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Molecular psychiatry v.22 no.2, 2017년, pp.215 - 226   SCI SCIE
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Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses

Wang, Y (Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada ) ; Gu, N (Department of Psychiatry, Xijing Hospital, Xi' an, China ) ; Duan, T (Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada ) ; Kesner, P (Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada ) ; Blaskovits, F (Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada ) ; Liu, J (Departments of Psychiatry and Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada ) ; Lu, Y (Department of Anesthesiology, Xijing Hospital, Xi' an, China ) ; Tong, L (Department of Anatomy, Histology and Embryology, Fourth Military Medical University, Xi' an, China ) ; Gao, F (Depart ) ; Harris, C ; Mackie, K ; Li, J ; Tan, Q ; Hill, M N ; Yuan, Z ; Zhang, X ;
  • 초록  

    The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB 1 cannabinoid receptor (CB 1 R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB 1 R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.


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