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

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 (I M ) regulates the excitability of DA VTA neurons. Zinc (Zn 2+ ) contributes to the regulation of neuronal excitation as a neuromodulator. In the present study, we investigated zinc effect on the properties of I M and the spontaneous firing frequency of DA VTA neurons. The standard deactivation protocol was used to measure I M during voltage-clamp recording with a hyperpolarizing voltage step to ﹣40 mV from a holding potential (V H ) of ﹣25 mV. Zn²⁺ (100 μM) inhibited I M amplitude and I M recovered completely from the inhibition after the washout of Zn2+. Zn2+ inhibited I M in a concentration-dependent manner (IC50: 5.8 μM). When hyperpolarizing voltage steps were given to ﹣65 mV (in 10 mV increments) from a V H of ﹣25 mV, Zn 2+ (100 μM) reduced IM amplitude at each voltage and zinc inhibition of IM was not voltage-dependent. Zn 2+ increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner, suggesting that Zn 2+ causes excitation of DA VTA neurons through an action on I M . I M of DA VTA neurons was inhibited by 100 μM divalent cations in increasing order of potency: Ba 2+ (16%) < Co 2+ (25%) < Ni 2+ (40%) < Cd 2+ (59%) < Zn 2+ (67%). These results suggest that Zn 2+ may exert physiologically significant regulation of neuronal excitability in DA VTA neurons.