Abstract
Ventral tegmental area dopamine (DA VTA) neurons are important for the reinforcing effects of drugs of abuse such as ethanol and nicotine. We have previously shown that M-current (IM) regulates the excitability of DA VTA neurons. Zinc (Zn2+) contributes to the regulation of neuronal excitation as a neuromodulator. In the present study, we investigated zinc effect on the properties of IM and the spontaneous firing frequency of DA VTA neurons. The standard deactivation protocol was used to measure IM during voltage-clamp recording with a hyperpolarizing voltage step to ﹣40 mV from a holding potential (VH) of ﹣25 mV. Zn2+ (100 μM) inhibited IM amplitude and IM recovered completely from the inhibition after the washout of Zn2+. Zn2+ inhibited IM in a concentration-dependent manner (IC50: 5.8 μM). When hyperpolarizing voltage steps were given to ﹣65 mV (in 10 mV increments) from a VH of ﹣25 mV, Zn2+ (100 μM) reduced IM amplitude at each voltage and zinc inhibition of IM was not voltage-dependent. Zn2+ increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner, suggesting that Zn2+ causes excitation of DA VTA neurons through an action on IM. IM of DA VTA neurons was inhibited by 100 μM divalent cations in increasing order of potency: Ba2+ (16%) 2+ (25%) 2+ (40%) 2+ (59%) 2+ (67%). These results suggest that Zn2+ may exert physiologically significant regulation of neuronal excitability in DA VTA neurons.
Highlights
The ventral tegmental area dopamine (DA VTA) neurons send axons which synapse in the nucleus accumbens (NAcb) [1] and the excitation of DA VTA neurons results in increased dopamine release in the NAcb [2]-[4], which is important for the reinforcing effects of drugs of abuse [5] [6]
We estimate the maximal inhibition of IM by zinc to be about 62% with 38% of this current remaining unblocked by Zn2+ in DA VTA neurons
Previous immunohistochemical studies have shown that KCNQ2 and KCNQ4 channel proteins are present in VTA neurons [11] [12]
Summary
The ventral tegmental area dopamine (DA VTA) neurons send axons which synapse in the nucleus accumbens (NAcb) [1] and the excitation of DA VTA neurons results in increased dopamine release in the NAcb [2]-[4], which is important for the reinforcing effects of drugs of abuse [5] [6]. Among the five types of channel subunits (KCNQ1 to 5) [10], immunohistochemical studies have shown that the KCNQ2 and KCNQ4 channel proteins are present in VTA neurons [11] [12]. DA VTA neurons have intrinsic pacemaker activity and a recent study has reported that the KCNQ4 channel subunit is the major component of IM in DA VTA neurons and critical for the excitability of these neurons [13]. KCNQ channels (IM) of DA VTA neurons may be a critical factor in the mediation of the reinforcing effect of drugs of abuse
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