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

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.

Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests

“…These effects include antinociception (Aceto et al 1983), sedative and analgesic effect (Mattila et al 1968), alterations in cognition (Levin and Simon 1998) and memory (Zarrindast et al 1996), convulsions and seizure induction (Damaj et al 1999), and antidepression-like effect (Hayase 2011;Mineur and Picciotto 2010;Vieyra-Reyes et al 2008) in experimental animals. Animal studies have demonstrated that both acute and chronic administration of nicotine, without affecting locomotor behavior, exerted antidepressant-like effects in rodent models of depression such as the learned helplessness and forced swimming test (Djurić et al 1999;Tizabi et al 1999).…”

Transient Receptor Potential Vanilloid Type 1 Channel May Modulate Opioid Reward

“…Intraprefrontal cortex or intraperitoneal (i.p.) administration of TRPV1 antagonist induces anxiolytic-like effects (Aguiar et al, 2009;Kasckow et al, 2004), and in preclinical models of depression-like behaviors induced by nicotine or immobilization stress, TRPV1 agonists show antidepressant-like effects in both the forced swimming and tail suspension tests (Hayase, 2011). Moreover, upregulation of TRPV1 in the dorsal root ganglion, spinal cord, and sciatic nerve through mitogen-activated protein kinase pathways after chronic morphine treatment contributed to morphine tolerance in rats (Chen et al, 2008).…”

Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain

“…GABAergic, dopaminergic and serotonergic terminals are additional purported candidates to be modulated by TRPV 1 Rs, as central TRPV 1 Rs are implicated in mood disorders, anxiety, panic responses, depression and psychosis Chahl, 2011;Hayase, 2011;Casarotto et al, 2012;Moreira et al, 2012, Micale et al, 2013). Yet no direct presynaptic TRPV 1 R modulation of dopamine and GABA release has been observed so far in the adult rodent brain (see Table 1), while to our knowledge, presynaptic TRPV 1 R modulation of serotonergic terminals in the brain has never been looked for.…”