Characterization of M-current in ventral tegmental area dopamine neurons

Abstract

M-current (I(M)) 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 I(M) in acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure I(M) during voltage-clamp recording with hyperpolarizing voltage steps to -65 mV (in 10-mV increments) from a holding potential of -25 mV. I(M) amplitude was voltage dependent and maximal current amplitude was detected at -45 mV. The deactivation time constant of I(M) was voltage dependent and became shorter at more negative voltages. The I(M)/KCNQ antagonist XE991 (0.3-30 microM) caused a concentration-dependent reduction in I(M) amplitude with an IC(50) of 0.71 microM. Tetraethylammonium (TEA, 0.3-10 mM) caused a concentration-dependent inhibition of I(M) with an IC(50) of 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 microM) 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 microM XE991 significantly shortened the interspike intervals in evoked spike trains. In conclusion, I(M) is active near threshold in DA VTA neurons, is blocked by XE991 (10 microM) and TEA (10 mM), may contribute to the shape of the AHP, and may decrease excitability of these neurons.