Peptides 25 (2004) 991–996 Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo M.J. Wayner a,∗ , D.L. Armstrong a , C.F. Phelix a , Y. Oomura b a Department of Biology, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 0662-78249, USA b Department of Integrative Physiology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-0054, Japan Received 23 March 2004; received in revised form 23 March 2004; accepted 24 March 2004 Available online 10 May 2004 Abstract Orexin-A (Hypocretin-1) has been localized in the posterior and lateral hypothalamic perifornical region. Orexin containing axon terminals have been found in hypothalamic nuclei and many other parts of the brain; for example, the hippocampus. Two types of orexin receptors have been discovered. Orexin 1 type of receptors have been described and been shown to be widely distributed in the rat brain including the hippocampus. Subsequently Orexin-A was found to impair both water maze performance and hippocampal long term potentiation (LTP). Leptin is expressed in adipose tissue and released into the blood where it affects food intake and can also produce widespread physiological changes mediated via autonomic preganglionic neurons, pituitary gland, and cerebral cortex. Immunoreactivity for leptin receptors has been found in various hypothalamic nuclei including the lateral hypothalamic area as well as the hippocampus especially in the dentate gyrus and CA1. Leptin receptor deficient rats and mice also show impaired LTP in CA1 and poor performance in the water maze. The present study was conducted to determine the effects of 0.0, 30, 60, 90, and 100 nM, orexin-A, and leptin, 0.0, 1.0, 100 nM, 1, and 10 M, in 1.0 l of ACSF, applied directly into the dentate gyrus, on LTP in medial perforant path dentate granule cell synapses in urethane anesthetized rats. Orexin-A specifically enhanced LTP at the 90 nM dose; and it was possible to block the enhancement by pretreating the animals with SB-334867, a specific orexin 1 receptor antagonist. Leptin enhanced normal LTP at 1.0 M but inhibited LTP at lower and higher doses. These results and previous data indicate that the same peptide could possibly have different modulatory post synaptic effects in different hippocampal synapses dependent upon different types of post synaptic receptors. © 2004 Elsevier Inc. All rights reserved. Keywords: Orexin-A; LTP; Dentate granule cells; Perforant path afferents; Hippocampus; Orexin 1 receptor; SB-334867; Leptin; Schaffer collaterals; CA1 1. Introduction Orexin-A and orexin-B (hypocretins) have been localized in the posterior and the perifornical region of the lateral hy- pothalamic area (LHA) and the dorsomedial hypothalamic nucleus in the rat brain; and both peptides have been found to stimulate feeding [4,5,21,24]. Orexin-containing axon ter- minals were found in hypothalamic nuclei and many other brain areas such as the hippocampus, amygdala, central gray, locus coeruleus, dorsal raphe, dorsal motor nucleus of the vagus, perirhinal, sensory and motor cortex, and the cerebellum [3,21]. Two types of orexin receptors, namely orexin 1 receptors OX1R and orexin 2 receptors OX2R, have also been described in the rat brain and shown to be widely distributed in the CNS. High levels of OX1R mRNA occur in the hippocampal formation, tenia tecta, dorsal raphe, and ∗ Corresponding author. Tel.: +1-210-4584482; fax: +1-210-4585658. E-mail address: mwayner@utsa.edu (M.J. Wayner). locus coeruleus; while OX2R mRA was found mainly in the cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, and the anterior pretectal nucleus [27]. Consequently, the activation of functional orexin circuits is complex and can involve many behavioral changes including arousal and motor activity [3], sleep [2], and also learning and memory [1]. Orexins were recently found to be produced in specific LHA glucose sensitive neurons [17] and the central administration of glucose has been shown to facilitate both spatial and avoidance learning [14]. More recently, LHA glucose sensitive orexin neurons that play a role in energy homeostasis also provide an awak- ening signal that triggers arousal, especially during food deprivation, and maintains a state of vigilance [18,32,33], related to successfully searching for food [28]. However, orexin-A also impairs water maze performance and CA-1 Schaeffer collateral long term potentiation (LTP) [1]. These results appear to be paradoxical since post training intracere- broventricular administration of orexin-A in mice improves 0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.03.018