Received for publication May 4, 2006.
Revised June 13, 2006.
Accepted for publication June 13, 2006.

The KCNQ opener Retigabine Inhibits the Activity of Mesencephalic Dopaminergic Systems of the Rat

Abstract

Homo- and heteromeric complexes of KCNQ subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K⁺ current with a well-established role in control of neural excitability. We investigated the effect of KCNQ channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ opener, retigabine. The effect of retigabine persisted in the presence of tetrodotoxin and simultanous blockade of GABA_A receptors, SK and I_h channels, and was potently reversed by the KCNQ channel blocker XE991, indicating a direct effect on KCNQ channels. Similarly, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of retigabine. Furthermore, retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D₂ autoreceptor antagonists. Again, the in vitro and in vivo effects of retigabine were completely reversed by pre-administration of XE991. Dual-immunocytochemistry revealed that KCNQ4 is the major KCNQ subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels.

Key words: Basal ganglia, Dopamine, KCNQ, M-current, Retigabine, Substantia nigra

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