Frequency-Dependent Effects of Ethanol on Dopamine Release in the Nucleus Accumbens

Abstract

Background Ethanol is known to have excitatory effects on dopamine (DA) release, with moderate to high doses (0.5–2.5 g/kg) of acute ethanol enhancing DA neuron firing rates in the ventral tegmental area (VTA) and DA levels in the nucleus accumbens (NAc). Ethanol has also been shown to reduce DA activity, with moderate doses (1–2 g/kg) attenuating electrically evoked release, and higher doses (5 g/kg) decreasing NAc DA levels, demonstrating a biphasic effect of ethanol on DA release. The purpose of the current study was to evaluate ethanol’s inhibitory effects on NAc DA terminal release under low- and high-frequency stimulation conditions. Methods Using fast-scan cyclic voltammetry in NAc slices from C57BL/6J mice, we examined ethanol’s (40–160 mM) effects on DA release under several different stimulation parameters, varying frequency (5–125 Hz), number of pulses (1–10), and stimulation intensity (50–350 µA). Additionally, calcium concentrations were manipulated under high-frequency stimulation conditions (20 Hz, 10 pulses, 350 µA) in order to determine if ethanol’s effects were dependent upon calcium concentration, and by extension, the amount of DA release. Results Acute ethanol (40–160 mM) inhibited DA release to a greater extent under high-frequency, multiple-pulse stimulation conditions, with increased sensitivity at 5 and 10 pulses and frequencies of 20 Hz or higher. High-frequency, multiple-pulse stimulations also resulted in greater DA release compared to single-pulse release, which was controlled by reducing stimulation intensity. Under reduced DA conditions, high-frequency stimulations still showed increased ethanol sensitivity. Reducing calcium levels also decreased DA release at high-frequency stimulations, but did not affect ethanol sensitivity. Conclusions Ethanol appears to inhibit DA release at NAc terminals under high-frequency stimulation conditions that are similar to release events observed during phasic burst firing in DAergic neurons, suggesting that ethanol may provide inhibition of DA terminals selectively during phasic signaling, while leaving tonic DA terminal activity unaffected.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…Because nicotine inhibition of evoked DA release in the core was blocked by the a6 antagonist a-CtxMII (100 nM), and we have previously demonstrated that ethanol similarly decreases evoked DA release in the core (Yorgason et al, 2014), we evaluated the effects of ethanol (20-160 mM) on DA release, as well as the effects of a-CtxMII (100 nM) on ethanol inhibition of DA release in the NAc core. From our previous experimentation, we have noted no disparities in the effects of ethanol in the NAc shell or core, as we have with nicotine.…”

“…Microdialysis studies typically show a rise in DA levels, whereas voltammetry studies show a fall in evoked DA responses by both short-term nicotine and ethanol (Budygin et al, 2001;Robinson et al, 2009;Zhang et al, 2009;Yorgason et al, 2014). The disparity between these techniques is attributed, in part, to differences in measurements of tonic versus phasic DA release (Robinson et al, 2009).…”

“…The disparity between these techniques is attributed, in part, to differences in measurements of tonic versus phasic DA release (Robinson et al, 2009). We have recently demonstrated that ethanol preferentially inhibits highfrequency phasic release but not low-frequency "tonic" release (Yorgason et al, 2014). Likewise, nicotinic mechanisms regulate the frequency dependence of DA release, albeit in a different direction, with greater DA release under phasic-like conditions and decreased release under tonic-like stimulations (Exley et al, 2008).…”

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…This hypothesis is supported by a lack of direct effect of acute ethanol on DA terminals when applied using physiologically relevant doses and stimulation parameters (Budygin et al 2001). Instead, long multi-pulse electrical stimulation trains are needed to detect ethanol inhibition of DA release (Yorgason et al 2014), reinforcing the idea that recruitment of local circuitry is required. Together, these possibilities support the use of targeted stimulation methods, as utilized in this study, to probe specific mechanisms of ethanol induced release modulation in the NAc.…”

Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors

“…Not only are the biphasic effects of ethanol on dopamine release dose-dependent, but we have recently shown that the inhibitory effect of ethanol on dopamine release is dependent upon the frequency of stimulation (Yorgason et al, 2014). High and low frequency stimulations are often used to model two distinct modes of firing that occur in VTA dopamine neurons and which have differential effects on dopamine release at terminals.…”