PMID- 23305991
OWN - NLM
STAT- MEDLINE
DCOM- 20131021
LR  - 20130416
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 73
IP  - 9
DP  - 2013 May 1
TI  - Presynaptic leptin action suppresses excitatory synaptic transmission onto 
      ventral tegmental area dopamine neurons.
PG  - 860-8
LID - S0006-3223(12)00953-5 [pii]
LID - 10.1016/j.biopsych.2012.10.026 [doi]
AB  - BACKGROUND: Leptin is an adipocyte-derived cytokine that can act in the brain to 
      suppress feeding and maintain energy homeostasis. Additionally, leptin activates 
      its receptors in the ventral tegmental area (VTA), a critical site for 
      neuroadaptations to rewarding stimuli, to modulate reward-seeking behaviors. 
      Although leptin can decrease intrinsic excitability of dopamine neurons in the 
      VTA, it is unknown whether leptin can modulate excitatory synaptic transmission 
      in this brain region. Because plasticity of glutamatergic synapses onto VTA 
      neurons can encode predictive information about reward, we hypothesized that 
      leptin can decrease excitatory synaptic transmission onto dopamine neurons. 
      METHODS: Using whole-cell patch clamp electrophysiology in mouse midbrain slices, 
      we tested the effects of leptin on evoked 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) or 
      N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents 
      (EPSCs) onto VTA dopamine neurons. RESULTS: Leptin depressed both AMPAR and NMDAR 
      EPSCs in VTA dopamine neurons and reduced frequency but not amplitude of mini 
      EPSCs. Bath application of the MEK1/2 inhibitor U0126 did not alter 
      leptin-induced suppression of AMPAR EPSCs. However, external, but not internal, 
      application of the phosphoinositol 3-kinase (PI3K) or Janus kinase 2 (Jak2) 
      tyrosine kinase inhibitors abolished leptin-induced synaptic depression. 
      CONCLUSIONS: This study demonstrates that leptin causes a presynaptic inhibition 
      of the probability of glutamate release onto VTA dopamine neurons. This synaptic 
      inhibition requires Jak2 and PI3K activation. Leptin-induced weakening of 
      synaptic strength onto dopamine cells may underlie its inhibitory effects on 
      appetitive behavior for rewarding stimuli.
CI  - Copyright (c) 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Thompson, Jennifer L
AU  - Thompson JL
AD  - Department of Anesthesiology, Pharmacology and Therapeutics, University of 
      British Columbia, Vancouver, Canada.
FAU - Borgland, Stephanie L
AU  - Borgland SL
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130107
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Butadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Leptin)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (U 0126)
SB  - IM
MH  - Animals
MH  - Butadienes/pharmacology
MH  - Dopaminergic Neurons/cytology/*drug effects/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Postsynaptic Potentials/*drug effects/physiology
MH  - Leptin/*pharmacology
MH  - Male
MH  - Mice
MH  - Nitriles/pharmacology
MH  - Patch-Clamp Techniques
MH  - Receptors, AMPA/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Signal Transduction/drug effects
MH  - Synaptic Transmission/drug effects/physiology
MH  - Ventral Tegmental Area/cytology/*drug effects/metabolism
EDAT- 2013/01/12 06:00
MHDA- 2013/10/22 06:00
CRDT- 2013/01/12 06:00
PHST- 2012/07/14 00:00 [received]
PHST- 2012/10/31 00:00 [revised]
PHST- 2012/10/31 00:00 [accepted]
PHST- 2013/01/12 06:00 [entrez]
PHST- 2013/01/12 06:00 [pubmed]
PHST- 2013/10/22 06:00 [medline]
AID - S0006-3223(12)00953-5 [pii]
AID - 10.1016/j.biopsych.2012.10.026 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2013 May 1;73(9):860-8. doi: 10.1016/j.biopsych.2012.10.026. 
      Epub 2013 Jan 7.