Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume

The neuropeptide substance P and its receptor, the neurokinin 1 receptor (NK1R) have been proposed as possible targets for new antidepressant therapies. The present study investigated the effect of the NK1R antagonist L-760,735 and the tricyclic antidepressant clomipramine in the chronic psychosocial stress paradigm of adult male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of L-760,735 (10 mg kg−1 day−1) or clomipramine (50 mg kg−1 day−1). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Cell proliferation in the dentate gyrus and hippocampal volume were measured post mortem. Stress significantly decreased in vivo concentrations of N-acetyl-aspartate (−14%), creatine and phosphocreatine (−15%) and choline-containing compounds (−15%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (−45%), and hippocampal volume was decreased (−14%). The stress-induced changes of brain metabolites, hippocampal volume and dentate cytogenesis rate were prevented by concomitant drug administration. Elevated myo-inositol concentrations after both treatments hint to an astrocytic enhancement. These results suggest that—despite a different pharmacological profile—the NK1R antagonist L-760,735, a member of a novel class of antidepressant drugs, has comparable neurobiological efficacy to tricyclic antidepressants such as clomipramine.

[1]  G. Moore,et al.  Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic–depressive illness , 2000, Biological Psychiatry.

[2]  R. Hen,et al.  Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Nutt,et al.  Substance P antagonists: novel agents in the treatment of depression , 2000, Expert opinion on investigational drugs.

[4]  T. Hökfelt,et al.  Neuroanatomical localisation of Substance P in the CNS and sensory neurons , 2000, Neuropeptides.

[5]  T Takahashi,et al.  BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone , 1992, Journal of neurocytology.

[6]  N. Peet,et al.  Neurokinin receptor antagonists , 2000, Expert opinion on investigational drugs.

[7]  J. Frahm,et al.  Gender-specific alterations of cerebral metabolites with aging and cortisol treatment. , 2001, Journal of psychiatric research.

[8]  Nadia M J Rupniak,et al.  New insights into the antidepressant actions of substance P (NK1 receptor) antagonists. , 2002, Canadian journal of physiology and pharmacology.

[9]  Charles G. Gross,et al.  Neurogenesis in the adult brain: death of a dogma , 2000, Nature Reviews Neuroscience.

[10]  D. Gadian,et al.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  D. Leibfritz,et al.  Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. , 1993, Developmental neuroscience.

[12]  Neural plasticity to stress and antidepressant treatment , 1999, Biological Psychiatry.

[13]  R Tao,et al.  Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin. , 2000, The Journal of pharmacology and experimental therapeutics.

[14]  D. Jessop,et al.  Stress and Inflammatory Disease: Widening Roles for Serotonin and Substance P , 2001, Stress.

[15]  E. Gould,et al.  Neurogenesis in the Dentate Gyrus of the Adult Tree Shrew Is Regulated by Psychosocial Stress and NMDA Receptor Activation , 1997, The Journal of Neuroscience.

[16]  Christoph Hiemke,et al.  Diazepam Has No Beneficial Effects on Stress-Induced Behavioural and Endocrine Changes in Male Tree Shrews , 2000, Pharmacology Biochemistry and Behavior.

[17]  R. Kikinis,et al.  Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder , 1996, Biological Psychiatry.

[18]  A. Saria,et al.  The tachykinin NK1 receptor in the brain: pharmacology and putative functions. , 1999, European journal of pharmacology.

[19]  W. Drevets,et al.  The cellular neurobiology of depression , 2001, Nature Medicine.

[20]  S. Boyce,et al.  Intra-amygdala injection of the substance P (NK1 receptor) antagonist L-760735 inhibits neonatal vocalisations in guinea-pigs , 2001, Neuropharmacology.

[21]  S. Provencher Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[22]  Eric J. Nestler,et al.  Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus , 2000, The Journal of Neuroscience.

[23]  D. Triggle,et al.  Specific and non-specific desensitization of guinea-pig ileal smooth muscle. , 1984, Journal of autonomic pharmacology.

[24]  Jens Frahm,et al.  Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  William H. Oldendorf,et al.  N-Acetyl-L-Aspartic acid: A literature review of a compound prominent in 1H-NMR spectroscopic studies of brain , 1989, Neuroscience & Biobehavioral Reviews.

[26]  M. Wong,et al.  Research and treatment approaches to depression , 2001, Nature Reviews Neuroscience.

[27]  M. Kramer,et al.  The Chronic Psychosocial Stress Paradigm in Male Tree Shrews: Evaluation of a Novel Animal Model for Depressive Disorders , 2002, Stress.

[28]  C. Kirschbaum,et al.  Effect of chronic psychosocial stress and long-term cortisol treatment on hippocampus-mediated memory and hippocampal volume: a pilot-study in tree shrews , 2000, Psychoneuroendocrinology.

[29]  G. Rajkowska,et al.  Enhancement of Hippocampal Neurogenesis by Lithium , 2000, Journal of neurochemistry.

[30]  M. Millan,et al.  Selective blockade of neurokinin (NK)1 receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats , 2001, Journal of neurochemistry.

[31]  P. Renshaw,et al.  Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy , 2000, Biological Psychiatry.

[32]  A. Wheeldon,et al.  Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice , 2000, Neuropharmacology.

[33]  Guang Chen,et al.  Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? , 2000, Biological Psychiatry.

[34]  C. Nemeroff,et al.  Neurokinin(1) receptor antagonists as potential antidepressants. , 2001, Annual review of pharmacology and toxicology.

[35]  R. Sapolsky,et al.  Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. , 2000, Archives of general psychiatry.

[36]  S. Yi Hippocampal atrophy in major depression: a result of depression-induced neurotoxicity? , 1996 .

[37]  N. Sousa,et al.  Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement , 2000, Neuroscience.

[38]  Bernadette Lipinski,et al.  Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study , 2000, Biological Psychiatry.

[39]  B. McEwen Stress and hippocampal plasticity. , 1999, Annual review of neuroscience.

[40]  L. Staib,et al.  Hippocampal volume reduction in major depression. , 2000, The American journal of psychiatry.

[41]  Christoph Hiemke,et al.  Psychosocial stress in tree shrews: Clomipramine counteracts behavioral and endocrine changes , 1996, Pharmacology Biochemistry and Behavior.

[42]  N. Smalheiser,et al.  Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. , 2001, European journal of pharmacology.

[43]  R G Hill,et al.  Distinct mechanism for antidepressant activity by blockade of central substance P receptors. , 1998, Science.

[44]  J. Frahm,et al.  Proton MRS of oral creatine supplementation in rats. Cerebral metabolite concentrations and ischemic challenge , 1999, NMR in biomedicine.

[45]  B. Jacobs,et al.  Adult brain neurogenesis and psychiatry: a novel theory of depression , 2000, Molecular Psychiatry.

[46]  E. Nestler,et al.  A molecular and cellular theory of depression. , 1997, Archives of general psychiatry.

[47]  A. Zangen,et al.  Elucidation of the neurobiology of depression: insights from a novel genetic animal model , 2000, Progress in Neurobiology.

[48]  E. Adalsteinsson,et al.  Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder , 1998, Biological Psychiatry.

[49]  H. Manev,et al.  Fluoxetine increases the content of neurotrophic protein S100beta in the rat hippocampus. , 2001, European journal of pharmacology.

[50]  R. Frey,et al.  Myo-inositol in depressive and healthy subjects determined by frontal 1H-magnetic resonance spectroscopy at 1.5 tesla. , 1998, Journal of psychiatric research.

[51]  B. McEwen,et al.  Effects of adverse experiences for brain structure and function , 2000, Biological Psychiatry.

[52]  T. Hökfelt,et al.  Serotonin and substance P co-exist in dorsal raphe neurons of the human brain. , 1999, Neuroreport.

[53]  K. Kendler,et al.  Causal relationship between stressful life events and the onset of major depression. , 1999, The American journal of psychiatry.

[54]  S. Hunt,et al.  5-Hydroxytryptamine (5-HT)1A Autoreceptor Adaptive Changes in Substance P (Neurokinin 1) Receptor Knock-Out Mice Mimic Antidepressant-Induced Desensitization , 2001, The Journal of Neuroscience.

[55]  R. Hargreaves,et al.  Enantiospecific inhibition of emesis induced by nicotine in the house musk shrew (Suncus murinus) by the neurokinin1 (NK1) receptor antagonist CP-99,994 , 1995, Neuropharmacology.

[56]  N. Ogawa,et al.  Effect of immobilization stress on neuropeptides and their receptors in rat central nervous system , 1986, Regulatory Peptides.

[57]  E. Fuchs,et al.  Responsiveness of mesolimbic, mesocortical, septal and hippocampal cholecystokinin and substance P neuronal systems to stress, in the male rat , 1984, Neurochemistry International.

[58]  D. Kunze,et al.  Brain-Derived Neurotrophic Factor Acutely Inhibits AMPA-Mediated Currents in Developing Sensory Relay Neurons , 2000, The Journal of Neuroscience.

[59]  B. McEwen,et al.  Chronic Psychosocial Stress Causes Apical Dendritic Atrophy of Hippocampal CA3 Pyramidal Neurons in Subordinate Tree Shrews , 1996, The Journal of Neuroscience.

[60]  A. Stoll,et al.  Basal ganglia choline levels in depression and response to fluoxetine treatment: An in vivo proton magnetic resonance spectroscopy study , 1997, Biological Psychiatry.

[61]  D. McTavish,et al.  Clomipramine , 2012, Drugs.

[62]  J. Csernansky,et al.  Hippocampal atrophy in recurrent major depression. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[63]  P. Blier,et al.  Sustained blockade of neurokinin-1 receptors enhances serotonin neurotransmission , 2001, Biological Psychiatry.

[64]  E. Fuchs,et al.  Psychosocial conflict in the tree shrew: Effects on sympathoadrenal activity and blood pressure , 1993, Psychoneuroendocrinology.

[65]  G. Rajkowska,et al.  Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells , 2000, Biological Psychiatry.