Antidepressant-like effect of creatine in mice involves dopaminergic activation

J Psychopharmacol. 2012 Nov;26(11):1489-501. doi: 10.1177/0269881112447989. Epub 2012 Jun 6.


Creatine has been shown to play a significant role in health and disease. However, studies concerning its effect on mood are scarce. This study investigated the effect of creatine (p.o.) in the tail suspension test, a predictive test of antidepressant activity. Creatine reduced the immobility time in the tail suspension test (0.1-1000 mg/kg, male and female mice), without affecting locomotor activity. Furthermore, the involvement of the dopaminergic system in creatine-induced antidepressant-like effect in male mice in the tail suspension test was investigated. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pre-treatment of mice with haloperidol (0.2 mg/kg, intraperitoneal (i.p.) route, non-selective dopamine receptor antagonist), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.05 mg/kg, subcutaneous (s.c.) route, dopamine D₁ receptor antagonist) and sulpiride (50 mg/kg, i.p., dopamine D₂ receptor antagonist). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (SKF38393; 0.1 mg/kg, s.c., dopamine D₁ receptor agonist), apomorphine (0.5 µg/kg, i.p., preferential dopamine D₂ receptor agonist) or bupropion (1 mg/kg, p.o., dopamine reuptake inhibitor with subtle activity on noradrenergic reuptake) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of dopamine D₁ and D₂ receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology
  • Creatine / administration & dosage
  • Creatine / metabolism*
  • Depression / drug therapy
  • Depression / physiopathology
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Male
  • Mice
  • Motor Activity / drug effects
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism*


  • Antidepressive Agents
  • Dopamine Agonists
  • Dopamine Antagonists
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Creatine
  • Dopamine