Characterization of neuropeptide, monoamine, and amino acid release in the basal ganglia of the rat : neuronal dependence and reciprocal interactions

Abstract

Functional interactions in the basal ganglia of rats were characterized with in vivomicrodialysis. 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 inthe neostriatum and substantia nigra under basal conditions. The release of these peptides wasCa++- 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 Band 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-nigraldynorphin 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 inextracellular 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 in Çease 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.) orintracerebrally at high concentrations (10-100 ~lM) increased DA release, which indicates atonic 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 DAD, 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.