Endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor

Activation of cannabinoid CB1 receptor is shown to inhibit marble-burying behavior (MBB), a behavioral model for assessing obsessive-compulsive disorder (OCD). Anandamide, an endogenous agonist at CB1 receptor also activates the transient receptor potential vanilloid type 1 (TRPV1) channels but at a higher concentration. Furthermore, anandamide-mediated TRPV1 effects are opposite to that of the CB1 receptor. Therefore, the present study was carried out to investigate the influence of low and high doses of anandamide on MBB in CB1 and TRPV1 antagonist pre-treated mice. The results revealed that i.c.v. administration of lower doses of anandamide (1–10 μg/mouse) or its analogues (AM404 or URB597; 1–5 μg/mouse) inhibited MBB indicating the anticompulsive activity. Conversely, at higher doses (40 or 20 μg/mouse) these compounds increased MBB similar to capsaicin (TRPV1 agonist, 100 μg/mouse) exhibiting a pro-compulsive effect. Pretreatment with AM251 (CB1 antagonist, 1 μg/mouse) antagonized the anticompulsive effect of these compounds, while their pro-compulsive effect at higher doses was attenuated by inactive dose of capsazepine (TRPV1 antagonist, 10 μg/mouse). However, capsazepine per se at a higher dose (100 μg/mouse) inhibited MBB. When given daily for 14 days, the anticompulsive effect of anandamide and its analogues gradually disappeared, whereas capsazepine either alone or with URB597 produced consistent inhibition of MBB comparable to fluoxetine. Thus, the study indicates the biphasic influence of anandamide on MBB, and chronic administration of capsazepine either alone or with URB597 might be an effective tool in the treatment of OCD.

► Anandamide, an endocannabinoid exhibits pro-and anticompulsive effect on marble-burying behavior.
► CB1 receptor mediates the anticompulsive effect of low doses of anandamide.
► The procompulsive effect of high dose of anandamide is via TRPV1.
► On chronic administration, the anticompulsive effect of CB1 agonists gradually declined.
► While, TRPV1 antagonist alone or with FAAH inhibitor exhibit anticompulsive effect.