Cholecystokinin and Adrenal‐Cortex Secretion

15 Cholecystokinin and Adrenal‐Cortex Secretion Gastone G. Nussdorfer, Raffaella Spinazzi, and Giuseppina Mazzocchi Department of Human Anatomy and Physiology, Section of Anatomy, University of Padua, I‐35121 Padua, Italy

I. Introduction II. Biology of CCK and Adrenocortical Cells A. CCK and Its Receptors B. Adrenocortical Secretion and Its Regulation III. CCK and Its Receptors in the HPA Axis A. Hypothalamus and Pituitary Gland B. Adrenal Gland IV. EVects of CCK on Adrenal‐Cortex Secretion A. Aldosterone Secretion B. Glucocorticoid Secretion V. Concluding Remarks References

Cholecystokinin, or CCK, is a 33–amino acid peptide, originally considered a gut hormone, that acts via two subtypes of receptors, named CCK1‐R and CCK2‐R. CCK, along with its receptors, has been subsequently localized in the central nervous system, where it exerts, among other fuctions, antiorexinogenic actions. In this survey, we describe findings indicating that CCK, similar to other peptides modulating food intake (e.g., neuropeptide Y, leptin, and orexins), is also able to regulate the function of the Vitamins and Hormones, Volume 71 Copyright 2005, Elsevier Inc. All rights reserved.

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hypothalamo–pituitary–adrenal axis, acting on both its central and peripheral branches. CCK stimulates aldosterone secretion via specific receptors (CCK1‐Rs and CCK2‐Rs in rats, and CCK2‐Rs in humans) located in zona glomerulosa cells and coupled to the adenylate cyclase‐ dependent signaling cascade; and enhances glucocorticoid secretion from zona fasciculata‐reticularis cells via an indirect mechanism mainly involving the CCK2‐R‐mediated stimulation of corticotropin‐releasing hormone‐dependent ACTH release. # 2005 Elsevier Inc.

I. INTRODUCTION It is widely known that adrenal–cortex secretory activity undergoes a multifactorial regulation that involves, in addition to the ‘‘classic’’ agonists, several regulatory peptides, part of which are locally synthesized in the gland and act in an autocrine‐paracrine manner (for review, see Nussdorfer, 1996). In the last decade, findings have accumulated indicating that neuropeptides participating in the central regulation of feeding also control the function of neuroendocrine axes—including the hypothalamo–pituitary–adrenal (HPA) axis—and for one of which they regulate both the central and the peripheral branch. The most studied among these orexinogenic or antiorexinogenic neuropeptides are neuropeptide‐Y (Krysiak et al., 1999; Nussdorfer and Gottardo, 1998; Renshaw and Hinson, 2001), leptin (Ahima and Flier, 2000; Glasow and Bornstein, 2000; Wauters et al., 2000), and orexins (hypocretins) (Malendowicz et al., 2001a; Mazzocchi et al., 2001; Wolf, 1998). Cholecystokinin (CCK), originally considered a gut hormone, has been subsequently found in the central nervous system, where it exerts, among others, important antiorexinogenic functions (Crawley and Corwin, 1994; Noble et al., 1999). In the following sections of this chapter, we survey findings indicating that CCK, similar to the other peptides modulating food intake, is involved in the regulation of the adrenal‐cortex secretion.

II. BIOLOGY OF CCK AND ADRENOCORTICAL CELLS A. CCK AND ITS RECEPTORS

1. CCK CCK was originally discovered in the gut and subsequently isolated from the porcine intestine and identified as a 33–amino acid polypeptide that stimulates pancreatic secretion and gallbladder contraction (Ivy and

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Oldberg, 1928; Jorpes and Mutt, 1966; Mutt and Jorpes, 1968). Then, CCK was localized in the mammalian central nervous system (Vanderhaeghen et al., 1975), where it is now recognized to be one of the most abundant neuropeptides. CCK derives from the posttranslational processing of the 115–amino acid precursor prepro‐CCK, through a multistep process involving sulfation of tyrosine residues and several cleavages mediated by nontrypsin proteases. This process leads to the formation not only of the 33–amino acid sequence (CCK-33) but also of other biologically active molecules, among which are sulfated CCK-8 and CCK-5, which is similar to the final amino acid sequence of gastrin (pentagastrin) (Crawley and Corwin, 1994; Noble et al., 1999) (Fig. 1). From an evolutionary point of view, CCK is thought to derive, along with gastrin, from a common ancestor, referred to as CCK‐ like peptide (Johnsen, 1998), so it is easily understandable why gastrin and CCK share the final amino acid sequence and interact with the same receptors (see below). 2. CCK Receptors CCK acts through two main G protein‐coupled receptor (R) subtypes, the CCK1‐R and the CCK2‐R, formerly named CCKA‐R (alimentary) and CCKB‐R (brain) on the basis of their prevalent localization. CCK1‐R and CCK2‐R have been cloned, and selective antagonists have been identified. CCK-33 and CCK-8 are agonists of both receptor subtypes, whereas gastrin and pentagastrin are selective agonists of the CCK2‐R. At present, only few CCK1‐R agonists have been identified, most of them being CCK analogs (containing the [NMe] Asp residue) or benzodiazepine derivatives (Dunlop, 1998; Kopin et al., 2000; Noble et al., 1999). The signaling mechanisms of the CCK1‐R have been investigated mainly in the exocrine pancreas and seem to involve the activation of phospholipase (PL)C‐, PLA2‐, and adenylate cyclase‐dependent cascades. The activation of PLC leads to the breakdown of phosphatidylinositol to inositol‐trisphosphate (IP3) and diacylglycerol. Diacylglycerol activates protein kinase (PK)C, and IP3 enhances Ca2þ release from intracellular stores, thereby raising cytosolic calcium concentration ([Ca2þ]i), which in turn activates PKC. PLA2 releases arachidonic acid from plasma membrane phospholipids, and arachidonate, via the cyclooxygenase and lipoxygenase pathways, is converted to prostaglandins and 12‐hydroxyeicosatetraneoic acid. Adenylate cyclase converts ATP to cyclic‐AMP, which activates PKA. Arachidonate may also derive from diacylglycerol by action of a diglyceride lipase, and PKA may be also activated by an increase in [Ca2þ]i (Fig. 2). Evidence has been also provided that CCK1‐R may activate Ras and mitogen‐activated protein kinase cascades, leading to the enhanced expression of transcriptional factors (c‐myc, c‐jun, and c‐fos) and the ensuing stimulation of cell proliferation (Noble et al., 1999). The few studies

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FIGURE 1. Amino acid sequence of human CCK (A), caerulein (B), and pentagastrin (C). Amino acid residues of caerulein and pentagastrin molecules identical to those of the CCK-8 sequence are indicated in grey.

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FIGURE 2. Pathway of mineralo‐ and glucocorticoid synthesis in adrenocortical cells.

carried out on brain CCK2‐R indicate that these receptors signal via the PLC‐dependent cascade. 3. Biological Functions of CCK CCK, via the CCK1‐R, stimulates the secretion of pancreatic amylase and the contraction of gallbladder, and via the CCK2‐R, in cooperation with gastrin, enhances gastric acid secretion. Moreover, CCK, via CCK1‐Rs mainly located on the vagus nerve eVerents, induces satiety and consequently inhibits food consumption (Crawley and Corwin, 1994; Noble et al., 1999). CCK, via the CCK1‐R, also seems to regulate in an autocrine‐paracrine manner cell proliferation in various normal and tumorous tissues (Forguet‐Lafitte et al., 1996; Nagata et al., 1996; Todisco et al., 1997; Xu et al., 1996). Brain CCK and CCK2‐R appear to play a pivotal role in the regulation of anxiety and memory, as well as satiety (Crawley and Corwin, 1994; Liddle, 1997; Noble et al., 1999). Proof is also available that they can be involved in

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the negative modulation of neuroendocrine responses to acute stresses (Bhatnagar et al., 2000). The involvement of CCK in the regulation of HPA axis and adrenocortical secretion will be described in detail in the following sections of this survey. B. ADRENOCORTICAL SECRETION AND ITS REGULATION

1. Steroid‐Hormone Synthesis The synthesis of the main mineralcorticoid (aldosterone) in the zona glomerulosa (ZG) and glucocorticoids (cortisol in humans, dogs, sheep, and pigs, and corticosterone in rodents) in the zonae fasciculata‐reticularis (ZF/R) involves a series of sequential steps occurring in both mitochondria and smooth endoplasmic reticulum (SER) (Nussdorfer, 1986; Nussdorfer et al., 1999; Torpy et al., 2000). Briefly, cholesterol esters, stored in lipid droplets, are hydrolyzed to free cholesterol that is transported to mitochondria, where cytochrome P450scc (cholesterol side‐chain cleaving enzyme) converts it to pregnenolone. This is the rate‐limiting step of steroid synthesis and involves the sterol carrier protein-2‐ and steroidogenic acute regulatory protein–mediated transport of cholesterol to the outer mitochondrial membrane, and its translocation to the cytochrome P450scc located on the inner membrane (Gallegos et al., 2000; Lehoux et al., 2003; Stocco, 2001). Pregnenolone leaves mitochondria and reaches SER, where 3b‐hydroxysteroid dehydrogenase transforms it to progesterone (PROG). In the species secreting cortisol (e.g., humans), PROG is converted in SER to 17‐hydroxyprogesterone (17OH‐PROG) by cytochrome P450c17 (17a‐hydroxylase). Then, cytochrome P450c21 (21‐hydroxylase), located in SER, transforms PROG and 17OH‐PROG into 11‐deoxycorticosterone and 11‐deoxycortisol, respectively. Further steps occur in the mitochondria. In the ZF/R, cytochrome P450c11 (11b‐hydroxylase) converts 11‐deoxycorticosterone and 11‐deoxycortisol to corticosterone and cortisol, respectively. In the ZG, 11‐deoxycorticosterone is converted to corticosterone, and corticosterone is transformed into 18OH‐corticosterone and then aldosterone by the cytochrome P450c18 (a mixed 11b‐/18‐hydroxylase‐dehydrogenase, also named aldosterone synthase) (Fig. 3). 2. Regulation of Adrenocortical Cell Secretion The main agonists involved in the physiological regulation of adrenocortical cell secretion are adrenocorticotropic hormone (ACTH), angiotensin‐II (Ang‐II), and Kþ (for review, see Ganguly and Davis, 1994; Nussdorfer et al., 1999; Spa¨ t and Hunyady, 2004). ACTH stimulates both ZG and ZF/R cells, via specific receptors mainly coupled to the adenylate cyclase/PKA‐dependent cascade. Ang‐II stimulates aldosterone secretion

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FIGURE 3. Main pathways in the signaling mechanisms of the CCK1‐R and CCK2‐R. AC, adenylate cyclase; CM, calmodulin; CO, cyclooxygenase; G, G protein; HETE, hydroxyeicosatetraneoic acid; LO, lipoxygenase; PGs, prostaglandins; PIP2, phosphatidylinositol biphosphase. Other abbreviations are indicated in the text.

from ZG cells, acting through AT1 receptors mainly coupled to the PLC‐ dependent signaling pathway. Ang‐II is also able to stimulate glucocorticoid secretion from ZF/R cells in calves and humans. ACTH and Ang‐II may also activate the PLA2‐dependent cascade. Kþ selectively depolarizes the plasma membrane of ZG cells, thereby opening voltage‐gated Ca2þ channels and increasing [Ca2þ]i (Fig. 2). In addition to the ‘‘classic’’ agonists, catecholamines and a pleiad of regulatory peptides appear to control aldosterone and glucocorticoid secretion, acting via specific receptors located in ZG and ZF/R cells. These regulatory peptides belong to the opioid peptide (e.g., enkephalins and endorphins), neuromedin (e.g., neurokinins and substance P), pancreatic polypeptide (e.g., pancreatic polypeptide and neuropeptide Y), vasoactive intestinal polypeptide– secretin‐glucagon (also including pituitary adenylate cyclase‐activating polypeptide, gastric inhibitory peptide, and exendins), galanin, neurotensin, endothelin, adrenomedullin and calcitonin gene‐related peptide, natriuretic peptide, leptin, orexin, and CCK (see following sections) families. Moreover, some hypothalamic peptides, including corticotropin‐releasing hormone (CRH), arginin‐vasopressin (AVP), oxytocin, somatotropin release inhibiting hormone (or somatostatin), and thyrotropin‐releasing hormone exert a modulatory role on adrenal secretion (for review and references, see Delarue et al., 2001, 2004; Ehrhart‐Bornstein et al., 1998; Glasow and Bornstein, 2000; Mazzocchi et al., 2001; Nussdorfer, 1996, 2001; Nussdorfer and Gottardo,

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1998; Nussdorfer and Malendowicz, 1998a,b; Nussdorfer et al., 1999, 2000; Renshaw and Hinson, 2001; Vaudry et al., 2000).

III. CCK AND ITS RECEPTORS IN THE HPA AXIS A. HYPOTHALAMUS AND PITUITARY GLAND

1. CCK CCK‐immunoreactivity has been immunocytochemically demonstrated in the rat and human hypothalamus, especially in the paraventricular and supraoptic nuclei (Anhut et al., 1983; Kiss et al., 1984; Micevych et al., 1987; Vanderhaeghen et al., 1980), and the coexistence of CCK with CRH, AVP, or oxytocin has been clearly shown in some neurons of the parvocellular or magnocellular part of the rat paraventricular nucleus (Cecatteli et al., 1989; Mezey et al., 1986; Vanderhaeghen et al., 1981). The expression of CCK mRNA and protein also has been detected in the anterior pituitary cells (Houben and Denef, 1994; Vanderhaeghen et al., 1980) and mouse pituitary tumor AtT–20 cells (Beinfeld, 1992). 2. CCK Receptors Radio‐ligand studies demonstrated the presence of the CCK1‐R and CCK2‐R in several hypothalamic nuclei of rodents, monkeys, and humans, including supraoptic, paraventricular, and dorsomedial nuclei, as well as in the infundibular region (Carlberg et al., 1992; Dietl et al., 1987; Hill et al., 1987, 1990; Jagerschmidt et al., 1994; Moran et al., 1986; Sekiguchi and Moroji, 1986; Williams et al., 1986; Zajac et al., 1996). In situ hybridization studies confirmed these findings in the rat (Honda et al., 1993). Investigations on CCK‐R distribution in the pituitary gland are surprisingly scarce. Using reverse transcription–polymerase chain reaction, the expression of both CCK1‐R and CCK2‐R mRNAs has been demonstrated in the pituitary gland of adult rats, and semiquantitative polymerase chain reaction showed that the prolonged CCK-8 administration down‐regulated the expression of both CCK‐R subtypes (Malendowicz et al., 2003). B. ADRENAL GLAND

1. CCK Proof is available that CCK‐immunoreactivity is present in adrenal venous eZuent of cats (Gaumann and Yaksh, 1998a,b), as well as in human pheochromocytomas (Bardram et al., 1989) and medullary cells of the avian interrenals (Ohmori et al., 1997). Moreover, CCK‐immunoreactivity is contained in several substance P–positive nerve fibers of the human and guinea‐pig adrenals (Heym, 1997; Heym et al., 1995a,b).

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2. CCK Receptors The expression of both CCK1‐R and CCK2‐R mRNAs has been detected by reverse transcription–polymerase chain reaction in the ZG, but not ZF/R, cells of rat (Malendowicz et al., 2001b, 2003) and human adrenal cortex (Mazzocchi et al., 2004). Accordingly, autoradiography demonstrated the presence of [125I]CCK-8‐binding sites in the ZG and, to a lesser extent, in the medulla of the rat adrenal gland, whereas ZF/R was not labeled. Binding was eliminated by cold CCK-8 and decreased by both CCK1‐R and CCK2‐ R antagonists. When added together, the two antagonists completely displaced binding, thereby indicating that rat ZG and adrenal medulla are provided with both subtypes of CCK receptors (Malendowicz et al., 2001b). This last observation is in contrast with previous findings indicating that caerulein activates IP3 in primary cultures of bovine adrenomedullary cells, and that the eVect is reversed by a CCK1‐R antagonist and unaVected by a CCK2‐R antagonist (Aarnisalo et al., 1996).

IV. EFFECTS OF CCK ON ADRENAL‐CORTEX SECRETION CCK enhances both mineralocorticoid and glucocorticoid secretion from adrenal cortex; however, the bulk of evidence indicates that the former action occurs through a direct mechanism, while the latter ensues from the activation of the central branch of the HPA axis. This contention agrees with the demonstration that CCK receptors are expressed in the ZG, but not ZF/R, of the adrenal cortex (see Section III.B).

A. ALDOSTERONE SECRETION

1. Indirect Mechanisms Although ACTH and AVP are potent aldosterone secretagogues (see Section II.B.2), and CCK was found to enhance the blood levels of both these agonists (see Section IV.B), evidence is not available that systemic prolonged CCK administration raises aldosterone plasma concentration in rats (Malendowicz et al., 2003). Disappointingly, the numerous studies dealing with the acute eVect of systemic CCK administration on the HPA axis assayed the blood levels of glucocorticoids but not of aldosterone (see Section IV.B). 2. Direct Mechanisms CCK-8 was found to increase basal aldosterone secretion from dispersed rat and human ZG cells in a concentration‐dependent manner, with minimal and maximal eVective concentrations being 10 8 and 10 6 M in the rat, and

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10 10 and 10 8 M in humans (Malendowicz et al., 2001b; Mazzocchi et al., 2004). CCK (10 6 M) did not alter rat ZG‐cell response to 10 9 M ACTH but evoked a small, but significant (20%), increase in the responses to both 10 9 M Ang‐II and 10 mM Kþ (Malendowicz et al., 2001b). a. CCK Receptors Involved Both CCK1‐R and CCK2‐R antagonists blunted the aldosterone response of rat ZG cells to 10 6 M CCK-8, and when added together, they abolished it (Malendowicz et al., 2001b). In contrast, in human ZG cells, aldosterone response to 10 8 M CCK-8 was not aVected by CCK1‐R antagonists but was suppressed by CCK2‐R antagonists (Mazzocchi et al., 2004). This finding indicates that, at variance with rats, only the CCK2‐R mediates the aldosterone secretagogue eVect of CCK. This contention is also supported by the fact that CCK-8 and the selective CCK2‐R agonist pentagastrin displayed similar potency and eYcacy in their stimulating action on human ZG cells (Mazzocchi et al., 2004). b. Signaling Mechanisms Evidence has been provided that both CCK1‐R and CCK2‐R in rat ZG cells and CCK2‐R in human ones are coupled to the adenylate cyclase/PKA pathway (Malendowicz et al., 2001b; Mazzocchi et al., 2004), a contention in keeping with the lack of additivity between the aldosterone secretagogue action of CCK-8 and that of ACTH, but not of Ang‐II and Kþ (see Section II.B.1). CCK-8 was found to enhance cyclic‐AMP, but not IP3 release from ZG cell preparations, and the eVect was blunted by both CCK1‐R and CCK2‐R antagonists in rat and only by CCK2‐R antagonists in humans. Likewise, pentagastrin raised cyclic‐AMP production from human ZG cells, and the eVect was annulled by either CCK2‐R antagonists or the adenylate cyclase inhibitor SQ-22536. Moreover, the aldosterone secretagogue eVect of CCK-8 and pentagastrin were abrogated by both SQ-22536 and the PKA inhibitor H-89, whereas the PLC inhibitor U-73122 and the PKC inhibitor calphostin‐C were ineVective. Of interest, CCK-8 and pentagastrin were found to evoke within 60 min in human ZG‐cell preparations a marked CCK2‐R antagonist‐reversible increase in the mRNA expression of steroidogenic acute regulatory protein (Mazzocchi et al., 2004), which is the rate‐limiting step of steroidogenesis and the main locus of action of ACTH (see Section II.B). B. GLUCOCORTICOID SECRETION

1. Indirect Mechanisms The bulk of the investigations clearly indicates that CCK stimulates glucocorticoid secretion by activating the central branch of the HPA axis. The acute systemic or intracerebroventricular administration of CCK was

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found to increase ACTH and cortisol plasma concentrations in healthy human volunteers, with the ACTH response preceding the glucocorticoid response (Calogero et al., 1993). Similar findings were obtained in humans after acute administration of caerulein, a decapeptide analogous to CCK-8 (Spa¨ th‐Schwalbe et al., 1988) (Fig. 1). Acute ACTH or glucocorticoid responses to CCK or CCK analogs were observed in rats (Day and Akil, 1999; Itoh and Hirota, 1983; Itoh et al., 1979a, 1980; Kamilaris et al., 1992; Katsuura et al., 1992; Parrott and Forsling, 1992; Parrott et al., 1991; Porter and Sander, 1981; Reisine and Jensen, 1986; Sander and Porter, 1982, 1988), sheep (Ebenezer and Parrott, 1996; Ebenezer et al., 1989), and dogs (Thomas and Sander, 1985), but not in the pig (Ebenezer et al., 1996). The eVect of the prolonged CCK administration on the HPA axis has been investigated in rats. Although earlier studies reported that three subcutaneous injections of CCK–8 (4, 16, and 24 h before death) evoked a significant rise in ACTH and corticosterone blood levels (Malendowicz et al., 1998), subsequent investigations did not confirm this finding (Malendowicz et al., 2003). a. Locus of Action of CCK Collectively, available findings do not support the view that pituitary corticotropes are a main target for CCK. Although CCK has been reported to enhance ACTH release from cultured rat anterior‐pituitary cells (Reisine and Jensen, 1986), other investigators were unable to find any eVect (Kamilaris et al., 1992; Sander and Porter, 1982). CCK1‐R and CCK2‐R mRNA expression has been detected in the rat adenohypophysis (Malendowicz et al., 2003), which was down‐regulated by the prolonged CCK treatment (see Section III.A.2). By assuming that CCK‐R expression occurs in pituitary corticotropes, this finding could easily account for the lack of eVect of the prolonged CCK treatment on ACTH plasma level in rats (see earlier). However, RNA was extracted from the entire pituitary gland, and there is proof that CCK acts on pituitary somatotropes and lactotropes, eliciting within 45 min marked rises in the blood levels of growth hormone and prolactin (Calogero et al., 1993; Malarkey et al., 1981; Nair et al., 1983; Vijayan and McCann, 1987; Vijayan et al., 1979). Convincing evidence indicates that the main targets of CCK are hypothalamic neurons releasing the main ACTH secretagogues CRH and AVP (Antoni, 1986; Buckingham et al., 1992; Hauger and Aguilera, 1993), where both CCK and its receptors are abundantly expressed (see Section III.A). Investigations showed that systemic administration of CCK evokes a very rapid increase in the blood level of AVP in rats (Parrott and Forsling, 1992), pigs (Parrott et al., 1991), and humans (Calogero et al., 1993; Miaskiewicz et al., 1989). CCK was also found to induce the release of AVP from rat neural pituitary lobe (Bondy et al., 1989). Despite the fact that Calogero et al. (1993) failed to find any sizable rise in CRH plasma concentration after systemic CCK administration in healthy humans, the stimulating eVect of CCK on CRH hypothalamic neurons has

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been well demonstrated in rats (Biro´ et al., 1993; Kamilaris et al., 1992; Verbalis et al., 1991). Moreover, the administration of a CRH antiserum was found to notably blunt ACTH and corticosterone response to CCK–8 in rats (Kamilaris et al., 1992). b. CCK Receptors Involved Investigations showed that some CCK1‐R antagonists decrease ACTH or corticosterone response to CCK in rats (Katsuura et al., 1992; Malendowicz et al., 1998; Ruiz‐Gayo et al., 2000). This finding, along with the reported lack of eVect of pentagastrin in rats and sheep (Ebenezer and Parrott, 1996; Itoh et al., 1979b), would indicate that CCK1‐R mediates the stimulating action of CCK on the HPA axis. However, other studies reported that CCK1‐R antagonists blunt AVP response to CCK in the pig, but neither CCK1‐R nor CCK2‐R antagonists aVect glucocorticoid response, thereby indicating the involvement of a novel CCK‐R subtype, at least in this species (Parrott and Forsling, 1992). In spite of these studies, at present the bulk of evidence supports the main involvement of the CCK2‐R in the mediation of the eVect of CCK on the HPA axis, inasmuch as the selective CCK2‐R agonist pentagastrin was able to rise ACTH and glucocorticoid plasma concentrations in rats and humans (Abelson and Liberzon, 1999; Abelson and Young, 2003; Abelson et al., 1994; Degli Uberti et al., 1983; De Montigny, 1989), and CCK2‐R antagonists were found to blunt the CCK‐induced stimulation of the HPA axis in rats (Kamilaris et al., 1992). Completely diVerent results were obtained by Malendowicz et al. (2000), who observed that the acute systemic administration of a CCK1‐R antagonist did not per se alter plasma levels of ACTH and corticosterone in rats, whereas a CCK2‐R antagonist raised ACTH at 15 min and corticosterone at 60 and 120 min. These investigators suggested that endogenous CCK, acting via CCK2‐R, exerts a tonic inhibitory action on rat HPA axis by suppressing pituitary ACTH release. However, this ‘‘unorthodox’’ contention has not been confirmed by following chronic experiments (Malendowicz et al., 2003). A CCK1‐R antagonist, although per se being ineVective, when coadministered with CCK-8 enhanced the blood level of corticosterone, whereas a CCK2‐R antagonist, either administered alone or with CCK-8, decreased plasma corticosterone concentration. These results, along with the lack of eVect of any treatment on the level of circulating ACTH, cast doubts on the involvement of endogenous CCK in the physiological regulation of rat HPA axis. Furthermore, these findings may indicate that the activation of the CCK1‐Rs inhibits and that of CCK2‐Rs stimulates corticosterone secretion independent of any eVect on pituitary ACTH release. 2. Direct Mechanisms Dispersed rat and human inner adrenocortical cells did not evidence any sizable glucocorticoid response to CCK (Malendowicz et al., 2001b; Mazzocchi et al., 2004; Sander and Porter, 1988). This observation is in

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keeping with the reported lack of CCK‐Rs in inner adrenocortical cells (see Section III.B.2) and rules out the possibility of a direct eVect of CCK on these cells. However, the fact that the prolonged blockade of CCK‐Rs altered the blood level of corticosterone in rats without aVecting ACTH release (see earlier), could indicate that CCK in vivo may act directly on the entire adrenal gland. Adrenal medulla is provided with CCK1‐R and CCK2‐R (see Section III.B.2), and medullary chromaYn cells, by releasing catecholamines and other regulatory peptides, are known to regulate the secretion of adrenocortical cells in a paracrine manner (Nussdorfer, 1996). Whether CCK‐Rs are involved in the physiological tuning of adrenal‐medulla secretion is not known, and further investigations are needed to explore this appealing possibility, which parenthetically has been already demonstrated for other regulatory peptides, including vasoactive intestinal polypeptide and pituitary adenylate cyclase‐activating polypeptide (Bernet et al., 1994a; Hinson et al., 1992; Neri et al., 1996), neuropeptide‐Y (Bernet et al., 1994a,b; Mazzocchi et al., 1996a; Renshaw et al., 2000), tachykinins (Mazzocchi et al., 1994), cerebellin (Albertin et al., 2000; Mazzocchi et al., 1999), and adrenomedullin (Andreis et al., 1997; Mazzocchi et al., 1996b).

V. CONCLUDING REMARKS The preceding sections of this survey have shown that in the last 20 years, a quite large number of investigations has accumulated, indicating that CCK plays a potentially important role in the regulation of the HPA axis. The bulk of evidence indicates that this peptide enhances aldosterone secretion acting directly on adrenal via CCK‐Rs located in the ZG, and glucocorticoid secretion acting on the central branch of the HPA axis. However, many problems remain open, and we here take the opportunity to stress some topics, the examination of which should be the task of future investigative eVorts. The blood concentrations of CCK in healthy humans range from 2 to 7  10 12 M (Sturm et al., 2003); hence, about two orders of magnitude less than the minimal eVective concentration in vitro (see Section IV.A). This could cast doubts about the physiological relevance of the aldosterone secretagogue eVect of CCK. However, evidence is available that CCK may be produced by adrenal medulla (see Section III.B.1), and a large mass of studies indicates that many regulatory peptides secreted by adrenomedullary cells may act on the cortex through a paracrine mechanism. It has been calculated that if the adrenal content of a regulatory peptide is 100 fmol/g, its 30% release can produce a local concentration of about 10 9 M (see for review, Nussdorfer, 1996). Further studies are needed to ascertain whether CCK may be included in this group of adrenomedullary regulatory peptides. Human ZG cells express both the CCK1‐R and CCK2‐R, but the aldosterone secretagogue action of CCK is exclusively mediated by the latter

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receptor subtype. The possibility that the CCK1‐R is a silent receptor does not seem tenable, because CCK1‐R antagonists do not potentiate the aldosterone secretagogue action of CCK (Mazzocchi et al., 2004). We have already mentioned (see Section II.A.3) that CCK1‐Rs appear to regulate the growth of normal and neoplastic tissues, and preliminary findings would indicate that CCK, via the CCK1‐R, enhances the proliferative activity of immature rat adrenocortical cells and thymocytes (Malendowicz et al., 1999). ZG in mammals is the cambium layer involved in adrenocortical cell renewal (for review, see Nussdorfer, 1986), and the appealing possibility that CCK plays a role in the regulation of the growth of human normal and tumorous adrenal tissues surely awaits future study. Although there is general consensus that CCK stimulates CRH/ACTH system under normal conditions (see Section IV.B.2), some sporadic findings would indicate that CCK, via the CCK2‐R, blunts other stress–induced ACTH secretion in rats (Malendowicz et al., 2000, 2003). These observations could be in keeping with the results of investigations indicating that CCK released from lateral‐parabrachial, periaqueductal‐gray, and dorsal‐raphe regions of the rat brain inhibits ACTH response to acute restraint stress by activating CCK2‐Rs located in the posterior paraventricular nucleus of the thalamus (Bhatnagar et al., 2000). The possible role of endogenous CCK in dampening the exceedingly high responses of the HPA axis to stresses should be addressed and elucidated in the coming years. In conclusion, it seems that the continuous investigation of CCK and the HPA axis, along with the development of novel potent and more selective agonists and antagonists of the CCK1‐R and CCK2‐R, will not only open new frontiers in our knowledge of adrenal physiology but also shed light on possible novel and important perspectives in the therapy and prevention of diseases causing dysregulation of adrenal secretory activity.

ACKNOWLEDGMENTS This work was supported by Ministero dell’Universita` e Ricerca Scientifica Grant FIRB RBAU–01‐PPBS to GGN. The authors are indebted to Alberta Coi for outstanding secretarial support.

REFERENCES Aarnisalo, A. M., Vainio, P. J., Mannisto, P. T., Vasar, E., and Tuominen, R. K. (1996). Evidence for cholecystokinin A receptors in bovine adrenal chromaYn cells. Neuroreport 7, 2167–2170. Abelson, J. L., and Liberzon, I. (1999). Dose response of adrenocorticotropin and cortisol to the CCK‐B agonist pentagastrin. Neuropsychopharmacology 21, 485–494.

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