Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors

Behav Brain Res. 2016 Oct 1;312:64-76. doi: 10.1016/j.bbr.2016.06.014. Epub 2016 Jun 13.


Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Keywords: Agmatine; Dopaminergic system; NMDA receptors; Nitric oxide; Orofacial dyskinesia; Oxidative stress; Reserpine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agmatine / administration & dosage*
  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesias / metabolism*
  • Dyskinesias / prevention & control
  • Excitatory Amino Acid Antagonists / pharmacology
  • Locomotion / drug effects
  • Male
  • Mice
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Oxidative Stress / drug effects*
  • Receptors, Dopamine / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Reserpine / toxicity*
  • Tyrosine 3-Monooxygenase / metabolism


  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Excitatory Amino Acid Antagonists
  • Ppp1r1b protein, mouse
  • Receptors, Dopamine
  • Receptors, N-Methyl-D-Aspartate
  • Nitric Oxide
  • Dizocilpine Maleate
  • Agmatine
  • Reserpine
  • Nitric Oxide Synthase
  • Tyrosine 3-Monooxygenase
  • Dopamine