Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area

Anuradha Madhavan, Emanuela Argilli, Antonello Bonci, Jennifer Whistler

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/ NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.

Original languageEnglish (US)
Pages (from-to)12329-12336
Number of pages8
JournalJournal of Neuroscience
Volume33
Issue number30
DOIs
StatePublished - Jul 30 2013
Externally publishedYes

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Ventral Tegmental Area
Dopamine D2 Receptors
Cocaine
N-Methyl-D-Aspartate Receptors
AMPA Receptors
Protein Transport
GTP-Binding Proteins
Glutamic Acid
Down-Regulation
Neurons
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
N-Methylaspartate
Lysosomes
Pharmacology
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. / Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello; Whistler, Jennifer.

In: Journal of Neuroscience, Vol. 33, No. 30, 30.07.2013, p. 12329-12336.

Research output: Contribution to journalArticle

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