Neurochemical Research

, Volume 35, Issue 10, pp 1659–1665 | Cite as

Imbalance Between Nitric Oxide and Dopamine May Underly Aggression in Acute Neurological Patients

  • J. Ramírez-Bermudez
  • I. Perez-Neri
  • S. Montes
  • M. Ramirez-Abascal
  • F. Nente
  • A. Abundes-Corona
  • J. L. Soto-Hernandez
  • C. Rios


The neurochemical basis of aggressive behavior in humans is not fully understood. In this study we explored the relationship between aggressiveness (as measured by the Overt Aggression Scale), cognitive performance (as measured by the Mini Mental State Examination), and biochemical markers of dopamine neurotransmission (homovanillic acid, HVA) and nitric oxide synthesis (nitrite plus nitrate, NO x ) in cerebrospinal fluid from 70 patients with acute brain disorders, mainly brain infections. Aggressive behavior and cognitive performance showed an inverse correlation. NO x /HVA ratio was inversely correlated to aggressive behavior, and positively correlated to cognitive performance. A subanalysis with antipsychotic-naïve patients confirmed those results. The balance between nitric oxide and dopamine could be related to the cognitive control of aggressive impulse.


Dopamine Nitric oxide Cerebrospinal fluid Aggressive behavior Brain infections 


  1. 1.
    Grafman J, Schwab K, Warden D, Pridgen A, Brown HR, Salazar AM (1996) Frontal lobe injuries, violence, and aggression: a report of the Vietnam head injury study. Neurology 46:1231–1238PubMedGoogle Scholar
  2. 2.
    Ramirez-Bermudez J, Ruiz-Chow A, Pérez-Neri I, Soto-Hernández JL, Flores-Hernández R, Nente F, Montes S, Rios C (2008) Cerebrospinal fluid homovanillic acid is correlated to psychotic symptoms in neurological patients with delirium. Gen Hosp Psychiatry 30:337–343CrossRefPubMedGoogle Scholar
  3. 3.
    Kunik ME, Snow AL, Davila JA, Steele AB, Balasubramanyam V, Doody RS, Schulz PE, Kalavar JS, Morgan RO (2010) Causes of aggressive behavior in patients with dementia. J Clin Psychiatry. Epub ahead of printGoogle Scholar
  4. 4.
    Reif A, Jacob CP, Rujescu D, Herterich S, Lang S, Gutknecht L, Baehne CG, Strobel A, Freitag CM, Giegling I, Romanos M, Hartmann A, Rösler M, Renner TJ, Fallgatter AJ, Retz W, Ehlis AC, Lesch KP (2009) Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans. Arch Gen Psychiatry 66:41–50CrossRefPubMedGoogle Scholar
  5. 5.
    Chiavegatto S, Nelson RJ (2003) Interaction of nitric oxide and serotonin in aggressive behaviour. Horm Behav 44:233–241CrossRefPubMedGoogle Scholar
  6. 6.
    Neumann ID, Veenema AH, Beiderbeck DI (2010) Aggression and anxiety: social context and neurobiological links. Front Behav Neurosci 4:1–16Google Scholar
  7. 7.
    Trainor BC, Workman JL, Jessen R, Nelson RJ (2007) Impaired nitric oxide synthase signaling dissociates social investigation and aggression. Behav Neurosci 121:362–369CrossRefPubMedGoogle Scholar
  8. 8.
    Nelson RJ, Trainor BC, Chiavegatto S, Demas GE (2006) Pleiotropic contributions of nitric oxide to aggressive behavior. Neurosci Biobehav Rev 30:346–355CrossRefPubMedGoogle Scholar
  9. 9.
    Craig IW, Halton KE (2009) Genetics of human aggressive behaviour. Hum Genet 126:101–113CrossRefPubMedGoogle Scholar
  10. 10.
    Arancio O, Kiebler M, Lee CJ, Lev-Ram V, Tsien RY, Kandel ER, Hawkins RD (1996) Nitric oxide acts directly in the presynaptic neuron to produce long-term potentiation in cultured hippocampal neurons. Cell 87:1025–1035CrossRefPubMedGoogle Scholar
  11. 11.
    Seo D, Patrick CJ (2008) Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav 13:83–395CrossRefGoogle Scholar
  12. 12.
    Tsiouris JA (2010) Pharmacotherapy for aggressive behaviours in persons with intellectual disabilities: treatment or mistreatment? J Intellect Disabil Res 54:1–16CrossRefPubMedGoogle Scholar
  13. 13.
    Rudissaar R, Harro J, Pruus K, Rinken A, Allikmets L (2008) Repeated administration of the dopaminergic agonist apomorphine: development of apomorphine aggressiveness and changes in the interaction between dopamine D2 receptors and G-proteins. Pharmacol Rep 60:827–833PubMedGoogle Scholar
  14. 14.
    Smith JCE, Whitton PS (2001) The regulation of NMDA-evoked dopamine release by nitric oxide in the frontal cortex and raphe nuclei of the freely moving rat. Brain Res 889:57–62CrossRefPubMedGoogle Scholar
  15. 15.
    Karolewicz B, Paul IA, Antkiewicz-Michaluk L (2001) Effect of nos inhibitor on forced swim test and neurotransmitters turnover in the mouse brain. Pol J Pharmacol 53:587–596PubMedGoogle Scholar
  16. 16.
    Hoque KE, Indorkar RP, Sammut S, West AR (2010) Impact of dopamine–glutamate interactions on striatal neuronal nitric oxide synthase activity. Psychopharmacology 207:571–581CrossRefPubMedGoogle Scholar
  17. 17.
    Ramirez J, Garnica R, Boll MC, Montes S, Rios C (2004) Low concentration of nitrite and nitrate in the cerebrospinal fluid from schizophrenic patients: a pilot study. Schizophr Res 68:357–361CrossRefPubMedGoogle Scholar
  18. 18.
    Perez-Neri I, Castro E, Montes S, Boll MC, Barges-Coll J, Soto-Hernández JL, Ríos C (2007) Arginine, citrulline and nitrate concentrations in the cerebrospinal fluid from patients with acute hydrocephalus. J Chromatogr B 851:250–256CrossRefGoogle Scholar
  19. 19.
    American Psychiatric Assciation (1994) DSM-IV. American Psychiatric Press, WashingtonGoogle Scholar
  20. 20.
    Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D (1986) Aggression scale for the objective rating of verbal and physical aggression. Am J Psychiatry 143:35–39PubMedGoogle Scholar
  21. 21.
    Paez F, Licon E, Fresan A, Apiquian R, Herrera-Estrella M, Garcia-Anaya M, Robles-Garcia R, Pinto T (2002) Estudio de validez y confiabilidad de la escala de agresividad explícita en pacientes psiquiátricos. Salud Mental 25:21–26Google Scholar
  22. 22.
    Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMedGoogle Scholar
  23. 23.
    Nelson RJ, Trainor BC (2007) Neural mechanisms of aggression. Nat Rev Neurosci 8:536–546CrossRefPubMedGoogle Scholar
  24. 24.
    Jollant F, Lawrence NS, Olie E, O’Daly O, Malafosse A, Courtet P, Phillips ML (2010) Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior. Neuroimage 51:1275–1281CrossRefPubMedGoogle Scholar
  25. 25.
    Bondar NP, Boyarskikh UA, Kovalenko IL, Filipenko ML, Kudryavtseva NN (2009) Molecular implications of repeated aggression: TH, DAT1, SNCA and BDNF gene expression in the VTA of victorious male mice. PLoS One 4:e4190CrossRefPubMedGoogle Scholar
  26. 26.
    Soderstrom H, Blennow K, Sjodin AK, Forsman A (2003) New evidence for an association between the CSF HVA: 5-HIAA ratio and psychopathic traits. J Neurol Neurosurg Psychiatry 74:918–921CrossRefPubMedGoogle Scholar
  27. 27.
    Wultsch T, Chourbaji S, Fritzen S, Kittel S, Grünblatt E, Gerlach M, Gutknecht L, Chizat F, Golfier G, Schmitt A, Gass P, Lesch KP, Reif A (2007) Behavioural and expressional phenotyping of nitric oxide synthase-I knockdown animals. J Neural Trans Suppl 72:69–85CrossRefGoogle Scholar
  28. 28.
    Weitzdoerfer R, Hoeger H, Engidawork E, Engelmann M, Singewald N, Lubec G, Lubec B (2004) Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance. Nitric Oxide 103:130–140CrossRefGoogle Scholar
  29. 29.
    Rujescu D, Giegling I, Mandelli L, Schneider B, Hartmann AM, Schnabel A, Maurer K, Möller HJ, Serretti A (2008) NOS-I and -III gene variants are differentially associated with facets of suicidal behavior and aggression-related traits. Am J Med Genet B Neuropsychiatr Genet 147B:42–48CrossRefPubMedGoogle Scholar
  30. 30.
    Wegener G, Volke V, Rosenberg R (2000) Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol 130:575–580CrossRefPubMedGoogle Scholar
  31. 31.
    Wang JQ, Lau YS (2001) Dose-related alteration in nitric oxide synthase mRNA expression induced by amphetamine and the full D1 dopamine receptor agonist SKF-82958 in mouse striatum. Neurosci Lett 311:5–8CrossRefPubMedGoogle Scholar
  32. 32.
    Hoptman MJ, D’Angelo D, Catalano D, Mauro CJ, Shehzad ZE, Kelly AM, Castellanos FX, Javitt DC, Milham MP (2009) Amygdalofrontal functional disconnectivity and aggression in schizophrenia. Schizophr Bull. doi: 10.1093/schbul/sbp012
  33. 33.
    Cruz-Rizzolo RJ, Horta-Júnior Jde A, Bittencourt JC, Ervolino E, de Oliveira JA, Casatti CA (2006) Distribution of NADPH-diaphorase-positive neurons in the prefrontal cortex of the Cebus monkey. Brain Res 1083(1):118–133CrossRefPubMedGoogle Scholar
  34. 34.
    Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP, Wienker T, Töpner T, Fritzen S, Walter U, Schmitt A, Fallgatter AJ, Lesch KP (2006) A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11:286–300CrossRefPubMedGoogle Scholar
  35. 35.
    Sammut S, Park DJ, West AR (2007) Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal NOS-dependent mechanism. J Neurochem 103:1145–1156CrossRefPubMedGoogle Scholar
  36. 36.
    Overeem KA, Ota KT, Monsey MS, Ploski JE, Schafe GE (2010) A role for nitric oxide-driven retrograde signaling in the consolidation of a fear memory. Front Behav Neurosci 4:2CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • J. Ramírez-Bermudez
    • 1
  • I. Perez-Neri
    • 2
  • S. Montes
    • 2
  • M. Ramirez-Abascal
    • 1
  • F. Nente
    • 1
  • A. Abundes-Corona
    • 1
  • J. L. Soto-Hernandez
    • 3
  • C. Rios
    • 2
  1. 1.The Department of NeuropsychiatryNational Institute of Neurology and Neurosurgery of MexicoCiudad de méxico, Distrito FederalMexico
  2. 2.The Department of NeurochemistryNational Institute of Neurology and Neurosurgery of MexicoCiudad de méxico, Distrito FederalMexico
  3. 3.The Department of NeuroinfectologyNational Institute of Neurology and Neurosurgery of MexicoCiudad de méxico, Distrito FederalMexico

Personalised recommendations