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

Abstract

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