Ethanol Inhibition of M-Current and Ethanol-Induced Direct Excitation of Ventral Tegmental Area Dopamine Neurons

Abstract

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 (I(M)) regulates action potential generation through fast and slow afterhyperpolarization phases. In the present study we thus examined whether ethanol inhibition of I(M) contributes to the excitation of DA VTA neurons using nystatin-perforated patch current- and voltage-clamp recordings. Ethanol (20-120 mM) reduced I(M) 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 I(M) with a slope value of 1.3. Specific I(M) inhibition by XE991 (0.3-10 microM) increased spontaneous firing frequency which correlated positively with I(M) inhibition with a slope value of 0.5. In the presence of 10 muM XE991, a concentration that produced maximal inhibition of I(M), 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 I(M) 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.

The mechanism of ethanol action on midbrain dopaminergic neuron firing: a dynamic-clamp study of the role ofIhand GABAergic synaptic integration

“…3Bb). The non-I h effects of ethanol may be mediated by barium-sensitive potassium currents (McDaid et al 2008) and/or the M current (Koyama et al 2007). Fig.…”

“…Okamoto et al (2006) demonstrated a clear link between ethanol-induced increases in the firing of mouse pacemaker DA neurons in vitro and the hyperpolarization-activated and cyclic nucleotidegated (HCN) channel current I h . In addition to its effects on I h , ethanol may also modify firing in DA VTA neurons through reduction of a barium-sensitive potassium current (Appel et al 2003;McDaid et al 2008) and M current (Koyama et al 2007).…”

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…EtOH also decreases M-current (Koyama et al, 2007), and the effect of ACD on M-current is unknown. M-current is a voltage dependent, sustained potassium current that affects the firing frequency of dopaminergic VTA neurons (Koyama and Appel, 2006b).…”

“…A study of the effects of EtOH on the ion channel responsible for M-current is one example of the difficulty in cataloging the effects of agents on ionic currents and then postulating a functional role for those currents on cell activity. EtOH reduces M-current of dopaminergic VTA neurons in a concentration-dependent manner (Koyama et al, 2007), but the selective M-current blocker XE-991 did not significantly reduce EtOH-induced excitation (Koyama et al, 2007). The effects of EtOH on M-current may be physiologically important in some processes, (for example, adaptation to chronic EtOH exposure), modulation of M-current does not alter the acute excitatory effect of EtOH.…”

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Neuronal M-current is a subthreshold voltage-gated K þ current encoded by Kv7/KCNQ channels that modulate firing frequency of mesencephalic dopamine neurons 14 and are functionally coupled to dopamine D2 receptors, providing essential modulatory inputs to their striatal and limbic targets 15,16 . Both Kv7/KCNQ channels and GHS-R are expressed in the SNc, hippocampus, dorsal root ganglion (DRG), hypothalamus and cortex 11,15,[17][18][19][20][21][22][23] .…”