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

Cereb Cortex. 2014 Apr;24(4):945-55. doi: 10.1093/cercor/bhs376. Epub 2012 Dec 12.


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.

Keywords: D1 receptor; dopamine transporter; executive function; prefrontal cortex; synaptic depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Animals, Newborn
  • Dopamine / metabolism
  • Dopamine Agents / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Electric Stimulation
  • Evoked Potentials / physiology
  • In Vitro Techniques
  • Long-Term Synaptic Depression / physiology*
  • Male
  • Neural Inhibition / drug effects
  • Neurotransmitter Agents / pharmacology
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / physiology*
  • Pyramidal Cells / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / metabolism*


  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Neurotransmitter Agents
  • Receptors, Dopamine D1
  • Dopamine