The Effects of Zinc and Other Divalent Cations on M-Current in Ventral Tegmental Area Dopamine Neurons

Ethanol-induced excitation of ventral tegmental area dopamine (DA VTA) neurons is thought to be critical for the reinforcing effects of ethanol. Although ligand-gated ion channels are known to be the targets of ethanol, ethanol modulation of voltage-dependent ion channels of central neurons has not been well studied. We have demonstrated that ethanol excites DA VTA neurons by the reduction of sustained K+ currents and recently reported that M-current ( IM) regulates action potential generation through fast and slow afterhyperpolarization phases. In the present study we thus examined whether ethanol inhibition of IM contributes to the excitation of DA VTA neurons using nystatin-perforated patch current- and voltage-clamp recordings. Ethanol (20–120 mM) reduced IM in a concentration-dependent manner and increased the spontaneous firing frequency of DA VTA neurons. Ethanol-induced increase in spontaneous firing frequency correlated positively with ethanol inhibition of IM with a slope value of 1.3. Specific IM inhibition by XE991 (0.3–10 μM) increased spontaneous firing frequency which correlated positively with IM inhibition with a slope value of 0.5. In the presence of 10 μM XE991, a concentration that produced maximal inhibition of IM, ethanol still increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner. Thus we conclude that, although ethanol causes inhibition of IM and this results in some increase in the firing frequency of DA VTA neurons, another effect of ethanol is primarily responsible for the ethanol-induced increase in firing rate in these neurons.

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Characterization of M-Current in Ventral Tegmental Area Dopamine Neurons

Journal of Neurophysiology ◽

10.1152/jn.00574.2005 ◽

2006 ◽

Vol 96 (2) ◽

pp. 535-543 ◽

Cited By ~ 45

Author(s):

Susumu Koyama ◽

Sarah B. Appel

Keyword(s):

Action Potential ◽

Ventral Tegmental Area ◽

Neuronal Excitability ◽

Drugs Of Abuse ◽

Dopamine Neurons ◽

M Current ◽

Potential Shape ◽

Voltage Dependent ◽

Dependent Inhibition ◽

Ventral Tegmental

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 IM in acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure IM during voltage-clamp recording with hyperpolarizing voltage steps to −65 mV (in 10-mV increments) from a holding potential of −25 mV. IM amplitude was voltage dependent and maximal current amplitude was detected at −45 mV. The deactivation time constant of IM was voltage dependent and became shorter at more negative voltages. The IM/KCNQ antagonist XE991 (0.3–30 μM) caused a concentration-dependent reduction in IM amplitude with an IC50 of 0.71 μM. Tetraethylammonium (TEA, 0.3–10 mM) caused a concentration-dependent inhibition of IM with an IC50 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 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, IM is 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.

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