Substance P receptor antagonist in lateral habenula improves rat depression-like behavior

• We examined the effects of SPA in LHb on the rat depression-like behavior.
• SPA microinjected into LHb of depressive rats decreased the immobility time of FST.
• SPA microinjected into LHb of depressive rats increased the climbing time of FST.
• SPA microinjected into LHb of depressive rats increased the 5-HT levels in DRN.
• SPA in LHb improves rat depression-like behavior via increasing 5-HT levels in DRN.

Substance P (SP) levels are closely related with the pathogenesis of depression. Recent work has focused on antidepressive effect of substance P receptor antagonist (SPA), however, its action site and mechanism remain largely unresolved. Our previous results showed that the lateral habenula (LHb) plays a key role in the pathogenesis of depression. The current study investigated the effects of SPA microinjected into LHb on the behavioral responses of two rat models that exhibit depression-like behavior. To produce adult rats that exhibit depression-like behavior, rats were either exposed to chronic mild stress (CMS), or chronically administered clomipramine (CLI), a tricyclic antidepressant, during the neonatal state of life. The forced-swimming test (FST) was used to evaluate behavioral responses. Furthermore, we measured serotonin (5-HT) levels in dorsal raphe nucleus (DRN) using microdialysis. The FST showed a decreased immobility time and an increased climbing time after SPA injection into the LHb of depression-like behavior rats. In addition, 5-HT levels in DRN increased after SPA was microinjected into LHb of the rats that exhibited depression-like behavior. This study demonstrates that LHb mediates antidepressive effect of SPA by increasing 5-HT levels in the DRN, suggesting that the LHb may be a potential target of antidepressant.