Endocrine Abstracts (2003) 6 OC26

Suppression of the hypothalamo-pituitary adrenal axis by long-term intra-arcuate Cocaine- and Amphetamine-regulated transcript (CART) peptide

SA Stanley, WM Kong, CR Abbott, JV Gardiner, MA Ghatei, CJ Small & SR Bloom

Endocrine Unit, Imperial College, Hammersmith Campus, London, UK.

Hypothalamic Cocaine- and Amphetamine-regulated transcript (CART) is regulated by circulating glucocorticoids. In adrenalectomised rodents, CART expression is reduced in the arcuate nucleus. However, CART also modulates the hypothalamo-pituitary-adrenal (HPA) axis. Acute intracerebroventricular injection of CART peptide significantly increases plasma ACTH and corticosterone but the long-term actions of CART are unknown. The aim of these studies was to determine the effect of long-term intra-arcuate CART on the HPA axis.

In the first study, targeted gene transfer was used to over-express CART mRNA. CART cDNA was cloned into the plasmid pcDNA1.1 and the transgene was delivered using polyethylenimine (PEI). Adult rats were injected with 1 microgram pcDNA-CART/PEI or pcDNA1.1/PEI into the arcuate nucleus. Arcuate CART cDNA expression for 25 days resulted in a non-significant reduction in plasma ACTH (control 40.3 plus/minus 11.4, CART 26.6 plus/minus 4.2 picograms per microlitre, p = 0.2) and plasma corticosterone (control 293 plus/minus 53, CART 192 plus/minus 29 nanograms per microlitre, p = 0.09). In the second study, twice daily intra-arcuate injection of CART(55-102) peptide (0.2 nmole) for seven days significantly suppressed plasma ACTH (saline 21.5 plus/minus 2, CART 15.9 plus/minus 1.4 picograms per microlitre, p less than 0.05) and plasma corticosterone (saline 350 plus/minus 35 vs. CART 214 plus/minus 37 nanograms per microlitre, p less than 0.05).

Repeated administration of CART peptide into the arcuate nucleus or intra-arcuate over-expression of CART suppressed the HPA axis. The mechanism of this action is unclear. The reduction in intra-arcuate CART following adrenalectomy might suggest a feedback mechanism which in turn reduces the inhibitory action of arcuate CART on the HPA axis.

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