Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors

Tamaki Hayase

doi:10.1186/1471-2210-11-6

Abstract

BackgroundThe contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse.ResultsRepeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM).ConclusionsThe antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse.

Highlights

The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective
In the NC- and immobilization stress (IM)-only groups, significantly attenuated “time until immobility” and attenuated “activity counts”, i.e. the indices which reflected both the overall activity during the swim behaviors and the minimum activity after immobility, were observed as compared to the control group. In both NC and IM groups co-treated with CP (F(6, 108) = 3.46, P < 0.01), OL (F(6, 108) = 3.40, P < 0.01), or AR (F(6, 108) = 3.22, P < 0.01), the analysis of variance (ANOVA) with a 3 (NC, IM versus vehicle) × 4 factorial design revealed significant recoveries from the attenuated activity counts as compared to the NC- or IM-only group (Figure 1a, b, and 1f)
In the NC- and IMonly groups, a significantly increased “total immobility time” as compared to the control group was observed. In both NC and IM groups co-treated with CP (F(6, 108) = 3.88, P < 0.01), OL (F(6, 108) = 3.70, P < 0.01), or AR (F(6, 108) = 4.21, P < 0.001), the ANOVA with a 3 (NC, IM versus vehicle) × 4 factorial design revealed significant recoveries from the increased total immobility times as compared to the NC- or IM-only group (Figure 2a, b, and 2f)

Summary

Introduction

The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. The effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the “antidepressant-like” contributions of TRPV1 receptors against the NC-induced “depression” observed in various types of tobacco abuse. NC-induced “depression-like” behavioral alterations in animal experimental models have been quantified as exacerbated immobility in behavioral tests, such as the forced swimming test [9,10,13]. This test is used for screening antidepressants, which suppress immobility in swimming behaviors [14]. Repeated NC administration caused exacerbated immobility in these behavioral tests [9,10,13]

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Discussion

Conclusion