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

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.