Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor antagonists

The anxiolytic- and antidepressant-like effects of the neurokinin (NK) receptor antagonists have been shown in behavioral studies. According to the involvement of neurotrophin signaling in the mechanisms of action of psychotropic agents, we aimed to investigate whether the selective NK1, NK2, or NK3 receptor antagonists (GR-205171, SR48968, and SR142801, respectively) affect nerve growth factor (NGF) contents in the brain regions involved in the modulation of emotions. To gain a mechanistical insight into the process by which the NK antagonists regulate brain NGF levels, we evaluated the role of the cannabinoid system which is linked to depression and/or antidepressant effects and appears to interact with neurotrophin signaling. According to the results, single injection of the NK receptor antagonists (3, 5, and 10 mg/kg, i.p.) into gerbils did not alter NGF or endocannabinoid (eCB) levels quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. Three-week administration of 10 mg/kg NK antagonists significantly elevated both NGF and eCB levels in brain-region specific fashion. Pre-application of the CB1 receptor neutral antagonist AM4113 (5.6 mg/kg) prevented the elevation of NGF or eCB induced by the NK antagonists. AM4113 showed no effect by itself. We conclude that the cannabinoid system is implicated in the mechanisms of action of NK receptor antagonists including the upregulation of brain NGF levels.