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Volume 16, Number 24,
Issue of December 15, 1996
pp. 8057-8066
Copyright ©1996 Society for Neuroscience
Effects of Chronic Treatment with
 9-Tetrahydrocannabinol on Cannabinoid-Stimulated
[35S]GTP S Autoradiography in Rat Brain
Received June 10, 1996; revised Sept. 30, 1996; accepted Oct. 2, 1996.
Laura J. Sim,
Robert E. Hampson,
Sam A. Deadwyler, and
Steven R. Childers
Department of Physiology and Pharmacology, Center for the
Neurobiological Investigation of Drug Abuse, and Center for
Investigative Neuroscience, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, North Carolina 27157
Chronic  9-tetrahydrocannabinol
(9-THC) administration produces tolerance to cannabinoid
effects, but alterations in signal transduction that mediate these
changes are not yet known. The present study uses in
vitro autoradiography of agonist-stimulated [35S]GTP S binding to localize cannabinoid
receptor-activated G-proteins after chronic 9-THC
treatment. Cannabinoid (WIN 55212-2)-stimulated
[35S]GTPS binding was performed in brain sections from
rats treated chronically with 10 mg/kg 9-THC for 21 d. Control animals received saline or an acute injection of
9-THC. Acute 9-THC treatment had no
effect on basal or WIN 55212-2-stimulated [35S]GTPS
binding. After chronic 9-THC treatment, net WIN
55212-2-stimulated [35S]GTPS binding was reduced
significantly (up to 70%) in most brain regions, including the
hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus
pallidus, substantia nigra, and cerebellum. In contrast, chronic
9-THC treatment had no effect on
GABAB-stimulated [35S]GTPS binding. In
membranes and brain sections, 9-THC was a partial
agonist, stimulating [35S]GTPS by only 20% of the
level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated
[35S]GTPS at high concentrations. Because the
EC50 of WIN 55212-2-stimulated [35S]GTPS
binding and the KD of cannabinoid receptor
binding were unchanged by chronic 9-THC treatment, the
partial agonist actions of 9-THC did not produce the
decrease in cannabinoid-stimulated [35S]GTPS binding.
These results suggest that profound desensitization of
cannabinoid-activated signal transduction mechanisms occurs after
chronic 9-THC treatment.
Key words:
9-THC;
[35S]GTPS
autoradiography;
cannabinoid receptor;
GABAB receptor;
G-protein
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