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Endocrinology Vol. 145, No. 4 1695-1699
Copyright © 2004 by The Endocrine Society

Cocaine- and Amphetamine-Regulated Transcript Co-Contained in Thyrotropin-Releasing Hormone (TRH) Neurons of the Hypothalamic Paraventricular Nucleus Modulates TRH-Induced Prolactin Secretion

Stefanos Raptis, Csaba Fekete, Sumit Sarkar, William M. Rand, Charles H. Emerson, György M. Nagy and Ronald M. Lechan

Neuroendocrine Research Laboratory (S.R., G.M.N.), Semmelweis University, and Department of Endocrine- and Behavioral Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary; Tupper Research Institute and Department of Medicine (S.S., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, and Departments of Community Health (W.M.R.) and Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; and Department of Medicine (C.H.E.), Division of Endocrinology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Ronald M. Lechan M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Box No. 268, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}tufts-nemc.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
TRH synthesized in hypophysiotropic neurons of the hypothalamic paraventricular nucleus (PVN) stimulates the release of TSH and prolactin from the anterior pituitary gland. Recent data from our laboratories have demonstrated that TRH and cocaine- and amphetamine-regulated transcript (CART) are co-contained only in hypophysiotropic neurons in the PVN. To determine whether CART and TRH interact in the regulation of anterior pituitary function, we have studied the effects of CART on TRH-induced release of TSH and prolactin in anterior pituitary cell cultures, and the effects of hypo- and hyperthyroidism on CART mRNA in the PVN. Dispersed anterior lobe cells from male rats were treated with CART (10-6, 10-8, 10-10, and 10-12 M) or TRH (10-7 M) alone and TRH (10-7 M) combined with various concentrations of CART for 4 h at 37 C. The medium was assayed for prolactin and TSH by RIA. TRH resulted in a marked increase of both prolactin and TSH release, whereas CART had no effect on prolactin or TSH secretion. When the two peptides were used in combination, CART dose-dependently inhibited TRH-induced prolactin release but had no significant effect on TRH-induced TSH release. By semiquantitative analysis of in situ hybridization autoradiographs, CART mRNA was significantly elevated in hypothyroid animals, whereas a reduction in CART mRNA was observed in hyperthyroid animals compared with euthyroid controls. These data raise the possibility that CART expressed in hypophysiotropic TRH neurons has an important role in the modulation of TRH-induced prolactin secretion. Increased secretion of CART may be responsible for the reduced TRH-induced prolactin response during hypothyroidism.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HYPOPHYSIOTROPIC NEURONS OF the hypothalamic paraventricular nucleus (PVN) that synthesize the tripeptide, TRH, comprise the primary locus in the central nervous system for the regulation of the hypothalamic-pituitary-thyroid axis (1). These neurons integrate central and peripheral influences on the hypothalamic-pituitary-thyroid axis to mediate TSH secretion (1) but also are involved in the regulation of prolactin secretion in the anterior pituitary gland (2). Recent data (3) from our laboratories have demonstrated that TRH and cocaine- and amphetamine-regulated transcript (CART) are co-contained only in hypophysiotropic neurons in the PVN. CART is not only present in neuronal perikarya of these neurons but also coexists with TRH in axon terminals in the external zone of the median eminence (3), where it is released into the portal circulation for conveyance to the pituitary gland (4), suggesting a role in anterior pituitary regulation.

In these studies, therefore, we tested the hypothesis that cosecretion of CART with TRH from axon terminals in the median eminence can modulate the effects of TRH on TSH and/or prolactin secretion from the anterior pituitary. Accordingly, we determined the effects of CART on TRH-induced TSH and prolactin release from anterior pituitary cells in culture, and examined whether hypothyroidism, a disorder that results in activation of hypophysiotropic TRH neurons and altered anterior pituitary secretion (1), is associated with alterations in the gene expression of CART in the PVN.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The experiments were carried out on adult male Sprague Dawley rats, weighing 200–250 g. The animals were housed under standard environmental conditions (light between 0600–1800 h, temperature 22 ± 1 C, rat chow and water ad libitum). All experimental protocols were reviewed and approved by the Animal Welfare Committees of Semmelweis University, the Institute of Experimental Medicine of the Hungarian Academy of Sciences, and Tufts-New England Medical Center.

In vitro studies
Preparation of anterior pituitary cell culture has been described in detail elsewhere (5). Briefly, the pituitary glands obtained from male rats were removed under aseptic conditions. The anterior lobe was separated from the neurointermediate lobe and placed into a 35-mm Petri dish containing MEM (Invitrogen GmbH, Lofer, Austria) and 0.1% BSA (Sigma, Budapest, Hungary) and minced into 1-mm3 pieces. Tissue fragments of the anterior lobe were dispersed with trypsin (8 mg/10 ml MEM), aliquoted into 24-well plates (~150,000 cells/well), then cultured in DMEM (Invitrogen GmbH) containing 0.1% BSA and 2.5% fetal calf serum for 3–4 d (5). On the day of experiments, cells were washed with serum free fresh medium (DMEM-0.1% BSA), preincubated for 1 h, then either incubated with 1 ml test medium (DMEM with 0.1% BSA and 0.01% ascorbic acid, pH 7.4) (controls), or exposed to CART (10-6, 10-8, 10-10, and 10-12 M), TRH (10-7 M), or a mixture of TRH (10-7 M) and the various concentrations of CART diluted in 1 ml test medium for 4 h at 37 C. Incubations were terminated by removal of the medium, and the medium was then stored at -70 C.

Animal and tissue preparation for in situ hybridization histochemistry
To inhibit thyroid hormone production, six adult male Sprague Dawley rats were treated with 0.02% methimazole in their drinking water for 2 wk. Control rats received regular drinking water. Hyperthyroid rats were treated with 10 µg T4 ip for 10 d. At the end of treatments, the animals were anesthetized with sodium pentobarbital (50 mg/kg BW ip), blood taken from inferior vena cava for measurements of T4, and the animals immediately perfused transcardially with 20 ml 0.01 M PBS (pH 7.4) containing 15,000 U/liter heparin sulfate followed by 150 ml 4% paraformaldehyde in PBS. The brains were removed and postfixed by immersion in the same fixative for 2 h at room temperature. Tissue blocks containing the hypothalamus were cryoprotected in 20% sucrose in PBS at 4 C overnight, then frozen on dry ice. Serial 18-µm-thick coronal sections through the rostrocaudal extent of the PVN were cut on a cryostat (Leica CM 30505) and adhered to Superfrost/Plus glass slides (Fisher Scientific Co., Pittsburgh, PA) to obtain four sets of slides, each set containing every fourth section through the PVN. The tissue sections were desiccated overnight at 42 C and stored at -80 C until prepared for in situ hybridization histochemistry.

In situ hybridization histochemistry
Every fourth section of the PVN was hybridized with a single-stranded [35S]UTP-labeled cRNA probe for CART, previously characterized by Couceyro et al. (6). Methods for in situ hybridization histochemistry have been previously described in detail (3, 7, 8, 9). Briefly, the hybridizations were performed under plastic coverslips in a buffer containing 50% formamide, a 2-fold concentration of standard sodium citrate, 10% dextran sulfate, 0.5% sodium dodecyl sulfate, 250 µg/ml denatured salmon sperm DNA, and 6 x 105 cpm radiolabeled probe for 16 h at 56 C. Slides were dipped into Kodak NTB2 autoradiography emulsion (Eastman Kodak, Rochester, NY), and the autoradiograms were developed after 3 d of exposure at 4 C.

Image analysis
Autoradiograms were visualized under dark-field illumination using a COHU 4910 video camera (COHU, Inc., San Diego, CA). The images were analyzed with a Macintosh G4 computer using Scion Image. Background density points were removed by thresholding the image, and integrated density values (density x area) of hybridized neurons in the same region of each side of the PVN were measured in five consecutive sections for each animal. Because CART is expressed in both parvocellular and magnocellular neurons in the PVN (10) and the vast majority of CART neurons in caudal portions of the medial parvocellular PVN co-contain TRH (3), the analysis was confined exclusively to caudal portions of the medial parvocellular PVN. For comparative purposes, a second prominent region of nonhypophysiotropic CART-expressing neurons in the posterior hypothalamus surrounding the fornix (10) was also analyzed. Nonlinearity of radioactivity in the emulsion was evaluated by comparing density values with a calibration curve created from autoradiograms of known dilutions of the radiolabeled probes immobilized on glass slides in 1.5% gelatin fixed with 4% formaldehyde, and exposed and developed simultaneously with the in situ hybridization autoradiograms.

Thyroid hormone, TSH, and prolactin measurements
Serum T4 concentration was measured by RIA as previously described (11). Antisera was obtained from Ventrex (Portland, ME) and [125I]-T4 from NEN Life Science Products (Boston, MA). Serum T3 concentration was determined using the rat total T3 RIA kit obtained from Diagnostic Products Co. (Los Angeles, CA). Intra- and interassay coefficients of variation were 6.1% and 9.5%, respectively. The Cobra 500 program was used for calculation of the RIA results.

Materials for the TSH and prolactin RIA were provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Hormone and Pituitary Program (Baltimore, MD) using NIDDK rat TSH RP-2 and prolactin RP-3 as standards. The RIA procedure for TSH was according to the instructions provided with the kit. Data collection and calculation for the curve fitting were made using LKB Clinigamma software (Pharmacia Wallac Oy, Wallac, Finland). Intra- and interassay coefficients of variation were 4.4% and 9.2%, respectively. For the prolactin RIA, the procedure was similar to instruction provided with the kit, with modifications as described previously (12). Intra- and interassay coefficients of variation were 10% and 14%, respectively.

Statistical analysis
Results are presented as means ± SE (SEM). The data of the hormone measurements and in situ hybridization analyses were compared with one-way ANOVA followed by Newman-Keuls post hoc testing. Because data of the in vitro experiments were gathered on two separate occasions, the data were examined with two-way ANOVA (to test dose and experiment day), followed by Newman-Keuls post hoc testing where appropriate. The results of this analyses showed that the day of the experiment was not a significant factor for both TSH (P = 0.83) and prolactin (P = 0.13). P-values less than 0.05 were considered statistically significant. Data were entered into and analyzed using SPSS version 11.5 (SPSS Inc. Chicago, IL.)


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of CART on prolactin and TSH secretion from primary anterior pituitary cell cultures
The concentration of prolactin and TSH accumulating in the media of control wells at the end of the 4-h incubation period was readily detected, measuring 315.0 ± 62.0 ng/ml for prolactin and 2.0 ± 0.8 ng/ml for TSH (Fig. 1Go). When TRH (10-7 M) was added to the medium, both prolactin (849.2 ± 69.1 ng/ml) and TSH levels (9.9 ± 0.8 ng/ml) were significantly different from control values (P < 0.05) at the end of the 4-h incubation period (Fig. 1Go, B and D). No significant effects on prolactin or TSH secretion were observed when graded doses of CART (10-12 to 10-6 M) were added to the media, although a tendency for higher doses of CART to reduce prolactin release was noted (Fig. 1Go, A and C). When CART was combined with TRH, however, CART inhibited TRH-induced prolactin release at concentrations of 10-8 M and 10-6 M (P < 0.05) (Fig 1BGo). No significant effects of CART on TRH-induced TSH release were observed, however, even at the highest concentration of CART (Fig 1DGo).



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  		FIG. 1. Effects of CART, TRH, and CART+TRH on the prolactin and TSH release from anterior pituitary cells in vitro. Note the inhibitory effect of CART on the TRH-induced prolactin release. Asterisks, Not significantly different from each other, but significantly different from levels without asterisks at P < 0.05. Levels without asterisks are not significantly different from each other.

 
Effects of thyroid status on CART mRNA levels in the PVN
T4 and T3 levels were significantly decreased in hypothyroid animals receiving methimazole, whereas animals treated with high-dose T4 had significantly increased levels compared with euthyroid controls [T4 (µg/dl), eu- vs. hypo- vs. hyperthyroid: 11.3 ± 0.8 vs. 2.9 ± 0.1 vs. 39.3 ± 6.0; T3 (ng/dl), eu- vs. hypo- vs. hyperthyroid: 173 ± 8 vs. 31 ± 2 vs. 379 ± 44]. In euthyroid animals, neurons containing CART mRNA were readily visualized by in situ hybridization histochemistry in the PVN. In caudal regions of the medial parvocellular subdivision, CART neurons were tightly clustered into a triangular configuration, closely underlying the ependymal layer of the third ventricle (Fig. 2AGo), and highly reminiscent of the organization of hypophysiotropic TRH neurons (13). Hypothyroidism increased the hybridization signal over neurons in the caudal portion of the medial parvocellular subdivision (Fig. 2BGo), whereas hyperthyroidism had an opposite effect (Fig 2CGo). By image analysis, density values of CART mRNA hybridization in hypothyroid and hyperthyroid animals were 146% and 47%, respectively, of the euthyroid controls (Fig. 3Go). Statistical analysis revealed that density values of the euthyroid animals significantly differed from both the hypo- and hyperthyroid animals (P < 0.05). A second study in a separate group of animals (n = 4/group), using a shorter exposure time of the emulsion (2d), also demonstrated an increase in CART mRNA induced by hypothyroidism (euthyroid vs. hypothyroid, integrated density units: 2.33 ± 0.30 vs. 7.90 ± 2.03; P < 0.05). In contrast, no significant differences among the groups were observed for CART mRNA in the posterior hypothalamus (euthyroid vs. hypothyroid vs. hyperthyroid, integrated density units: 1.5 ± 0.2 vs. 2.9 ± 0.8 vs. 2.3 ± 0.7, P = 0.47).



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  		FIG. 2. Dark-field illumination micrographs of CART mRNA in the hypothalamic PVN in (A) euthyroid, (B) hypothyroid, and (C) hyperthyroid animals. Note the increased density of silver grains over the PVN in hypothyroid animals compared with controls, whereas hyperthyroidism reduced the accumulation of silver grains. III, Third ventricle.

 


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  		FIG. 3. Computerized image analysis of CART mRNA in the PVN of euthyroid, hypothyroid, and hyperthyroid animals. Both hypothyroid and hyperthyroid groups differ significantly (*) from the euthyroid group.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
CART is a newly discovered peptide that is widely distributed in the central nervous system (14, 15). Although originally identified in the striatum as a mRNA increased by cocaine and amphetamine administration, it is most abundant in the hypothalamus (16). Included among presumed hypothalamic mediated functions of CART are stimulation of the hypothalamic-pituitary-thyroid axis via axosomatic and axodendritic interactions on hypophysiotropic TRH neurons in the PVN (3, 17). CART is not only contained in axon terminals in contact with hypophysiotropic TRH neurons, but also is expressed within these neurons themselves (3). The vast majority of hypophysiotropic TRH neurons in the PVN cosynthesize CART, and both TRH and CART are transported to its axon terminals in the external zone of the median eminence (3), where they are released into the portal circulation for conveyance to the pituitary (4). Because CART is practically the only peptide that has been found to coexist with TRH in neurons of the PVN and its coexistence with TRH is highly selective for hypophysiotropic TRH neurons, we raised the possibility that CART may exert effects on the anterior pituitary, independently or in concert with TRH (3). In addition, because the exogenous administration of CART into the cerebrospinal fluid in fasted animals results in marked activation of proTRH gene expression in hypophysiotropic TRH neurons (3), we hypothesized that CART may act independently or in concert with TRH to promote the secretion of TSH from the anterior pituitary.

Using primary cultures of cells from the anterior pituitary, we demonstrate that CART alone does not influence TSH secretion or potentiate the effects of TRH on TSH secretion. However, when administered together with TRH, CART dose-dependently inhibits the effect of TRH on prolactin secretion. Presumably, the ability of CART to regulate prolactin, but not TSH secretion, is due to cell type-specific expression of CART receptor(s) in the anterior pituitary. Until the discovery of the CART receptor(s), however, this hypothesis remains uncertain.

The primary role for CART on anterior pituitary function, therefore, may be to regulate prolactin secretion, particularly in response to TRH. It is conceivable that CART may modulate prolactin secretion under various physiological states that are associated with an increase in TRH, allowing or disallowing a simultaneous rise in prolactin together with TSH. Hypothyroidism in male rats, for example, results in a marked elevation in TRH gene expression in the PVN (7) and an increase in TRH in the portal capillary blood (18), yet is not associated with a rise in prolactin (19, 20). Nevertheless, TRH is a potent prolactin secretogogue when administered to anterior pituitary cell cultures or when given exogenously as an iv bolus (21, 22). The observations in this study, that CART mRNA in PVN neurons is inversely related to circulating thyroid hormone levels and, in particular, is increased in parvocellular neurons in the PVN in association with hypothyroidism, raises the possibility that, under these conditions, the cosecretion of CART with TRH into the portal system may modulate the effects of TRH on prolactin secretion. Conversely, because TRH mRNA in PVN neurons is increased by suckling and immunoneutralization of TRH partially abolishes suckling-induced prolactin release (23), it is intriguing to speculate that inhibition of CART from hypophysiotropic TRH neurons contributes to prolactin elevation under these conditions, a hypothesis that will require experimental confirmation.

Inverse regulation of CART by thyroid hormone was also reported by Lopez et al. (24), but they were only able to show that hyperthyroidism reduces CART mRNA in the PVN. Because their density analysis was performed on x-ray film, rather than emulsion, it may have been difficult to differentiate CART neurons in the magnocellular division of the PVN from CART neurons in the parvocellular divisions, which would be expected to be under a different set of regulatory controls. Furthermore, we observed that longer exposure times of the emulsion, which allow better differentiation between euthyroid and hyperthyroid CART mRNA levels in the PVN, reduce differences in density values between euthyroid and hypothyroid animals as near saturation levels of silver grains in the emulsion are reached.

In addition to the coexistence of CART with TRH in hypophysiotropic neurons, CART is also expressed in other cell types that might influence anterior pituitary lactotrophs. These include somatostatin-containing cells of the hypothalamic periventricular nucleus (25) that contribute to the hypothalamic tuberoinfundibular system (26), and CART-producing cells within the anterior pituitary, itself, (10), particularly in the pars tuberalis (27). Thus, CART may exert its effects on anterior pituitary secretion not only by secretion into the portal system but also through paracrine and/or autocrine regulation (27).

We conclude that CART has an important role in the regulation of anterior pituitary secretion. The amount of CART secreted together with TRH may provide a more refined mechanism by which to modulate the potent effects of TRH on prolactin secretion.


   Footnotes
 
This work was supported by Grants NIH TW01494, DK-37021, and OTKA T 43370.

S.R. and C.F. contributed equally to this work.

Abbreviations: CART, Cocaine- and amphetamine-regulated transcript; PVN, paraventricular nucleus.

Received November 20, 2003.

Accepted for publication December 17, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals