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Receptor diversity in combination with receptor-receptor subtype specific interactions, which can be antagonistic or synergistic in character, markedly increase plasticity in WT and VT in the nervous system. In this way switching among transmission lines for the various DA receptor subtypes becomes possible. Some of these aspects are supported by our work on selective modulation of D2 receptors by CCK and NT. Selective regulation of D2 receptors via CCK-8 receptor subtypes and NT receptors may underlie CCK/DA interactions and NT/DA interactions in the basal ganglia. These studies underline the importance of receptor-receptor interactions exerted at the membrane level between neuropeptide receptors and D2 receptors, which are determined at least in part by the ongoing activity at D1 receptors. In the case of both CCK/D2 and NT/D2 receptor interactions, it has been possible, by means of intrastriatal and intraaccumbens microdialysis, to obtain a functional correlate to the receptor interactions found in the membrane preparations from the striatum. Schizophrenia may be in part related to reduced release of CCK and/or NT peptides or to alterations in their receptor interactions with the D2 receptor. This view may lead to new therapeutic approaches.

Cholecystokinin may play a role in regulation of interdigestive motility, but this still remains to be investigated. CCK constitutes the major hormonal stimulus for postprandial gallbladder emptying. CCK exerts its contractile effects mainly through interaction directly with receptors on the gallbladder smooth muscle cells in the muscle layer, but also through interaction with cholinergic nerves extrinsic and/or intrinsic in nature. Furthermore, CCK can enhance ongoing nicotinic ganglionic transmission occurring in the serosal layer by release of acetylcholine. CCK interaction with the gallbladder smooth muscle CCKA receptor was studied in further detail. CCK contracts strips of gallbladder muscle in a concentration-dependent way with a potency in the nanomolar range in all tested species. The potency is 1,000-fold better than that of gastrin; thus, the receptor is of type CCKA. CCK binding to this receptor is specific and of high affinity, 1,000-fold better than that of gastrin with no differences between the tested species including bovine, porcine, and human. Also, CCK binding affinity was independent of age, gender, or weight of the person and pathology of the human gallbladder. The biochemistry of the CCKA receptor varies between the tested species (bovine and human). Both CCKA receptors are heavily glycosylated, but of different size and carbohydrate content. The bovine CCKA receptor is of apparent size M(r) = 70-85 kD with N-linked complex carbohydrates and sialic acids. The human CCKA receptor is of M(r) = 85-95 kD, with N-linked complex carbohydrates, but no sialic acids. They both have a protein core of apparent size M(r) = 43 kD, with almost identically sized fragments after enzymatic cleavage. Probably the protein cores contain the receptor binding region, which seems well preserved between species. CCK and the CCKA gallbladder muscularis receptor are main regulators of postprandial gallbladder emptying. The biochemistry of the CCKA gallbladder smooth muscle receptor is in accord with newly generated data of purification and cloning of the rat pancreatic CCKA receptor.

Gastric emptying after food ingestion is regulated by neural and hormonal factors. However, the relative contributions of each pathway is not yet clearly defined. The classic gut hormone CCK seems to be involved in the regulation of gastric emptying in humans. Experimental evidence is best for gastric emptying of liquid meals that release CCK from the duodenum: (1) CCK infused at postprandial plasma concentrations inhibits gastric emptying of a liquid and a semisolid meal. (2) Administration of the CCK antagonist loxiglumide significantly accelerated gastric emptying of a liquid mixed meal and a glucose meal. Discrepant results with the antagonist MK329 are difficult to explain considering the marked acceleration of gastric emptying rates by the specific and potent antagonist MK329 shown in several animal studies. Taken together, current information favors the conclusion, however, that CCK mainly controls gastric emptying of the liquid but not the solid components. Thus, CCK is involved in the physiologic regulation of gastric emptying and gastric motility in man. Blocking CCK-A receptors accelerates gastric emptying of liquid meals and abolishes the gastrocolonic reflex. Therefore, CCK may play a role as a common regulator of postprandial gallbladder contraction and pancreatic enzyme secretion as well as of gastric emptying rates under certain conditions. Such common control would optimize the nutrient-to-digestive juices concentration ratio. The importance of endogenous CCK on gastric emptying of solid meals, however, is poorly understood and remains to be defined. Only very limited information is available on gastric motility. Much more work has to be done before a clear concept can be developed.

Cholecystokinin (CCK) stimulates vagal afferent fiber discharge, both gastric and intestinal, which seems to result in reflex decrease in gastric motility, gastric acid secretion, and stimulation of pancreatic protein secretion. Endogenous release of CCK by fat or soybean trypsin inhibitor also alters function by way of a capsaicin-sensitive pathway. We suggest that CCK is released locally from the intestine and acts locally or systemically to stimulate vagal afferent fiber discharge to alter proximal gastrointestinal function (Fig. 14). In this way, in addition to its effect on food intake, CCK and the neural pathway integrate function in the proximal gastrointestinal tract, regulating the entry of food into the duodenum to ensure effective digestion and absorption.