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    • Acknowledgments br Introduction Stress plays a key role in t

    2022-01-24

    Acknowledgments
    Introduction Stress plays a key role in the etiology and/or exacerbation of major depressive disorder characterized by loss of energy, feelings of hopelessness and anhedonia [1]. Ample evidence clearly suggests that endocannabinoids (eCBs) participate in stress-associated neuronal signaling alterations and behavioral changes in the brain, leading to development of depression [2], [3]. Brain eCB system consists mainly of the G-protein coupled receptor cannabinoid CB1 (CB1R) and two arachidonate-derived ligands, i.e., anandamide or arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) [4], [5], [6], [7]. AEA and 2-AG are primarily hydrolyzed by fatty S-Adenosylhomocysteine amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively [5], [7]. Neuronal CB1R is distributed primarily in the presynaptic terminals, and its activation inhibits presynaptic release of neurotransmitters [6]. Thus, eCB activation of presynaptic CB1R can induce either short-term synaptic depression, i.e., depolarization-induced suppression of inhibition (DSI) and excitation (DSE), respectively at GABAergic and glutamatergic synapses, or long-term depression (LTD), depending on its pattern of synthesis [6]. More recently, we found the existence of CB1R in astroglial cells [8] and its activation by either synthetic cannabinoids or 2-AG leads to postsynaptically expressed LTD at glutamatergic CA3-CA1 synapses of the hippocampus [8], [9]. Stress has been shown to enhance activity of FAAH, resulting in a significant decline of AEA content in the brain [10]. Thus, restoring deficient AEA signaling may be served as a therapeutic mechanism in acutely stressed naïve animals [11], [12]. In support of this idea, administration of the FAAH inhibitor URB597 or genetic deletion of FAAH alleviated depression-like behavioral responses in the forced swim and tail suspension tests [13], [14], [15], [16]. The AEA-transport inhibitor AM404 also exerted similar anti-depressant effects [15], [17]. We have recently shown that MAGL inhibitors produced antidepressant effects through astroglial CB1R-mediated LTD at glutamatergic CA3-CA1 synapses [9]. MAGL inhibitors, but not FAAH inhibitors, induce physical dependence, tolerance, and impairment of eCB-dependent synaptic plasticity via CB1R downregulation and desensitization [13], [18], [19], [20], [21]. In the past decades, the coping behavior of rodents in response to acute inescapable stress in the FST has been widely and successfully used to investigate antidepressant efficacy, where shorter or longer immobility time indicates, respectively, passive or active behavioral coping to acute stress challenge. In the present study, the shortened immobility time of naïve mice in the FST was used to represent antidepressant behavioral responses of mice after an acute exposure to the FAAH inhibitor PF3845. Therefore, we examined the hypothesis that FAAH inhibition could also produce antidepressant effects through astroglial CB1R-mediated LTD at CA3-CA1 synapses.
    Materials and methods
    Results
    Discussion PF3845 has exceptional potency and selectivity to FAAH [5], as 1–10mg/kg PF3845 completely blocked FAAH activity to produce maximal elevations in brain AEA levels [27]. In this study, we observed that both 10 and 20mg/kg PF3845 consistently exerted significant antidepressant behavioral responses, while 10mg/kg did not produce significant tolerance or significantly affect basal locomotor activity and motor balance. We also found that the CB1R antagonist AM281 abolished PF3845-induced antidepressant effects, supporting the idea that PF3845 produces antidepressant effects through its capacity to increase AEA content in the brain. However, these results are not conclusive for three reasons. First, AM281 is CB1R antagonist and inverse agonist, thus excluding the conclusion that its blockade of PF3845-induced antidepressant effects is solely achieved by it antagonist action on CB1R. Second, an acute i.p. administration of AM281 can antagonize CB1R both within and outside of the brain, thus leading to the possibility that peripheral CB1R is also involved in the antidepressant effects of PF3845. Third, even if we assume that in the present study AM281 produced antidepressant effects mainly through its blockade of brain CB1R because peripheral CB1R is less likely involved in depressive behavior, AM281 can block CB1R in both neurons and astroglial cells. Therefore, our findings that AM281 abolishment of PF3845 effects does not provide valuable information regarding the identification of which type of brain cells participates in PF3845-induced antidepressant effects. To overcome these potential problems, we employed mutant mouse line for an inducible deletion of gene from brain cells in adult mice [8], [9]. We found that similar to systemic AM281 injection, deletion from adult brain astroglial cells not GABA- or glutamate cells abolished antidepressant behavioral responses produced by PF3845. These findings strongly suggest that PF3845 produces antidepressant effects through increase of brain AEA levels to activate brain astroglial CB1R.