TY - JOUR

T1 - The pan-Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo

AU - Hansen, Henrik H

AU - Weikop, Pia

AU - Mikkelsen, Maria D

AU - Rode, Frederik

AU - Mikkelsen, Jens D

N1 - © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2017/1

Y1 - 2017/1

N2 - Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.

AB - Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo.

KW - Animals

KW - Anticonvulsants

KW - Biomarkers

KW - Carbamates

KW - Corpus Striatum

KW - Cortical Excitability

KW - Dopamine Antagonists

KW - Drug Interactions

KW - Gene Expression Regulation

KW - Haloperidol

KW - Injections, Intraventricular

KW - KCNQ Potassium Channels

KW - Male

KW - Membrane Transport Modulators

KW - Nerve Tissue Proteins

KW - Neurons, Afferent

KW - Neurons, Efferent

KW - Nucleus Accumbens

KW - Phenylenediamines

KW - Protein Subunits

KW - Proto-Oncogene Proteins c-fos

KW - Rats, Wistar

KW - Synaptic Transmission

KW - Journal Article

U2 - 10.1111/bcpt.12636

DO - 10.1111/bcpt.12636

M3 - Journal article

C2 - 27377794

VL - 120

SP - 46

EP - 51

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 1

ER -