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Journal of Neuroscience, Vol 13, 5066-5081, Copyright © 1993 by Society for Neuroscience
Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum
H Steiner and CR Gerfen
Section of Neuroanatomy, National Institute of Mental Health, Bethesda, Maryland 20892.
The effects of the indirect dopamine receptor agonist cocaine in the
striatum on levels of mRNAs of the immediate-early gene c-fos and the
neuropeptides dynorphin, substance P, and enkephalin were analyzed with
quantitative in situ hybridization histochemistry. Both single (acute) and
repeated (twice a day for 4 d) systemic injections of cocaine (3.75- 30
mg/kg) to rats resulted in dose-dependent, regionally specific elevations
of mRNA expression in striatal neurons. A single drug treatment elevated
c-fos mRNA expression, whereas repeated treatments resulted in little c-fos
expression but elevated dynorphin mRNA levels. Both the regional and
temporal patterns of gene expression revealed an inverse relationship
between dynorphin and c-fos expression. This relationship was examined in a
time course experiment in which cocaine (30 mg/kg) was administered for 1,
2, 3 or 4 d. Basal levels of dynorphin expression were relatively high in
the ventral striatum, including the nucleus accumbens, a ventrolateral
region, and an area along the medial bank of the striatum. A single
injection of cocaine induced c-fos mRNA in striatal areas with low basal
expression of dynorphin. Thus, c-fos mRNA induction was highest in the
dorsal central striatum, where basal dynorphin mRNA levels were lowest. In
this region, dynorphin mRNA expression increased on subsequent treatment
days parallel to diminished c-fos mRNA induction. Changes in substance P.
mRNA levels appeared to match directly both the temporal and regional
patterns of c-fos induction. Enkephalin mRNA expression was altered, but
only slightly, by these cocaine treatments. Statistical analysis of the
regional patterns of basal and altered mRNA levels shows a unique inverse
relationship between basal dynorphin expression and c-fos induction by
cocaine. Further evidence of this relationship is provided by the
dose-dependent blockade of cocaine-induced c-fos expression by spiradoline,
a dynorphin agonist. Together, these results suggest that the restricted
regional pattern of cocaine-induced c-fos expression is related, in part,
to the basal level of dynorphin expression, and that cocaine treatment
elevates dynorphin expression in striatal regions with a strong c-fos
response, thereby limiting subsequent c-fos induction by cocaine. These
findings lead to the hypothesis that dynorphin acts to regulate the
responsiveness of striatal neurons to dopamine stimulation.
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