB1 receptors have been shown to be localized on the same
neurons as Gi-coupled dopamine D2 receptors. In this study
we have examined the interactions of CB1 and D2 receptors on adenylate
cyclase. In striatal neurons in primary culture, both the CB1 receptor
agonist
[3-(1,1-dimethylheptyl)-11-hydroxy- 8tetrahydrocannabinol]
(HU210) and the D2 receptor agonist quinpirole inhibited
forskolin-stimulated cAMP accumulation when applied separately. In
contrast, HU210 and quinpirole in combination augmented cAMP
accumulation. This augmentation was blocked by the CB1 receptor antagonist SR141716A or the D2 antagonist sulpride. Pertussis toxin
treatment of striatal neurons prevented the inhibition of cAMP
accumulation by D2 receptors but unmasked a cannabinoid
receptor-mediated stimulatory effect on cAMP accumulation. The
cannabinoid receptor-stimulated accumulation of cAMP was blocked in a
concentration-dependent manner by SR141716A, suggesting that the
response was regulated through the CB1 receptor. Similar augmentation
of cAMP accumulation after pertussis toxin treatment was observed in
Chinese hamster ovary (CHO) cells transfected with, and stably
expressing, the CB1 receptor. This stimulation of cAMP was not
Ca2+-sensitive and was unaffected by a range of
protein kinase inhibitors. Treatment of the pertussis toxin-treated
cells with cholera toxin before CB1 receptor activation amplified the
stimulatory pathway, suggesting that this response was mediated through
a Gs-type G-protein. Stimulation of cAMP accumulation was
not observed after pertussis toxin treatment of CHO cells expressing
the human CB2 receptor, suggesting that this novel signaling pathway is
unique to the cannabinoid CB1 receptor.
Key words:
cannabinoid;
G-protein;
adenylate cyclase;
CB1 receptor;
dopamine;
D2 receptor;
striatum
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