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Cerebrospinal Fluid Substance P-Like Immunoreactivity Correlates with Aggression in Personality Disordered Subjects

      Background

      Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters; some seem to play an inhibitory role, whereas others seem to play a facilitory role in the modulation of aggression. Laboratory animal studies of substance P suggest a facilitory role for this undecapeptide in the modulation of aggression, but no studies of substance P have yet been reported with regard to human aggression.

      Methods

      Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with personality disorder (PD) and substance P-like immunoreactivity was measured and correlated with measures of aggression and impulsivity.

      Results

      The cerebrospinal fluid substance P-like immunoreactivity levels were directly correlated with a composite measure of aggression and, more specifically, with Buss-Durkee Aggression. No correlation was seen with any measure of impulsivity or of general dimensions of personality.

      Conclusions

      These data suggest a direct relationship between central nervous system substance P containing neural circuits and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of impulsive aggression in human subjects.

      Key Words

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      References

        • Harrison S.
        • Geppetti P.
        Substance P.
        Int J Biochem Cell Biol. 2001; 33: 555-576
        • Atar P.
        • Srivastava S.
        • Coutinho E.
        • Govil G.
        Substance P: Structure, function, and therapeutics.
        Curr Top Med Chem. 2004; 4: 75-103
        • von Euler U.S.
        • Gaddum J.H.
        An unidentified depressor substance in certain tissue extracts.
        J Physiol. 1931; 72: 74-87
        • Maggi C.A.
        The mammalian tachykinin receptors.
        Gen Pharmacol. 1995; 26: 911-944
        • Yip J.
        • Chahl L.A.
        Localization of NK1 and NK3 receptors in guinea-pig brain.
        Regul Pept. 2001; 98: 55-62
        • Gobbi G.
        • Cassano T.
        • Radja F.
        • Morgese M.G.
        • Cuomo V.
        • Santarelli L.
        • et al.
        Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function.
        Eur Neuropsychopharmacol. 2007; 17: 328-338
        • Zubrzycka M.
        • Janecka A.
        Substance P: Transmitter of nociception (minireview).
        Endocr Regul. 2000; 34: 195-201
        • Ebner K.
        • Singewald N.
        The role of substance P in stress and anxiety responses.
        Amino Acids. 2006; 31: 251-272
        • Huston J.P.
        • Hasenöhrl R.U.
        • Boix F.
        • Gerhardt P.
        • Schwarting R.K.
        Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity.
        Psychopharmacology. 1993; 112: 147-162
        • Park S.W.
        • Yan Y.P.
        • Satriotomo I.
        • Vemuganti R.
        • Dempsey R.J.
        Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions.
        J Neurosurg. 2007; 107: 593-599
        • Smith G.S.
        • Savery D.
        • Marden C.
        • Lopez Costa J.J.
        • Averill S.
        • Priestley J.V.
        • et al.
        Distribution of messenger RNAs encoding enkephalin, substance P, somatostatin, galanin, vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene-related peptide in the midbrain periaqueductal grey in the rat.
        J Comp Neurology. 1994; 350: 23-40
        • Bhatt S.
        • Gregg T.R.
        • Siegel A.
        NK1 receptors in the medial hypothalamus potentiate defensive rage behavior elicited from the midbrain periaqueductal gray of the cat.
        Brain Res. 2003; 966: 54-64
        • Gregg T.R.
        • Siegel A.
        Brain structures and neurotransmitters regulating aggression in cats: Implications for human aggression.
        Prog Neuropsychopharmacol Biol Psychiatry. 2001; 25: 91-140
        • Han Y.
        • Shaikh M.B.
        • Siegel A.
        Medial amygdaloid suppression of predatory attack behavior in the cat: I.
        Brain Res. 1996; 716: 59-71
        • Shaikh M.B.
        • Steinberg A.
        • Siegel A.
        Evidence that substace P is utilized in medial amygdaloid facilitation of defensive rage behavior in the cat.
        Brain Res. 1993; 625: 283-294
        • Gregg T.R.
        • Siegel A.
        Differential effects of NK1 receptors in the midbrain periaqueductal gray upon defensive rage and predatory attack in the cat.
        Brain Res. 2003; 994: 55-66
        • Beyer C.
        • Caba M.
        • Banas C.
        • Komisaruk B.R.
        Vasoactive intestinal polypeptide (VIP) potentiates the behavioral effect of substance P intrathecal administration.
        Pharmacol Biochem Behav. 1991; 39: 695-698
        • Barbeau A.
        • Rondeau D.B.
        • Jolicoeur F.B.
        Behavioral effects of substance P in rats.
        Int J Neurol. 1980; 14: 239-252
        • Elliott P.J.
        • Iversen S.D.
        Behavioural effects of tachykinins and related peptides.
        Brain Res. 1986; 381: 68-76
        • American Psychiatric Association
        Diagnostic and Statistical Manual: Fourth Edition (DSM-IV).
        American Psychiatric Press, Washington, DC1994
        • Coccaro E.F.
        Intermittent explosive disorder: Development of integrated research criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
        Compr Psychiatry. 2011; 52: 119-125
        • Bunce S.C.
        • Noblett K.L.
        • McCloskey M.S.
        • Coccaro E.F.
        High prevalence of personality disorders among healthy volunteers for research: Implications for control group bias.
        J Psychiatr Res. 2005; 39: 421-430
        • Coccaro E.F.
        • Berman M.E.
        • Kavoussi R.J.
        Assessment of life history of aggression: Development and psychometric characteristics.
        Psychiatry Res. 1997; 73: 147-157
        • Buss A.H.
        • Durkee A.
        An inventory for assessing different kinds of hostility.
        J Consult Psychol. 1957; 21: 343-348
        • Eysenck S.B.G.
        • Eysenck H.J.
        The place of impulsiveness in a dimensional system of personality description.
        Br J Soc Clin Psychol. 1977; 16: 57-68
        • Patton J.H.
        • Stanford M.S.
        • Barratt E.S.
        Factor structure of the Barratt impulsiveness scale.
        J Clin Psychol. 1995; 51: 768-774
        • Coccaro E.F.
        • Lee R.
        • Kavoussi R.J.
        Aggression, suicidality, and intermittent explosive disorder: Serotonergic correlates in personality disorder and healthy control subjects.
        Neuropsychopharmacology. 2010; 35: 435-444
        • Eysenck H.J.
        • Eysenck S.B.G.
        Manual of the Eysenck Personality Questionnaire.
        Hodder and Stoughton, London1975
        • Coccaro E.F.
        • Lee R.
        Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: Reciprocal relationships with impulsive aggression in human subjects.
        J Neural Transm. 2010; 117: 241-248
        • Anand P.
        • Gibson S.J.
        • McGregor G.P.
        • Blank M.A.
        • Ghatei M.A.
        • Bacarese-Hamilton A.J.
        • et al.
        A VIP-containing system concentrated in the lumbosacral region of human spinal cord.
        Nature. 1983; 305: 143-145
        • Fernandes E.S.
        • Schmidhuber S.M.
        • Brain S.D.
        Sensory-nerve-derived neuropeptides: Possible therapeutic targets.
        Handb Exp Pharmacol. 2009; 194: 393-416
        • Nutt J.G.
        Substance P in human CSF.
        in: Wood J.H. Neurobiology of Cerebrospinal Fluid. Vol. 2. Plenum Press, New York1983 (95)
        • Landgraf R.
        • Klauschenz E.
        • Bienert M.
        • Ermisch A.
        • Oehme P.
        Some observations indicating a low brain uptake of [3H]Nle11-Substance P.
        Pharmazie. 1983; 38: 108-110
        • Rimón R.
        • Le Grevés P.
        • Nyberg F.
        • Heikkilä L.
        • Salmela L.
        • Terenius L.
        Elevation of substance P-like peptides in the CSF of psychiatric patients.
        Biol Psychiatry. 1984; 19: 509-516
        • Geracioti Jr, T.D.
        • Carpenter L.L.
        • Owens M.J.
        • Baker D.G.
        • Ekhator N.N.
        • Horn P.S.
        • et al.
        Elevated cerebrospinal fluid substance P concentrations in posttraumatic stress disorder and major depression.
        Am J Psychiatry. 2006; 163: 637-643
        • Li L.
        • Gao X.
        • Zhao J.
        • Ji X.
        • Wei H.
        • Luo Y.
        Plasma and cerebrospinal fluid substance P in post-stroke patients with depression.
        Psychiatry Clin Neurosci. 2009; 63: 298-304
        • Carpenter L.L.
        • Bayat L.
        • Moreno F.
        • Kling M.A.
        • Price L.H.
        • Tyrka A.R.
        • et al.
        Decreased cerebrospinal fluid concentrations of substance P in treatment-resistant depression and lack of alteration after acute adjunct vagus nerve stimulation therapy.
        Psychiatry Res. 2008; 157: 123-129
        • Stockmeier C.A.
        • Shi X.
        • Konick L.
        • Overholser J.C.
        • Jurjus G.
        • Meltzer H.Y.
        • et al.
        Neurokinin-1 receptors are decreased in major depressive disorder.
        Neuroreport. 2002; 13: 1223-1227
        • Burnet P.W.
        • Harrison P.J.
        Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood disorder and schizophrenia.
        Biol Psychiatry. 2000; 47: 80-83
        • Bondy B.
        • Baghai T.C.
        • Minov C.
        • Schüle C.
        • Schwarz M.J.
        • Zwanzger P.
        • et al.
        Substance P serum levels are increased in major depression: preliminary results.
        Biol Psychiatry. 2003; 53: 538-542
        • Deuschle M.
        • Sander P.
        • Herpfer I.
        • Fiebich B.L.
        • Heuser I.
        • Lieb K.
        Substance P in serum and cerebrospinal fluid of depressed patients: No effect of antidepressant treatment.
        Psychiatry Res. 2005; 136: 1-6
        • Kramer M.S.
        • Cutler N.
        • Feighner J.
        • Shrivastava R.
        • Carman J.
        • Sramek J.J.
        • et al.
        Distinct mechanism for antidepressant activity by blockade of central substance P receptors.
        Science. 1998; 281: 1640-1645
        • Keller M.
        • Montgomery S.
        • Ball W.
        • Morrison M.
        • Snavely D.
        • Liu G.
        • et al.
        Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder.
        Biol Psychiatry. 2006; 59: 216-223
        • Strittmatter M.
        • Grauer M.
        • Isenberg E.
        • Hamann G.
        • Fischer C.
        • Hoffmann K.H.
        • et al.
        Cerebrospinal fluid neuropeptides and monoaminergic transmitters in patients with trigeminal neuralgia.
        Headache. 1997; 37: 211-216
        • Martinez M.
        • Frank A.
        • Hernanz A.
        Relationship of interleukin-1 beta and beta 2-microglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer type.
        J Neuroimmunol. 1993; 48: 235-240
        • De Felipe C.
        • Herrero J.F.
        • O'Brien J.A.
        • Palmer J.A.
        • Doyle C.A.
        • Smith A.J.
        • et al.
        Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.
        Nature. 1998; 392: 394-397
        • Barbaresi P.
        Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: A light and electron microscopic study.
        J Comp Neurol. 1998; 398: 473-490
        • Gallagher A.W.
        • Chahl L.A.
        • Lynch A.M.
        Distribution of substance P-like immunoreactivity in guinea pig central nervous system.
        Brain Res Bull. 1992; 29: 199-207
        • Rosen A.
        • Brodin K.
        • Eneroth P.
        • Brodin E.
        Short-term restraint stress and s.c. saline injection alter the tissue levels of substance P and cholecystokinin in the peri-aqueductal grey and limbic regions of rat brain.
        Acta Physiol Scand. 1992; 146: 341-348
        • Moss M.S.
        • Basbaum A.I.
        The peptidergic organization of the cat periaqueductal gray: II.
        J Neurosci. 1983; 3: 1437-1449
        • Brodin E.
        • Rosen A.
        • Schott E.
        • Brodin K.
        Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions.
        Neuropeptides. 1994; 26: 253-260
        • Chi C.C.
        • Flynn J.P.
        Neural pathways associated with hypothalamically elicited attach behavior in cats.
        Science. 1971; 171: 703-706
        • Chi C.C.
        • Flynn J.P.
        Neuroanatomic projections related to biting attack elicited from hypothalamus in cats.
        Brain Res. 1971; 35: 49-66
        • Siegel A.
        • Roeling T.A.
        • Gregg T.R.
        • Kruk M.R.
        Neuropharmacology of brain-stimulation-evoked aggression.
        Neurosci Biobehav Rev. 1999; 23: 359-389
        • Bergström M.
        • Hargreaves R.J.
        • Burns H.D.
        • Goldberg M.R.
        • Sciberras D.
        • Reines S.A.
        • et al.
        Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.
        Biol Psychiatry. 2004; 55: 1007-1012
        • Siegel A.
        • Bhatt S.
        • Bhatt R.
        • Zalcman S.S.
        The neurobiological bases for development of pharmacological treatments of aggressive disorders.
        Curr Neuropharmacol. 2007; 5: 135-147
        • Mantyh P.W.
        • Gates T.
        • Mantyh C.R.
        • Maggio J.E.
        Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues.
        J Neurosci. 1989; 9: 258-279
        • Nakaya Y.
        • Kaneko T.
        • Shigemoto R.
        • Nakanishi S.
        • Mizuno N.
        Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat.
        J Comp Neurol. 1994; 347: 249-274
        • Jacobs C.
        • Van Den Broeck W.
        • Simoens P.
        Increased volume and neuronal number of the basolateral nuclear group of the amygdaloid body in aggressive dogs.
        Behav Brain Res. 2006; 170: 119-125
        • Jacobs C.
        • Van Den Broeck W.
        • Simoens P.
        Neurokinin-1 receptor in the basolateral nuclear group of the canine amygdala—comparative study in normal and aggressive dogs.
        Brain Res. 2006; 170: 106-112
        • Giegling I.
        • Rujescu D.
        • Mandelli L.
        • Schneider B.
        • Hartmann A.M.
        • Schnabel A.
        • et al.
        Tachykinin receptor 1 variants associated with aggression in suicidal behavior.
        Am J Med Genet B Neuropsychiatr Genet. 2007; 144B: 757-761
        • Herpfer I.
        • Katzev M.
        • Feige B.
        • Fiebich B.L.
        • Voderholzer U.
        • Lieb K.
        Effects of substance P on memory and mood in healthy male subjects.
        Hum Psychopharmacol. 2007; 22: 567-573
        • McCabe C.
        • Cowen P.J.
        • Harmer C.J.
        NK1 receptor antagonism and the neural processing of emotional information in healthy volunteers.
        Int J Neuropsychopharmacol. 2009; 12: 1261-1274
        • Kessler R.C.
        • Coccaro E.F.
        • Fava M.
        • Jaeger S.
        • Jin R.
        • Walters E.
        The prevalence and correlates of DSM-IV intermittent explosive disorder in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2006; 63: 669-678
        • Coccaro E.F.
        • Lee R.J.
        • Kavoussi R.J.
        A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.
        J Clin Psychiatry. 2009; 70: 653-662