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.