neuropeptide-y and Hyperprolactinemia

Risperidone is known to increase prolactin secretion in treating mental illness patients. This side-effect is thought to be mediated via central signaling pathway. However, the exact pathway involved between risperidone and hyperprolactinemia are still unknown. Therefore, we have treated mice with risperidone and investigated the central mechanisms. The present study showed that in risperidone treated group, the level of the serum prolactin significantly increased, which was consistent with increased positive prolactin staining in pituitary gland. Elevated c-fos expression was observed in the arcuate hypothalamic nucleus (Arc) where we found 65% c-fos positive neurons co-localised with neuropeptide Y (NPY) in mice treated with risperidone. In addition, the results from in situ hybridization showed that the NPY mRNA in the Arc was significantly increased, whereas the tyrosine hydroxylase (TH) mRNA dramatically decreased compared with control group in the paraventricular hypothalamic nucleus (PVN). These findings revealed that risperidone may mediate the transcriptional regulation of Arc NPY and TH in the PVN. Furthermore, risperidone induced a decreased dopamine synthesis in the PVN and thus reduced the dopamine-induced inhibition of prolactin release, ultimately lead to hyperprolactinemia. Therefore, insights into these neuronal mechanisms open up potential new ways to treat schizophrenia patients in order to ameliorate hyperprolactinemia.

Topics: Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Female; Hyperprolactinemia; Male; Mice, Inbred C57BL; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Risperidone; Tyrosine 3-Monooxygenase

Pregnancy and lactation provide excellent models of physiological hyperphagia and hyperprolactinemia. To identify possible factors associated with the increased feeding in these situations, we measured hypothalamic mRNA levels of three orexigenic neuropeptides--NPY, MCH, and orexins--in nonpregnant, pregnant, and lactating rats by in situ hybridization. NPY mRNA content in the arcuate nucleus was significantly increased during pregnancy and lactation. However, MCH and prepro-orexin expression was decreased in both states. 48 or 72 h of fasting in pregnant and lactating rats further elevated NPY mRNA levels and increased the low MCH mRNA content. Surprisingly, no effect was observed in prepro-orexin mRNA levels. Finally, we investigated the possible effect of high PRL levels on these orexigenic signals using a model of hyperprolactinemia induced by pituitary graft. NPY mRNA content was unchanged, but MCH and prepro-orexin mRNA levels were significantly decreased. Our results suggest that the increased NPY expression might be partly responsible for the hyperphagia observed during pregnancy and lactation. MCH and prepro-orexin may be involved in the adaptation of other homeostatic mechanisms and their decreased levels in these physiological settings could be mediated by the elevated circulating PRL levels.

Topics: Animals; Female; Gene Expression Regulation; Hyperphagia; Hyperprolactinemia; Hypothalamic Hormones; Hypothalamus; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Lactation; Melanins; Neuropeptide Y; Neuropeptides; Orexins; Pituitary Hormones; Pregnancy; Prolactin; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger

This study characterizes the responses of LHRH neurons to N-methyl-D-aspartate (NMDA), norepinephrine, epinephrine (E), and neuropeptide-Y (NPY), as evidenced indirectly by the measurement of circulating LH titers, and investigates whether neurons using these compounds as neurotransmitters might be involved in mediating hyperprolactinemic (HP) suppression of LH release. Male rats were orchidectomized, adrenalectomized, and implanted with a testosterone-containing Silastic capsule, a 50% corticosterone pellet, and third cerebroventricular and right atrial cannulae at time zero. Rats received sc injections of ovine PRL (2400 micrograms/250 microliters) in a polyvinylpyrrolidone depot or vehicle every 12 h for 48 h when experiments were performed. The mean maximal LH increments (delta LH) in response to two doses of LHRH (0.4 and 0.8 ng/100 g BW) were not altered in HP rats, indicating that ovine PRL did not cause a change in pituitary responsiveness. NMDA (20 mg/kg BW, iv)-induced LH release peaked 5 min after injection. The delta LH (0-5 min) in HP rats was suppressed by 53% compared with the control value. Epinephrine [5, 10, and 15 micrograms/2 microliters, intracerebroventricularly (icv)], but not norepinephrine (20 and 40 micrograms/2 microliters, icv), produced dose-dependent LH responses that peaked at 10 min. The delta LH (0-10 min) in HP rats in response to 10 micrograms/2 microliters E was suppressed by 68% compared with the control value. Two doses of NPY (2 and 10 micrograms/2 microliters, icv) produced dose-dependent LH increments that peaked at 10 min. In HP rats, the delta LH (0-10 min) in response to 10 micrograms/2 microliters NPY was suppressed 52% compared with the control value. The combined administration of E (10 or 16 micrograms) and NPY (5 or 10 micrograms) produced mean maximal LH responses that significantly exceeded the additive responses of these compounds individually. This synergistic effect may be mediated by separate adrenergic and NPYergic afferents to the LHRH neurons or may, in fact, reflect corelease of these two neurotransmitters from the same neurons. The LH responses to NMDA, E, and NPY were all inhibited in HP rats. This suggests that elevated PRL levels act on the LHRH neurons, either directly or indirectly through an inhibitory afferent neuronal system, to decrease their responsivity to all stimuli.

Topics: Adrenalectomy; Animals; Drug Implants; Epinephrine; Hyperprolactinemia; Luteinizing Hormone; Male; N-Methylaspartate; Neuropeptide Y; Norepinephrine; Orchiectomy; Prolactin; Rats; Rats, Sprague-Dawley; Testosterone