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Journal of Neuroscience, Vol 14, 6239-6247, Copyright © 1994 by Society for Neuroscience
Inactivation of Gi and G(o) proteins in nucleus accumbens reduces both cocaine and heroin reinforcement
DW Self, RZ Terwilliger, EJ Nestler and L Stein
Department of Pharmacology, College of Medicine, University of California, Irvine 92717.
The pertussis toxin (PTX)-sensitive G proteins Gi and G(o) may be
implicated in drug reinforcement and addiction, since certain reward-
related dopamine and opiate receptor subtypes are coupled to these G
proteins, and since chronic exposure to cocaine or morphine alters levels
of these G proteins in the nucleus accumbens (NAc). As a direct test of
this hypothesis, Gi and G(o) proteins in the NAc were selectively
inactivated by intra-accumbens injections of PTX in rats self-administering
either cocaine or heroin. In control animals, bilateral injections of
inactive PTX (0.1 microgram/1 microliter/side) in the NAc failed to alter
baseline rates of cocaine and heroin self- administration. In contrast, the
same dose of active PTX produced significant, long-lasting increases (up to
1 month) in the self- administration of both drugs, and shifted the
dose-response curves to the right. These results suggest that PTX reduces
or shortens the reinforcing efficacy of cocaine and heroin, leading to
compensatory increases in drug self-administration. Similar NAc injections
of PTX reduced the level of Gi alpha and G(o) alpha subunits as measured by
both ADP-ribosylation and Western blot, without affecting levels of Gs
alpha or G beta subunits. The effect of the toxin was mainly limited to the
NAc, and no evidence of abnormal cell death or gliosis was observed. The
onset of changes in self-administration rate coincided with the onset of
changes in ADP-ribosylation, suggesting that, initially, the increased drug
self-administration results directly from a reduction in functional Gi and
G(o) proteins. After 28 d, self- administration baselines began to recover
while levels of G protein ADP- ribosylation and immunoreactivity remained
low, suggesting that adaptive mechanisms are involved at later time points.
These results provide direct support for a common role of Gi and G(o)
proteins in the NAc in the reinforcing and addictive properties of
psychostimulant and opiate drugs.
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