title: Ethanol attenuation of long-term depression in the nucleus accumbens can be overcome by activation of TRPV1 receptors.
abstract: BACKGROUND
  Altered expression of synaptic plasticity within the nucleus accumbens (NAc) constitutes a critical neuroadaptive response to ethanol (EtOH) and other drugs of abuse. We have previously reported that N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) is markedly affected by chronic intermittent ethanol exposure in vivo; however, endocannabinoid (eCB)-dependent synaptic depression, despite being very well-documented in the dorsal striatum, is much less well understood in the NAc.
  
  
  METHODS
  Whole cell patch clamp electrophysiology was used to investigate interactions between these different plasticity-induction systems. Excitatory postsynaptic currents (EPSCs) were measured in the NAc shell and NMDAR-LTD was induced by a pairing protocol (500 stimuli at 1 Hz stimulation [low-frequency stimulation (LFS)] paired with postsynaptic depolarization to -50 mV). AM251, a CB1 receptor antagonist, was used to determine whether this form of LTD is modulated by eCBs. To determine the effect of EtOH on a purely eCB-dependent response in the NAc, depolarization-induced suppression of excitation (DSE) was used in the presence of 40 mM EtOH. Finally, we determined whether the enhancement of eCB signaling with URB597, a fatty acid amide hydrolase inhibitor, and AM404, an anandamide re-uptake inhibitor would also modulate LFS LTD in the presence of NMDAR blockade or EtOH.
  
  
  RESULTS
  In the presence of AM251, the LFS pairing protocol resulted in NMDAR-dependent long-term potentiation that was blocked with either EtOH or DL-APV. We also found that DSE in the NAc shell was blocked by AM251 and suppressed by EtOH. Enhanced eCB signaling rescued NAc-LTD expression in the presence of EtOH through a distinct mechanism requiring activation of TRPV1 receptors.
  
  
  CONCLUSIONS
  EtOH modulation of synaptic plasticity in the NAc is dependent upon a complex interplay between NMDARs, eCBs, and TRPV1 receptors. These findings demonstrate a novel form of TRPV1-dependent LTD in the NAc shell that may be critical for EtOH dependence.
authors.affiliation: Institute for Neuroscience, The College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: Rafael
authors.initials: R
authors.lastname: Renteria
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Jeanes
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morrisett
mesh_terms: D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C103505:AM 251; D000431:Ethanol
keywords: Depolarization-Induced Suppression of Excitation; Electrophysiology; Endocannabinoid; Plasticity; TRPV1