Inhibition of dopamine transporter activity impairs synaptic depression in rat prefrontal cortex through over-stimulation of D1 receptors.

TitleInhibition of dopamine transporter activity impairs synaptic depression in rat prefrontal cortex through over-stimulation of D1 receptors.
Publication TypeJournal Article
Year of Publication2014
AuthorsBai J, Blot K, Tzavara E, Nosten-Bertrand M, Giros B, Otani S
JournalCereb Cortex
Volume24
Issue4
Pagination945-55
Date Published2014 Apr
ISSN1460-2199
KeywordsAction Potentials, Animals, Animals, Newborn, Dopamine, Dopamine Agents, Dopamine Plasma Membrane Transport Proteins, Electric Stimulation, Evoked Potentials, In Vitro Techniques, Long-Term Synaptic Depression, Male, Neural Inhibition, Neurotransmitter Agents, Prefrontal Cortex, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1
Abstract

In rat prefrontal cortex (PFC), long-term depression induced by low-frequency single stimuli has never been studied. Combined with the well-documented involvement of dopamine transporters (DATs) in the regulation of PFC-dependent cognitive processes, it is important to test whether this form of plasticity can be modulated by DAT activity in the PFC. Here, we show first that prolonged 3-Hz stimuli successfully induced synaptic depression in rat PFC slices whose induction depended on endogenous stimulation of D1-like and D2-like receptors and the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This depression was found to be significantly impaired by selective inhibition of the DAT by GBR12909 (1-200 nM) or GBR12935 (100 nM). The excess amount of extracellular dopamine caused by DAT inhibition acted critically on D1-like receptors to impair depression. Furthermore, this impairment by GBR12 909 was cancelled by the allosteric-positive mGluR5 modulator CDPPB, the drug known to reverse hyperdopaminergia-induced abnormal PFC activity, and the associated cognitive disturbances. Finally, these induction, impairment, and restoration of synaptic depression were correlated by an inverted-U shape manner with the phosphorylation level of ERK1/2. We suggest that abnormal increases of the extracellular dopamine level by DAT inhibition impair synaptic depression in the PFC through over-stimulation of D1-like receptors.

DOI10.1093/cercor/bhs376
Alternate JournalCereb. Cortex
PubMed ID23236206

  • Douglas Hospital
  • Dobell Pavillion
  • Brain imaging centre