Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat.

Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat. Neuropharmacology. 2020 Jan 16;:107964 Authors: Worley NB, Varela JA, Gaillardetz GP, Hill MN, Christianson JP Abstract Neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. Pharmacological activation of the vmPFC during stress protects against stress-induced social anxiety suggesting that altering the excitatory/inhibitory (E/I) tone in the vmPFC may promote stress resilience. E/I balance is maintained, in part, by endogenous cannabinoid (eCB) signaling with the calcium dependent retrograde release of 2-arachidonoylglycerol (2-AG) suppressing presynaptic neurotransmitter release. We hypothesized that raising 2-AG levels, via inhibition of its degradation enzyme monoacylglycerol lipase (MAGL) with KML29, would shift vmPFC E/I balance and promote resilience. In acute slice experiments, bath application of KML29 (100 nM) augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. In whole-cell recordings, KML29 increased resting membrane potential but reduced the after depolarization, bursting rate, membrane time constant and slow after hyperpolarization. Intra-vmPFC administration of KML29 (200ng/0.5μL/hemisphere) prior to inescapable stress (IS) exposure (25, 5s tail ...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research