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Neuroscience 126 (2004) 241–246

CHRONIC CORTISOL SUPPRESSES PITUITARY AND HYPOTHALAMIC PEPTIDE MESSAGE EXPRESSION IN PIGTAILED MACAQUES
P. SZOT,a,c* C. W. WILKINSON,b,c S. S. WHITE,c J. B. LEVERENZ,b,c J. L. GREENUP,a E. A. COLASURDO,b E. R. PESKINDa,c AND M. A. RASKINDa,c
a Northwest Network Mental Illness Research, Education and Clinical Center S-116, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA b Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA c

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA

Abstract—The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic–pituitary–adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Proopiomelanocortin in the anterior pituitary and corticotropinreleasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function. Published by Elsevier Ltd on behalf of IBRO. Key words: hypercortisolemia, anterior pituitary, paraventricular nucleus (PVN), corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), monkey.

Circulating glucocorticoid concentrations are regulated by coordinated action at all levels of the hypothalamic–

*Correspondence to: P. Szot, PhD, Veterans Affairs Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center S-116, 1660 South Columbian Way, Seattle, WA 98108, USA. Tel: 1-206-277-5052; fax: 1-206-768-5456. E-mail address: [email protected] (P. Szot). Abbreviations: ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CRF, corticotropin-releasing factor; CRF-R1, corticotropin-releasing factor receptor subtype 1; HPA, hypothalamic– pituitary–adrenal; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus.
0306-4522/04$30.00 0.00 Published by Elsevier Ltd on behalf of IBRO. doi:10.1016/j.neuroscience.2004.03.030

pituitary–adrenal (HPA) axis. Glucocorticoid secretion from the adrenal cortex is controlled by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary. ACTH secretion is in turn stimulated by hypothalamic corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) acting synergistically. Activity of the axis is suppressed by glucocorticoid feedback inhibition acting at multiple levels: pituitary, hypothalamic, and suprahypothalamic. Chronic glucocorticoid treatment disrupts the auto-regulatory action of the axis and may alter expression of hypothalamic and hypophyseal peptides and receptors intrinsic to HPA function. There have been numerous studies performed in rodents examining the effects of chronic glucocorticoid administration on the HPA axis. In rodents, elevated circulating glucocorticoid concentrations decrease expression of pro-opiomelanocortin (POMC; the biosynthetic precursor of ACTH; Autelitano et al., 1987; Harbuz et al., 1990; Young et al., 1995; Zhou et al., 1996) and CRF receptor 1 (CRF-R1), at least transiently, in anterior pituitary (Luo et al., 1995; Makino et al., 1995; Zhou et al., 1996; Ochedalski et al., 1998; Aguilera et al., 2001). Glucocorticoids also down-regulate expression of the hypothalamic ACTH releasing peptides CRF (Harbuz et al., 1990; Albeck et al., 1994; Patchev and Almeida, 1996; Swanson and Simmons, 1989) and AVP (Davis et al., 1986; Albeck et al., 1994; Patchev and Almeida, 1996; Ferrini et al., 1997) in the paraventricular nucleus (PVN) of the hypothalamus. These functional alterations of the HPA axis in response to elevated glucocorticoids have been demonstrated repeatedly in rodents, but they have not been examined in primates. Knowledge of the potential existence of similar effects in primates is clinically relevant because glucocorticoids are commonly prescribed, on a chronic basis, for many immunological and inflammatory conditions. We attempted to determine whether chronic cortisol treatment in primates produces changes in the HPA axis similar to those found in rodents. Therefore, the effects of chronic hypercortisolemia in old (18 –29 years) Macaca nemestrina (pig-tailed macaques) were investigated by measuring anterior pituitary POMC and CRF-R1 message expression and PVN CRF and AVP mRNA by in situ hybridization after 1 year of high-dose oral glucocorticoid treatment. We hypothesized that the expression of these peptides and the CRF receptor would be down-regulated in older macaques receiving cortisol. To our knowledge, this is the first investigation of the effect of chronic glucocorticoid treatment on HPA-related peptide and receptor expression in primates.

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EXPERIMENTAL PROCEDURES
Monkey tissue
Fifteen (five males and 10 females) retired breeder pigtailed macaques (M. nemestrina) in mid- to late life (ages 18 –29 years with a mean S.E.M. of 23.1 1.0 years) received placebo (two males and six females) or cortisol (three males and four females) orally for 1 year. Hydrocortisone (cortisol) acetate (3.85–5.78 mg/kg/ day) was administered by mouth twice per day in a highly palatable mixture containing peanut butter, molasses, mashed potato flakes, and ground monkey chow (Leverenz et al., 1999). During the year of treatment, all animals were individually housed in the same room so that physical contact between animals was not possible, but visual and auditory communication was available. Housing temperature and humidity conditions conformed to the Animal Welfare Act and Guide for the Care and Use of Laboratory Animals. All animals were in good general health. Purina monkey chow was provided during the study on a twice-daily basis, with fruit supplements. The Washington Regional Primate Research Center is fully accredited by American Association for the Assessment and Accreditation of Laboratory Animal Care International, and all procedures were reviewed and approved by the University of Washington Animal Care and Use Committee. The minimum number of animals were used for these studies and care was taken to minimize any suffering. Both plasma (control 318 47 ng/ml and treated 467 61 ng/ml) and CSF (control 13.3 1.3 ng/ml and treated 40. 8 11.0 ng/ml) cortisol were significantly elevated in cortisol-treated monkeys at the time of necropsy (Leverenz et al., 1999). After 12 months of treatment, animals were killed by valium-phenobarbital injections. Brains were rapidly removed and sectioned into the two hemispheres. The pituitary was removed and frozen intact. The left portion of the brain was sectioned into 0.5-cm-thick coronal blocks of the cerebral hemispheres and 0.5-cm-thick horizontal blocks of the brainstem. The left hemisphere and brainstem blocks were rapidly frozen between cooled alumina plates in a 70 °C freezer and stored at that temperature. Blocks including the hypothalamus and the pituitary were sectioned (20 m) on a cryostat, thaw mounted onto Fisher Superfrost slides (Fisher Scientific, Houston, TX, USA) and stored at 70 °C.

hybridized with each of the [33P] oligonucleotide probes were coated with NTB2 Nuclear Track Emulsion (undiluted) and stored at 20 °C for 1 day for POMC, 2 days for AVP, 7 days for CRF-R1, and 2 weeks for CRF. The slides were developed in Kodak D-19 developer (diluted 1:1 with water) at 17 °C, rinsed in water, and fixed in Kodak general fixer. The slides were stained with Cresyl Violet acetate, dehydrated (70, 95 and 100% alcohol), allowed to air dry, and mounted with coverslips.

Quantification of mRNA in anterior pituitary
To quantify POMC and CRF-R1 mRNA expression in the anterior pituitary in the monkey tissue, three consecutive sections from each animal were processed, hybridized, and washed in the same session. The density of POMC and CRF-R1 grains/cell was determined by analyzing the quantity of silver grains over a cell body at a threshold value approximately three-fold higher than background under dark-field illumination with a 20 objective. Grain intensity (i.e. grains/cell) was measured as pixels using the MicroComputer Imaging Device (MCID; Imaging Research Inc., St. Catherines, Ontario, Canada). The data are represented as the mean S.E.M. of the number of grains localized over cell bodies (grains/cell) in the anterior pituitary from three sections. Data were analyzed with unpaired Student’s t-test using StatView (SAS Institute, Inc., Cary, NC, USA) with the significance level at P 0.05. Simple linear regressions were performed between mRNA measurements and age, urinary, plasma and CSF cortisol and plasma ACTH using StatView, with significance at P 0.05.

Quantification of mRNA in hypothalamic PVN
CRF and AVP mRNA expression in the monkey PVN tissue was quantified in the same way as POMC and CRF-R1 mRNA in the anterior pituitary tissue, with three consecutive sections from each animal processed, hybridized, and washed in the same session. Since an alteration in mRNA expression in neurons can result in either changes in the number of cells expressing the mRNA or the amount of mRNA expressed per cell (grains/cell), both of these measurements were performed in the PVN. The number of cells that achieved the threshold criteria described above was recorded and totaled unilaterally for the PVN and expressed as the number of positively labeled cells. Unilateral readings were made in the PVN (the other half of forebrain was fixed with paraformaldehyde for other studies). An average of three readings was used to determine a single value of grains/cell and number of positively labeled cells for each animal. Measurement and analysis of grain density (grains/cell) were as described for pituitary tissue.

Oligonucleotides
PVN sections were atlas matched to the same level for both treatment groups. The midsection of the PVN was chosen based on preliminary work, because this region exhibited intense CRF labeling. Pituitary sections for both treatment groups contained anterior and posterior regions of the pituitary to demonstrate the specificity of the oligonucleotide probes for the anterior lobe of the pituitary. Tissue was prepared as described in detail elsewhere (Szot et al., 2000). For each oligonucleotide probe studied, tissue from both treatment groups was processed at the same time. Oligonucleotide probes (Invitrogen, Carlsbad, CA, USA) complementary to the first 16 amino acids of the ACTH region of the POMC sequence (Whitfeld et al., 1982), to the binding region of the CRF-R1 sequence (Ross et al., 1994), to nucleotides 511–558 of the CRF sequence (Shibahara et al., 1983) and the first 16 amino acids of the neurophysin II portion of the rat AVP sequence (Land et al., 1982) were utilized. Preliminary work with each of the oligonucleotide probes indicated specific labeling to regions that have been previously documented (Pepe et al., 1994; Austin et al., 1995; Liebsch et al., 1995). Each oligonucleotide probe was 3 end-labeled with [33P]dATP (Perkin Elmer, Boston, MA, USA) using terminal deoxyribonucleotidyl transferase (Life Technologies, Gaithersburg, MD, USA) and then purified on NEN-Sorb columns. The hybridization buffer for POMC assay contained 1.35 106 cpm/50 l, for CRF-R1, 0.65 106 cpm/50 l, for CRF, 0.80 106 cpm/50 l, and for AVP, 0.55 106 cpm/50 l. Slides

RESULTS
Anterior pituitary Expression of POMC and CRF-R1 mRNA was observed in the anterior but not the posterior pituitary. Levels of POMC or CRF-R1 mRNA in the anterior pituitary of control- and cortisol-treated monkeys are shown in Fig. 1 as grains/cell. Levels of POMC mRNA expression in the anterior pituitary of control-treated monkeys demonstrated a significant negative correlation with plasma ACTH levels (r 0.776; P 0.02). POMC and CRF-R1 mRNA expression were not significantly correlated with age-within the narrow age range of these animals -or to urinary, plasma or CSF cortisol concentrations. POMC mRNA expression per cell (grains/cell) in cortisol-treated monkeys was significantly reduced in comparison with control animals (Fig. 1A; darkfield photomicrographs of POMC mRNA expression per cell [grains/cell] in control- [1C] and cortisol-treated [1D]

P. Szot et al. / Neuroscience 126 (2004) 241–246

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Cell Number

150 100 50 0

Control Treated

Grains/cell

300 200

Grains/cell

A

200

Control Treated

B 400

A

200

B

100

*

120 100 80 60 40 20 0

*

*
0

100

0
Fig. 2. (A) Number of positively labeled neurons and (B) grains/cell of CRF mRNA expression in grains/cell of CRF mRNA expression in the hypothalamic PVN of monkeys treated with either placebo or cortisol for 1 year. Dark-field images of CRF mRNA labeling in the PVN of placebo (control; C) and cortisol-treated (D) monkey. * Indicates significant difference from control treated group, P 0.05. Scale bar 300 m.

Fig. 1. Amount of POMC (A) and CRF-R1 (B) mRNA expression (grains/cell) in the anterior pituitary of monkeys treated with either placebo or cortisol (control) for 1 year. Dark-field images of POMC mRNA labeling in the anterior pituitary of placebo (control; C) and cortisol-treated (D) monkey. * Indicates significant difference from control treated group, P 0.05. Scale bar 200 m.

control-treated monkeys are shown in Fig. 3. AVP mRNA expression in cortisol-treated animals did not differ significantly from that of control animals, in either number of positively labeled neurons or grains/cell.

DISCUSSION
These studies comprise the first demonstration in a primate of the effects of 1-year, high-dose cortisol treatment on hypothalamic and hypophyseal expression of peptides and peptide receptors that are fundamental components of the regulation of the HPA axis. Chronic cortisol treatment resulted in marked decreases in anterior pituitary POMC and hypothalamic PVN CRF mRNA without significantly affecting pituitary CRF-R1 or PVN AVP expression. The decrease in CRF mRNA expression was negatively correlated with urinary, plasma and CSF cortisol levels, indicating suppression of CRF mRNA expression by elevated

monkeys). CRF-R1 mRNA expression in the anterior pituitary was not statistically different between treatment groups (Fig. 1B). PVN The cell number and grains/cell of CRF expression in the PVN of control- and cortisol-treated monkeys are shown in Fig. 2. CRF mRNA expression in the PVN was negatively correlated with urinary (r 0.724; P 0.01), plasma (r 0.648; P 0.05) and CSF (r 0.558; P 0.05) cortisol and positively correlated with plasma ACTH concentrations (r 0.616; P 0.05) when both groups (control and cortisol-treated) were combined, but analysis of each group separately did not result in a significant correlation with any parameter. AVP mRNA expression did not exhibit significant correlations with age, urinary, plasma or CSF cortisol or with plasma ACTH. CRF mRNA expression in the PVN of cortisol-treated monkeys was significantly reduced compared with controls, both in terms of the number of positively labeled neurons (Fig. 2A) and the amount of CRF expressed per cell (grains/cell; Fig. 2B; dark-field photomicrographs of CRF expression in control- [2C] and cortisol-treated [2D] monkeys). AVP mRNA expression was found only in the magnocellular region of the PVN, the region in which AVP peptide concentration is highest in monkeys (Kawata and Sano, 1982). AVP mRNA levels were undetectable in the parvicellular region of the PVN. The number of positively labeled neurons and grains/cell of AVP mRNA expression in the magnocellular region of the PVN of cortisol- and

A
300

B Grains/cell
250 200 150
p<0.10

Control Treated

200
p<0.20

Cell Number

150 100

100 50 0

50

0

Fig. 3. (A) Number of positively labeled neurons and (B) grains/cell of AVP mRNA expression in the hypothalamic PVN of monkeys treated with either placebo or cortisol for 1 year.

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cortisol levels. Since cortisol also suppresses ACTH secretion (Leverenz et al., 1999), CRF mRNA is positively correlated with plasma ACTH levels. Plasma ACTH concentrations in the control group exhibited a significant negative correlation with POMC mRNA expression, reflecting the increasing inhibition of POMC mRNA expression with increases in endogenous ACTH and cortisol. There was no significant correlation with POMC mRNA in the cortisol treated monkeys because of complete feedback inhibition of ACTH in this group. Four of the seven monkeys in the cortisol-treated group had unmeasurable plasma ACTH. The majority of studies in rats have also reported a significant reduction of POMC mRNA in the anterior pituitary and of CRF mRNA in the PVN (Davis et al., 1986; Autelitano et al., 1987; Swanson and Simmons, 1989; Harbuz et al., 1990; Albeck et al., 1994; Young et al., 1995; Zhou et al., 1996; Patchev and Almeida, 1996), although Konakchieva et al. (1998) found increases in rat hypothalamic CRF and AVP expression after 5 days of i.p. injections of very high doses of dexamethasone. In the single human study published to date, chronic glucocorticoid administration of varying duration (2–18 days) resulted in a significant decrease in the number of CRF immunohistochemically labeled neurons in the hypothalamus (PVN; Erkut et al., 1998). Therefore, the down-regulation of POMC and CRF mRNA in the pituitary and hypothalamus, respectively, is a consistent effect of chronic glucocorticoid administration in rodents and non-human primates despite differences in route of administration, type of glucocorticoid, dose, nature of the control group, or duration of treatment. Regulation of CRF-R1 has been shown to be complex and exerted at multiple levels including translational and post-translational modification (Aguilera et al., 2001; Xu et al., 2001). Glucocorticoid administration to rats generally has been shown to result in sustained decreases in CRF-R1 number and binding sites in the anterior pituitary (Childs et al., 1986; Schwartz et al., 1986; Hauger et al., 1987), but CRF-R1 mRNA has been found to exhibit only a transient reduction (Ochedalski et al., 1998; Iredale and Duman, 1997). In addition, pituitary CRF-R1 mRNA levels are not affected by long-term adrenalectomy and thus are not under tonic inhibition by glucocorticoids (RabadanDiehl et al., 1997). Therefore, the lack of effect of chronic glucocorticoid treatment on CRF-R1 mRNA in macaque anterior pituitary coincides with findings in rats. The lack of an effect on AVP mRNA expression in the hypothalamic PVN in the monkeys after 1 year of cortisol treatment is not completely consistent with rodent data, although there are major differences between the rodent studies and the one performed here. AVP is expressed in parvicellular and magnocellular neurons of the PVN with the majority of AVP being localized to magnocellular neurons (Kawata and Sano, 1982; Ma and Aguilera, 1999). However, AVP expression in magnocellular PVN neurons is not generally considered to be under regulatory control by cortisol feedback. The levels of AVP mRNA expression in parvicellular PVN neurons are low under physiological conditions, but are significantly increased following adre-

nalectomy in rodents. Glucocorticoid administration subsequent to adrenalectomy reduces AVP expression to basal levels (Davis et al., 1986; Albeck et al., 1994; Ferrini et al., 1997; Ma and Aguilera, 1999; Tanimura and Watts, 2000). In our study, AVP mRNA levels were undetectable in macaque parvicellular PVN neurons, and this extremely low parvicellular expression is reflected by low protein levels (Kawata and Sano, 1982). The lack of an effect on AVP mRNA expression in the hypothalamic PVN in monkeys after 1 year of cortisol treatment may be the result of a “floor” effect in parvicellular neurons and the relative insensitivity of magnocellular neurons to glucocorticoid feedback. However, there is some evidence to indicate that the magnocellular neurons of the PVN do respond to glucocorticoids under some conditions. Adrenalectomy followed by glucocorticoid replacement may not be an appropriate means of determining glucocorticoid regulation because removal of the adrenals also removes the source of mineralocorticoids. The consequent alterations of plasma osmolality can have a profound effect on magnocellular AVP neurons that may mask any effect of glucocorticoids on these neurons. Electrophysiologically, magnocellular AVP neurons in the PVN are inhibited by the administration of glucocorticoids (Saphier and Feldman, 1988). The expression of glucocorticoid receptors also increases in magnocellular neurons during chronic hyperosmolality (Berghorn et al., 1995). Adrenocortical insufficiency results in increased levels of plasma AVP, the source of which is magnocellular PVN neurons. Glucocorticoid administration reduces the plasma AVP concentrations (Ahmed et al., 1967). Erkut et al. (1998) found a significant decrease in total PVN AVP expression in postmortem tissue of subjects exposed to short term glucocorticoid treatment (2–18 days) but did not differentiate between parvicellular and magnocelluar neurons of the PVN. We have been unable to detect AVP mRNA in postmortem human parvicellular PVN (unpublished data), and in light of the extremely low expression of AVP in parvicellular neurons, the changes observed by Erkut et al. (1998) can be surmised to have occurred in the magnocellular PVN. It is possible that short-term glucocorticoid administration reduces AVP expression in the magnocellular neurons of the primate PVN, but that compensatory AVP expression may occur when glucocorticoid treatment is prolonged as in the current study. Overall, the changes in HPA-related peptide and receptor expression in the hypothalamus and anterior pituitary of macaques to prolonged glucocorticoids are very similar to the changes that have been documented in rodents. Significant suppression of pituitary POMC and hypothalamic CRF expression are consistent and predominant responses to chronic glucocorticoid administration. Suppression of pituitary CRF-R1 and PVN AVP expression may be transitory and/or regulated primarily by translational or post-translational mechanisms. Chronic therapeutic administration of high levels of glucocorticoids in humans is highly likely to result in prolonged suppression of pituitary POMC and hypothalamic CRF suppression. This

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prolonged suppression may not only alter HPA functional dynamics, but may also affect CRF-dependent CNS mediation of anxiety and/or POMC-dependent peripheral endorphin responses to pain.
Acknowledgements—These studies were supported by the Department of Veterans Affairs Research and Development Service, Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) and Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Health Care System; the National Alliance for Research on Schizophrenia and Depression and the University of Washington Alzheimer’s Disease Research Center (AGO5136); the Geriatric Academic program (AGO0503); and the Alhadeff Alzheimer’s Research Fund.

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(Accepted 18 March 2004)

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