DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens

Nat Neurosci. 2002 Jul;5(7):641-8. doi: 10.1038/nn877.

Abstract

The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • Animals
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dopamine / metabolism
  • Dopamine Agonists / pharmacology
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Ethanol / pharmacology*
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Rats
  • Receptors, Dopamine D1 / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Ventral Tegmental Area / physiology

Substances

  • Dopamine Agonists
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • NR1 NMDA receptor
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Receptors, Dopamine D1
  • Receptors, N-Methyl-D-Aspartate
  • Ethanol
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Dopamine