Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat

We have recently shown that intracerebroventricular (icv) administration of the hypothalamic neuropeptide cocaine-amphetamine-regulated transcript (CA RT) inhibits food intake and induces the expression of c-fos in several nuc lei involved in the regulation of food intake. A high number of CART-induce d c-Fos-positive nuclei in the paraventricular nucleus of the hypothalamus prompted us to examine the effect of icy recombinant CART-(42-89) on activa tion of CRH-, oxytocin-, and vasopressin-synthesizing neuroendocrine cells in the paraventricular nucleus (PVN). In addition, plasma levels of glucose were examined after central administration of CART-(42-89). Seventy-six ma le Wistar rats were fitted with icy cannulas and singly housed under 12-h l ight, 12-h dark conditions. One week postsurgery the animals were injected icy in the morning with 0.5 mu g recombinant CART-(42-89) or saline. Trunk blood was collected by decapitation at 0 (baseline), 10, 20, 40, 60, 120, o r 240 min. CART caused a strong increase in circulating corticosterone that was significantly different from saline at 20, 40, 60, and 120 min postinj ection (P < 0.05). Furthermore, CART caused a transient rise in plasma oxyt ocin levels (P < 0.05 at 10 and 20 min postinjection), whereas plasma vasop ressin levels were unaffected by icy CART. Animals injected icy with CART s howed a rise in blood glucose levels 10 min postinjection (P < 0.05). To ex amine whether the stimulatory effect of icy CART on corticosterone and oxyt ocin secretion is caused by activation of paraventricular nucleus/supraopti c nucleus (PVN/SON) neuroendocrine neurons, we used c-Fos as a marker of ne uronal activity. Animals injected with CART showed a strong increase in c-F os-immunoreactive nuclei in the PVN. Double immunohistochemistry revealed t hat a high (89 +/- 0.4%) number of CRH-immunoreactive neurons in the PVN co ntained c-Fos after CART icy. c-Fos expression was also observed in oxytoci nergic cells tin both magnocellular and parvicellular PVN neurons as well a s in the supraoptic nuclei) 120 min after CART administration, whereas none of the vasopressinergic neurons contained c-Fos. Triple immunofluorescence microscopy revealed that CART-immunoreactive fibers closely apposed c-Fos- positive CRH neurons, suggestive of a direct action of CART on PVN CRH neur ons. In summary, icy CART activates central CRH neurons as well as both mag nocellular (presumably neurohypophysial) and parvicellular (presumably desc ending) oxytocinergic neurons of the PVN. The effect of CART on CRH neurons most likely leads to corticosterone secretion from the adrenal gland, whic h may contribute to the inhibitory effects of CART on feeding behavior.