Brain Research 965 (2003) 45–50 www.elsevier.com / locate / brainres Research report Hypothalamic cocaine-amphetamine regulated transcript (CART) is regulated by glucocorticoids a, a a a * Niels Vrang , Philip J. Larsen , Mads Tang-Christensen , Leif Kongskov Larsen , b Peter Kristensen a Rheoscience, Glerupvej 2, 2610 Rodovre, Denmark b Health Care Discovery, Novo Nordisk A / S, Bagsværd, Denmark Accepted 19 November 2002 Abstract Cocaine-amphetamine-regulated transcript (CART) is one of the most abundantly expressed mRNAs in the rat hypothalamus. CART mRNA expression in the arcuate nucleus has been shown to be regulated by leptin, and CART peptides have been implicated in feeding behavior and in the regulation of the HPA-axis. To more fully understand the physiological regulation of CART gene expression, we have examined the effects of adrenalectomy and different types of glucocorticoid substitution (corticosterone and dexamethasone) on hypothalamic CART and POMC mRNA levels. In situ hybridization revealed a reduction in CART mRNA levels in both the hypothalamic paraventricular and arcuate nuclei in adrenalectomized rats, which was fully restored upon dexamethasone treatment but not by a subcutaneous 25% corticosterone pellet. Unlike CART mRNA levels hypothalamic POMC expression was unaltered by adrenenalectomy. The present results show that the CART gene is influenced by glucocorticoids, presumably via a GR dependent mechanism.  2002 Published by Elsevier Science B.V. Keywords: In situ hybridization; HPA-axis; GR receptor; Arcuate nucleus; Parventricular nucleus; POMC 1. Introduction ment of CART has been previously identified in porcine hypothalami [24]. Albeit isolated from striatal extracts, the Cocaine-amphetamine-regulated transcript (CART) was CART gene is most abundantly expressed in the hypo- discovered in 1995 by polymerase chain reaction (PCR) thalamus [12]. CART mRNA and CART peptide immuno- differential display in a search for mRNAs in the striatum reactivity are located in a number of hypothalamic struc- acutely up-regulated by psychostimulants [9]. In the rat the tures involved in the control of feeding behavior, such as primary CART transcript is differentially spliced and the the lateral hypothalamic area and the paraventricular and two different mRNAs encode peptides of either 116 or 129 arcuate nuclei [7,14–16,30]. Consistent with these ana- amino acids [9]. The leader sequence consists of 27 amino tomical observations we and others have shown that acids and mature CART peptides therefore contain either intracerebroventricular administration of CART peptides 89 or 102 residues [9]. Since only the short form of CART inhibit food intake in rats and mice [1,16,17,27,32]. (89 amino acids long) is present in human tissue [8], we Additionally, intracerebroventricularly administered have chosen to number CART peptides after this form CART(42–89) induces c-Fos expression in areas of the rat [CART(1–89)]. CART peptide processing is tissue depen- brain that are involved in feeding behavior [32]. dent and two forms predominate in the rat brain: The hypothalamic arcuate nucleus (Arc) contains a CART(42–89) and CART(49–89) [26]. The former frag- population of CART containing neurons that also co- express pro-opiomelanocortin (POMC) [10,30]. Interest- ingly, both CART and POMC expression in the Arc is *Corresponding author. Laboratory of Obesity Research, CCBR, regulated by leptin and fasting, pointing to an important Ballerup Byvej 222, 2750 Ballerup, Denmark. Tel.: 145-4470-4404; fax: role of these neurons in appetite regulation [16,19,23]. 145-4468-4220. E-mail address: nv@ccbr.dk (N. Vrang). Besides leptin and fasting, a number of experiments have 0006-8993 / 02 / $ – see front matter  2002 Published by Elsevier Science B.V. PII: S0006-8993(02)04064-7