Ethanol blocks long-term potentiation of GABAergic synapses in the ventral tegmental area involving mu-opioid receptors

Neuropsychopharmacology. 2010 Aug;35(9):1841-9. doi: 10.1038/npp.2010.51. Epub 2010 Apr 14.

Abstract

It is well documented that ethanol exposure alters GABA (gamma-aminobutyric acid)-releasing synapses, and ethanol addiction is associated with endogenous opioid system. Emerging evidence indicates that opioids block long-term potentiation in the fast inhibitory GABA(A) receptor synapses (LTP(GABA)) onto dopamine-containing neurons in the ventral tegmental area (VTA), a brain region essential for reward-seeking behavior. However, how ethanol affects LTP(GABA) is not known. We report here that in acute midbrain slices from rats, clinically relevant concentrations of ethanol applied both in vitro and in vivo prevents LTP(GABA), which is reversed, respectively, by in vitro and in vivo administration of naloxone, a mu-opioid receptor (MOR) antagonist. Furthermore, the blockade of LTP(GABA) induced by a brief in vitro ethanol treatment is mimicked by DAMGO ([D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin), a MOR agonist. Paired-pulse ratios are similar in slices, 24 h after in vivo injection with either saline or ethanol. Sp-cAMPS, a stable cAMP analog, and pCPT-cGMP, a cGMP analog, potentiates GABA(A)-mediated inhibitory postsynaptic currents in slices from ethanol-treated rats, indicating that a single in vivo ethanol exposure does not maximally increase GABA release, instead, ethanol produces a long-lasting inability to generate LTP(GABA). These neuroadaptations to ethanol might contribute to early stage of addiction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Animals, Newborn
  • Central Nervous System Depressants / pharmacology*
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / pharmacology
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Dopamine / metabolism
  • Electric Stimulation / methods
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Ethanol / pharmacology*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Long-Term Potentiation / drug effects*
  • Neurons / cytology
  • Neurons / drug effects*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism*
  • Synapses / drug effects*
  • Synapses / metabolism
  • Thionucleotides / pharmacology
  • Time Factors
  • Ventral Tegmental Area / cytology*
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Analgesics, Opioid
  • CPT-cGMP
  • Central Nervous System Depressants
  • Enzyme Inhibitors
  • Receptors, Opioid, mu
  • Thionucleotides
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • adenosine-3',5'-cyclic phosphorothioate
  • Ethanol
  • gamma-Aminobutyric Acid
  • Cyclic AMP
  • Cyclic GMP
  • Dopamine