Pharmacopsychiatry 2017; 50(01): 32-37
DOI: 10.1055/s-0042-109870
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Neuroleptics Affect Kisspeptin mRNA Expression in the Male Rat Hypothalamus and Hippocampus

Artur Pałasz
1   Department of Histology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
,
Ewa Rojczyk
1   Department of Histology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
,
Aleksandra Suszka-Świtek
1   Department of Histology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
,
Ryszard Wiaderkiewicz
1   Department of Histology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
› Author Affiliations
Further Information

Publication History

received 14 February 2016
revised 27 May 2016

accepted 30 May 2016

Publication Date:
07 July 2016 (online)

Abstract

Introduction: Kisspeptin has a multidirectional neuroendocrinal activity. It is especially considered to be a central regulator of reproductive function. Numerous data proved that neuroleptic administration may affect the peptidergic signaling in the various brain structures. However, there is no information concerning the relationship between treatment with neuroleptics and brain kisspeptin mRNA expression.

Methods: We assessed the kisspeptin mRNA level in the hypothalamus and hippocampus of rats shortly and chronically (28 days) treated with haloperidol, chlorpromazine, and olanzapine using a quantitative Real-Time PCR method.

Results: We have shown that all studied neuroleptics injected chronically have the ability to downregulate the kisspeptin mRNA expression in the hypothalamus, which may suggest the presence of an alternative mechanism for their orexigenic side effects. Long-term treatment with chlorpromazine increased the level of kisspeptin mRNA expression in the hippocampus.

Discussion: Our results shed a new light on the pharmacology of antipsychotics and may contribute to a better understanding of alternative mechanisms responsible for their action. The study also highlights a complex nature of potential connections between dopamine transmission and brain kisspeptin pathways.

 
  • References

  • 1 Navarro VM, Bosch MA, Leon S et al. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction. Endocrinology 2015; 156: 627-637
  • 2 Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev 2009; 30: 713-743
  • 3 Roa J, Navarro VM, Tena-Sempere M. Kisspeptins in reproductive biology: consensus knowledge and recent developments. Biol Reprod 2011; 85: 650-660
  • 4 Han SK, Gottsch ML, Lee KJ et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 2005; 25: 11349-11356
  • 5 Quaynor S, Hu L, Leung PK et al. Expression of a functional g protein-coupled receptor 54-kisspeptin autoregulatory system in hypothalamic gonadotropin-releasing hormone neurons. Mol Endocrinol 2007; 21: 3062-3070
  • 6 Navarro VM, Castellano JM, Fernandez-Fernandez R et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 2004; 145: 4565-4574
  • 7 Herbison AE, de Tassigny X, Doran J et al. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 2010; 151: 312-321
  • 8 Clarkson J, Busby ER, Kirilov M et al. Sexual differentiation of the brain requires perinatal kisspeptin-GnRH neuron signaling. J Neurosci 2014; 34: 15297-15305
  • 9 Backholer K, Smith J, Clarke IJ. Melanocortins may stimulate reproduction by activating orexin neurons in the dorsomedial hypothalamus and kisspeptin neurons in the preoptic area of the ewe. Endocrinology 2009; 150: 5488-5497
  • 10 Hrabovszky E. Neuroanatomy of the human hypothalamic kisspeptin system. Neuroendocrinology 2014; 99: 33-48
  • 11 Fu LY, van den Pol AN. Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J Neurosci 2010; 30: 10205-10219
  • 12 De Bond JA, Smith JT. Kisspeptin and energy balance in reproduction. Reproduction 2014; 147: R53-R63
  • 13 Stengel A, Wang L, Goebel-Stengel M et al. Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport 2011; 22: 253-257
  • 14 Mittelman-Smith MA, Williams H, Krajewski-Hall SJ et al. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci USA 2012; 109: 19846-19851
  • 15 Arai AC, Orwig N. Factors that regulate KiSS1 gene expression in the hippocampus. Brain Res 2008; 1243: 10-18
  • 16 Baratta MV, Lamp T, Tallent MK. Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate gyrus. J Neurophysiol 2002; 88: 3078-3086
  • 17 Klapstein GJ, Colmers WF. On the sites of presynaptic inhibition by neuropeptide Y in rat hippocampus in vitro. Hippocampus 1993; 3: 103-111
  • 18 Arai AC. The role of kisspeptin and GPR54 in the hippocampus. Peptides 2009; 30: 16-25
  • 19 Telegdy G, Adamik A. The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters. Behav Brain Res 2013; 243: 300-305
  • 20 Jiang JH, He Z, Peng YL et al. Kisspeptin-13 enhances memory and mitigates memory impairment induced by Abeta1-42 in mice novel object and object location recognition tasks. Neurobiol Learn Mem 2015; 123: 187-195
  • 21 Smith JT, Dungan HM, Stoll EA et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146: 2976-2984
  • 22 de Roux N, Genin E, Carel JC et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100: 10972-10976
  • 23 Seminara SB, Messager S, Chatzidaki EE et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349: 1614-1627
  • 24 Cardon M, Ron-Harel N, Cohen H et al. Dysregulation of kisspeptin and neurogenesis at adolescence link inborn immune deficits to the late onset of abnormal sensorimotor gating in congenital psychological disorders. Mol Psychiatry 2010; 15: 415-425
  • 25 Prentice LM, d’Anglemont de Tassigny X, McKinney S et al. The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent. BMC Genomics 2011; 12: 209
  • 26 Kim J, Semaan SJ, Clifton DK et al. Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 2011; 152: 2020-2030
  • 27 Cao J, Patisaul HB. Sex-specific expression of estrogen receptors alpha and beta and Kiss1 in the postnatal rat amygdala. J Comp Neurol 2013; 521: 465-478
  • 28 Rojczyk E, Palasz A, Wiaderkiewicz R. Effect of short and long-term treatment with antipsychotics on orexigenic/anorexigenic neuropeptides expression in the rat hypothalamus. Neuropeptides 2015; 51: 31-42
  • 29 Umathe SN, Wanjari MM, Manna SS et al. A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol. Neuropeptides 2009; 43: 251-257
  • 30 Park SW, Choi SM, Lee JG et al. Differential effects of ziprasidone and haloperidol on immobilization-stress-induced CRF mRNA expression in the hypothalamic paraventricular nucleus of rats. Neuropsychobiology 2011; 63: 29-34
  • 31 Markianos M, Hatzimanolis J, Lykouras L. Switch from neuroleptics to clozapine does not influence pituitary-gonadal axis hormone levels in male schizophrenic patients. Eur Neuropsychopharmacol 1999; 9: 533-536
  • 32 Fell MJ, Marshall KM, Williams J et al. Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats. J Psychopharmacol 2004; 18: 149-155
  • 33 Kaneda Y, Ohmori T. Impact of risperidone medication on quality of life and gonadal axis hormones in schizophrenia male patients with acute exacerbation. Int J Neuropsychopharmacol 2003; 6: 247-252
  • 34 Konarzewska B, Wolczynski S, Szulc A et al. Effect of risperidone and olanzapine on reproductive hormones, psychopathology and sexual functioning in male patients with schizophrenia. Psychoneuroendocrinology 2009; 34: 129-139
  • 35 Brown AS, Hembree WC, Friedman JH et al. The gonadal axis in men with schizophrenia. Psychiatry Res 1995; 57: 231-239
  • 36 Basta-Kaim A, Budziszewska B, Jaworska-Feil L et al. Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacology 2006; 31: 853-865
  • 37 Bradley AJ, Dinan TG. A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortality. J Psychopharmacol 2010; 24 (Suppl. 04) 91-118
  • 38 Smith S, Wheeler MJ, Murray R et al. The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002; 22: 109-114
  • 39 Zuckerman L, Rehavi M, Nachman R et al. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 2003; 28: 1778-1789