The Journal of Neuroscience, April 1, 2003, 23(7):2686
Dopamine D1-Class Receptors Selectively Modulate a Slowly
Inactivating Potassium Current in Rat Medial Prefrontal Cortex
Pyramidal Neurons
Yan
Dong1 and
Francis
J.
White2
Departments of 1 Neuroscience and
2 Cellular and Molecular Pharmacology, Finch University of
Health Sciences/The Chicago Medical School, North Chicago, Illinois
60064
The dopamine (DA) innervation of medial prefrontal cortex (mPFC)
regulates cognitive activity in a complex manner. Alterations of DA
function, particularly via the DA D1 receptor class (D1R), are
implicated in both schizophrenia and drug addiction, yet the precise
roles of DA in modulating mPFC excitability remain unclear. We focused
on DA modulation of voltage-gated K+ current (VGKC)
in acutely dissociated rat mPFC pyramidal neurons. We defined three
components of the whole-cell VGKC according to biophysical and
pharmacological properties. The A-type current (IA), with rapid activation and
inactivation kinetics, was completely inactivated by prolonged holding
of the membrane potential at
40 mV and was sensitive to the
K+ channel blocker 4-aminopyridine (4-AP) but not
tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating
K+ current (ID),
with rapid activation but relatively slow inactivation, was the major
contributor to VGKC and was completely inactivated at
40 mV and
sensitive to TEA and DTX but less so to 4-AP. The very slowly
inactivating K+ current
(IK) was elicited by command steps to
more depolarized potentials from a prolonged holding potential of
40
mV and was sensitive to all three blockers. Stimulation of DA D2
receptors failed to alter any component of whole-cell VGKC. Stimulation
of DA D1Rs selectively suppressed
ID, an effect mimicked by the adenylyl
cyclase activator forskolin, the active cAMP analog Sp-cAMP, and the
protein phosphatase inhibitor okadaic acid. Inhibition of protein
kinase A (PKA) with either PKI or Rp-cAMP abolished D1R
modulation. Thus, the DA D1R/cAMP/PKA signaling pathway mediates
modulation of ID by DA in rat mPFC
pyramidal neurons.
Key words:
dopamine; prefrontal cortex; potassium current; dopamine D1 receptors; drug addiction; schizophrenia
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