Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice

Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB1 agonist (AEA: 1–20 μg/mouse); AM404, an anandamide transport inhibitor (0.1–10 μg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05–10 μg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose–response curve). Fluoxetine (2.5–20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 μg/mouse, i.c.v.), AM404 (0.05 μg/mouse, i.c.v) or URB597 (0.01 μg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB1 antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 μg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 μg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior.

► Role of eCBs in antidepressant and anti-compulsive effect of fluoxetine (FLX) was studied.
► Mouse model of forced swim test (FST) and marble-burying behavior (MBB) were employed.
► eCBs exhibited antidepressant effect in FST and produced ‘U’-shaped response curve in MBB.
► Co-joint injections of FLX and eCBs in subthreshold doses potentiated the effect on both the tests.
► CB1 receptor antagonist blocked antidepressant and anti-compulsive effect of FLX.
► Indicating interplay between eCB and serotonergic system in depression and compulsive-like behavior.