Modulation of cholecystokinin concentrations in the rat hippocampus by chelation of heavy metals.

Abstract

Previously, we have reported that enkephalins, cholecystokinin, and heavy metals show roughly parallel distributional patterns in the hippocampus. A substantial body of evidence indicates that cholecystokinin-octapeptide (CCK-8) and enkephalins act as neurotransmnitters. A CCK-8 degrading enzyme was recently detected in brain synaptosomes. Its activity depended on free thiol groups and the presence of a heavy metal. Since the heavy metal-containing neuropil is closely related to CCK-immunoreactive nerve terminals, we have investigated the effect of metal chelation on CCK conmponents in the rat hippocampus. In vivo treatment of rats with a single dose of the chelating agent diethyldithiocarbamate caused a reversible chelation of heavy metals in the hippocampus. This effect was paralleled by a 3-fold increase in hippocampal content of CCK-8 and a smaller increase in the intermediate forms of CCK (CCK-58, CCK-39, CCK-33). Diethyldithiocarbamate also decreased the spontaneous motility and aggressiveness of the rats. These data show reversible changes of neuronal CCK processing by a drug, and hence they provide additional evidence that CCK is involved in the regulation of neuronal activities.Heavy metals occur in distinct layers of the rat hippocampus, associated with the terminal fields of certain neuronal systems, including the mossy fibers (1, 2). In the mossy fibers, there is ample evidence that most of the detectable metal is zinc (3, 4), which is located in the mossy fiber boutons (5, 6). Otherwise, the exact localization of specific metals is unknown (7).The role of zinc and other heavy metals in specific nerve terminals of the hippocampus is unknown. Recently, we have shown that both enkephalin-like molecules and heavy metals (mainly zinc) occur in the mossy fibers of rodents (8, 9). Subsequently, we have shown that zinc and other metal ions can down-regulate the binding capacity of opioid receptors (10, 11). These observations, together with the fact that endogenous opioid peptides excite hippocampal pyramidal cells via binding to opioid receptors (12), indicate that zinc, and possibly other neuronal metals, may regulate the binding capacity of opioid receptors (10, 11). The close relationship between enkephalin and zinc in the mossy fiber system may reflect that zinc is a cofactor for the recently discovered enkephalin degrading enzyme "enkephalinase" (13)(14)(15)(16).Also, cholecystokinin (CCK) nerve terminals occur closely associated with the heavy metal-containing neuropil in the rat hippocampus (8, 17). Thus, CCK immunoreactivity is located in the terminal areas of the medial perforant path and the temporo-ammonic tracts from the medial entorhinal cortex, as well as in the terminal area of the commissural-associational path of area dentata. CCK-containing cell bodies occur in all layers of the rat hippocampus, but'mostly in the stratum pyramidale, the mossy fiber zone, and the stratum radiatum (8, 17). The COOH-terminal octapeptide of 'CCK (CCK-8) appears to be a putative transmitter (18-30) wi...

Neuronal Cholecystokinin: One or Multiple Transmitters?

“…The rapid de nuvu synthesis of CCK-8 makes reuptake less likely . Moreover, evidence of CCK-8-degrading metallo-enzymes has now been found in the rat brain (Deschodt-Lanckman et al, 1981;Stengaard-Pedersen et al, 1984).…”

Cholecystokinin Expression in Tumors: Biogenetic and Diagnostic Implications

“…The I cells are, however, so disseminated in the intestinal mucosa, and the intensity of the biosynthesis per gram small intestine therefore so incomprehensive that dynamic biosynthesis studies have so far been impossible to perform. However, the dynamics of CCK synthesis have been studied in the brain [27,28]. In addition, a variety of proCCK-derived peptides of different chain lengths have been identified from extracts of both the small intestinal mucosa, the brain and the heart (for review, see [8]).…”

Cell-Specific Precursor Processing

“…The I-cells, however, are so disseminated in the intestinal mucosa, and the intensity of the biosynthesis in per gram of intestine is so small that dynamic biosynthesis studies have so far been impossible to perform. However, the dynamics of cerebral CCK synthesis have been studied in detail (Goltermann et al 1980;Stengaard-Pedersen et al 1984). In addition, a variety of procholecystokinin (proCCK)-derived peptides of different lengths have been identified from extracts of both the small intestine and the brain (Blanke et al 1993;Eberlein et al 1992;Eng et al 1984;Rehfeld and Hansen 1986).…”