Characterization of M-Current in Ventral Tegmental Area Dopamine Neurons

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Abstract
M-current ( IM) is a voltage-gated potassium current (KCNQ type) that affects neuronal excitability and is modulated by some drugs of abuse. Ventral tegmental area (VTA) dopamine (DA) neurons are important for the reinforcing effects of drugs of abuse. Therefore we studied IMin acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure IMduring voltage-clamp recording with hyperpolarizing voltage steps to −65 mV (in 10-mV increments) from a holding potential of −25 mV. IMamplitude was voltage dependent and maximal current amplitude was detected at −45 mV. The deactivation time constant of IMwas voltage dependent and became shorter at more negative voltages. The IM/KCNQ antagonist XE991 (0.3–30 μM) caused a concentration-dependent reduction in IMamplitude with an IC50of 0.71 μM. Tetraethylammonium (TEA, 0.3–10 mM) caused a concentration-dependent inhibition of IMwith an IC50of 1.56 mM. In current-clamp recordings, all DA VTA neurons were spontaneously active. Analysis of evoked action potential shape indicated that XE991 (1–10 μM) reduced the fast and slow components of the spike afterhyperpolarization (AHP) without affecting the middle component of the AHP. Action potential amplitude, duration, and threshold were not affected by XE991. In addition, 10 μM XE991 significantly shortened the interspike intervals in evoked spike trains. In conclusion, IMis active near threshold in DA VTA neurons, is blocked by XE991 (10 μM) and TEA (10 mM), may contribute to the shape of the AHP, and may decrease excitability of these neurons.