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You, Zhi-Bing
Characterization of neuropeptide, monoamine, and amino acid release in the basal ganglia
of the rat : Neuronal dependence and reciprocal interactions
Tisdagen den 30 januari 1996, kl. 09:30.
Farmakologiska
institutionens föreläsningssal, Karolinska institutet.
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Abstract:
Functional interactions in the basal ganglia of rats were characterized with in vivo
microdialysis. The study was mainly focused on the dynorphin and cholecystokinin (CCK)
systems. The extracellular levels of both dynorphin B and CCK were found in the pM range in
the neostriatum and substantia nigra under basal conditions. The release of these peptides was
Ca++- and K+-dependent. Dynorphin B, as well as GABA, levels in the neotriatum and
substantia nigra were significantly decreased following a lesion of the neostriatum, suggesting
that these dynorphin B and GABA levels reflect activity of the striato-nigral pathway. CCK
levels in the neostriatum were significantly decreased only by combined decortication and
callosotomy, confirming histochemical and biochemical evidence for a prominent cortico-
striatal CCK innervation of both ipsilateral and contralateral origin. HPLC analysis of
microdialysis samples showed that, under basal conditions, dynorphin immunoreactivity
represented only dynorphin B peptide, whereas under K-depolarizing conditions, both
dynorphin B and its precursor big dynorphin were observed. CCK immunoreactivity
measured in the neostriatum mainly represented the sulphated CCK octapeptide (CCK-8).
The dopamine (DA) D, receptor agonist, SKF 38393 stimulated the release of dynorphin B
and GABA both in the neostriatum and substantia nigra, while the D2 receptor agonist,
quinpirole was without effect, suggesting that DA modulates the function of the striato-nigral
dynorphin pathway via D, receptors. Ouinpirole inhibited the release of DA both in the
neostriatum and substantia nigra, supporting the idea that DA autoreceptors are of the D2
receptor subtype.
Local perfusion with CCK-8 (1-100 ~IM) induced a concentration-dependent increase in
extracellular dynorphin B and Asp levels, both in neostriatum and substantia nigra, whereas
DA levels were only increased in the substantia nigra. A 6-OHDA lesion of the nigro-striatal
DA pathway did not affect the effect of CCK-8 on dynorphin B and Asp levels. In the
neocortex, local CCK-8 administration increased both Asp and Glu levels. The CCKB
antagonist, L-365, 260 (20 mg/kg s. c.), but not the CCKA antagonist, L-364,718 (20 mg/kg s.
c.), significantly inhibited the effect of CCK-8 on striatal dynorphin B and Asp levels. In the
substantia nigra, however, the effect of CCK-8 on dynorphin B and Asp levels was inhibited
by both L-365,260 and L-364,718 to a similar extent, whereas L-364,718, but not L-365,260,
prevented the inÇease in nigral DA levels. Thus, it is suggested that CCK-8 modulates
dynorphin B and Asp release predominantly via the CCKB receptor subtype in the neostriatum
and via both CCKA and CCKB receptor subtypes in the substantia nigra.
Systemic as well as local administration of morphine stimulated nigral dynorphin B and
GABA release, an effect that was antagonized by a low dose of naloxone (0.2 mg/kg s. c.)
which has been shown to block mainly the ll-receptors. Morphine had no effect on DA release.
On the other hand, naloxone administered systemically at a high dose (4 mg/kg s. c.) or
intracerebrally at high concentrations (10-100 ~lM) increased DA release, which indicates a
tonic inhibitory role of endogenous opioid peptides on the nigro-striatal DA pathway. The
data implicate a previously unknown complexity for opioid regulation of the functions of the
basal ganglia.
In conclusion, the present study illustrates the complexity in the interactions between
neuronal pathways of the basal ganglia. The "classic" nigro-striatal DA pathway is under tonic
inhibitory opioid control, perhaps via the dynorphin pathway which can be activated via DA
D, receptors. The lesser-known CCK pathways are potentially able to interact at different
receptors and sites in a stimulatory manner. The study also provides functional support for a
neuronal system releasing Asp but not Glu.
Key words: amino acids; cholecystokinin; dopamine; dynorphin; microdialysis; morphine;
neostriatum; rat; substantia nigra.
ISBN 91-628-1871-6
1996 Zhi-Bing You
Keywords: amino acids cholecystokinin dopamine dynorphin microdialysis morphine
neostriatum rat substantia nigra.
