Mechanisms by which Dopamine Receptors May Influence Synaptic Plasticity

Marina Wolf, Simona Mangiavacchi, Xiu Sun

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

While dopamine (DA) receptors mediate acute effects of amphetamine and cocaine, chronic drug administration produces many glutamate-dependent adaptations, including LTP in reward-related neuronal circuits. An important question presents itself: How do DA receptors influence glutamate-dependent synaptic plasticity? Alterations in AMPA receptor phosphorylation and trafficking are critical for LTP. We hypothesize that D1 DA receptors modulate these processes, that chronic drug-induced adaptations in D1 receptor signaling, therefore, trigger compensatory changes in AMPA receptor function, and that this ultimately contributes to inappropriate plasticity in addiction-related neuronal circuits. Postnatal rat nucleus accumbens (NAc) cultures were used to study D1 receptor regulation of the AMPA receptor subunit GluR1. We found that D1 receptor stimulation enhances phosphorylation of GluR1 at the protein kinase A (PKA) site. Furthermore, D1 receptor stimulation increases GluR1 surface expression by increasing the rate of GluR1 externalization. The latter effect is prevented by the PKA inhibitors KT5720 and RpcAMPS, whereas the PKA activator SpcAMPS increases the rate of GluR1 externalization. These findings indicate that PKA phosphorylation is important in determining AMPA receptor surface expression and suggest a mechanism by which DA-releasing drugs of abuse may directly tap into fundamental mechanisms that enable synaptic plasticity. A limitation of our current model is that there are no intrinsic glutamate neurons in the NAc and thus no glutamate synapses in NAc cultures. To address this problem, we have restored excitatory synaptic inputs to NAc neurons by co-culturing them with prefrontal cortex (PFC) neurons. We are also studying GluR1 trafficking in PFC cultures. In both systems, synaptic AMPA receptors can be defined based on colocalization of GluR1 and the synaptic marker synaptobrevin. Preliminary results suggest that D1 receptor stimulation or PKA activation leads to increased surface GluR1 expression in PFC neurons but not to insertion into synaptic sites.

Original languageEnglish (US)
Pages (from-to)241-249
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume1003
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Neuronal Plasticity
Dopamine Receptors
Cyclic AMP-Dependent Protein Kinases
AMPA Receptors
Plasticity
Nucleus Accumbens
Phosphorylation
Neurons
Glutamic Acid
Prefrontal Cortex
R-SNARE Proteins
Dopamine D1 Receptors
Dopamine Agents
Neurotransmitter Receptor
Networks (circuits)
Street Drugs
Amphetamine
Protein Kinase Inhibitors
Reward
Cocaine

Keywords

  • AMPA receptor
  • Cell culture
  • D1 dopamine receptor
  • LTP
  • Nucleus accumbens
  • Phosphorylation
  • Prefrontal cortex
  • Receptor trafficking

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Mechanisms by which Dopamine Receptors May Influence Synaptic Plasticity. / Wolf, Marina; Mangiavacchi, Simona; Sun, Xiu.

In: Annals of the New York Academy of Sciences, Vol. 1003, 01.01.2003, p. 241-249.

Research output: Contribution to journalArticle

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