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Submitted on June 2, 2004
Accepted on July 16, 2004
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037
* To whom correspondence should be addressed. E-mail: vale{at}salk.edu.
Cocaine and amphetamine regulated transcript (CART) is a highly expressed hypothalamic transcript that is concentrated in areas associated with the stress response. There is evidence for a role of CART in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is not clear whether CART regulates activity of the HPA axis by directly stimulating ACTH release from pituitary corticotropes or through interaction with hypothalamic factors. To address this issue the effects of central and peripheral administration of CART on the HPA axis were compared. Central administration of CART (55-102) (1 µg) significantly increased circulating levels of ACTH (481 ± 122 vs. 93 ± 14 pg/ml; CART vs. vehicle) and corticosterone (460 ± 29 vs. 179 ± 62 ng/ml; CART vs. vehicle). In contrast, intravenous injection of CART (55-102) (0.09 -9.0nmol/kg) did not significantly affect circulating levels of ACTH or corticosterone. The corticotropin releasing factor (CRF) receptor antagonist Astressin B was used to determine whether CART (55-102) elicits ACTH secretion via a CRF receptor-dependent mechanism. Injection of Astressin B (50 µg/kg, iv) inhibited CART (55-102)-induced ACTH and corticosterone responses. The effects of CART (55-102) on CRF and AVP expression were also examined in static hypothalamic explants. RT-PCR analysis revealed a significant up-regulation of CRF and AVP mRNA levels following CART (55-102) (10 nM and 1 µM) treatment. Lastly, the effects of CART (55-102) on CRF and AVP mediated ACTH release was investigated in dispersed rat anterior pituitary cells. Incubation of CART (55-102) (10 nM - 100 nM) did not significantly affect ACTH release from anterior pituitary cells. Findings from the present study suggest that CART regulates activity of the HPA axis through a CRF dependent central mechanism and not by means of direct interaction with pituitary corticotropes.
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