NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice

Neuroscience. 2016 Aug 4:329:122-33. doi: 10.1016/j.neuroscience.2016.05.003. Epub 2016 May 7.


Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors.

Keywords: FST; NMDA receptors; TRPV1; amphetamine withdrawal; depression; splash test.

MeSH terms

  • Amphetamine / adverse effects*
  • Amphetamine / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology*
  • Central Nervous System Stimulants / adverse effects*
  • Central Nervous System Stimulants / pharmacology
  • Depressive Disorder / chemically induced
  • Depressive Disorder / drug therapy
  • Depressive Disorder / metabolism
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Male
  • Mice
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / psychology
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / metabolism
  • Time Factors


  • Antidepressive Agents
  • Central Nervous System Stimulants
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Dizocilpine Maleate
  • Amphetamine
  • capsazepine
  • Capsaicin