Withdrawal From Intermittent Ethanol Exposure Increases Probability of Burst Firing in VTA Neurons In Vitro

Abstract

Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I h was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…Recent studies report either no change (Trantham-Davidson et al, 2014) or an increase (Pleil et al, 2015) in AP firing in prelimbic mPFC pyramidal neurons from CIE-exposed rats and mice, respectively. Increases in neuronal excitability following chronic exposure to ethanol have also been reported in other brain areas, including the VTA (Hopf et al, 2007), nucleus accumbens (Hopf et al, 2010), hippocampus (Mulholland et al, 2011), dorsal raphe (Lowery-Gionta et al, 2014), and ventral BNST (Pleil et al, 2015). Several of these studies also reported decreases in SK channel function (Hopf et al, 2007(Hopf et al, , 2010Mulholland et al, 2011;Padula et al, 2015), suggesting that these channels are particularly sensitive to chronic ethanol exposure.…”

“…Increases in neuronal excitability following chronic exposure to ethanol have also been reported in other brain areas, including the VTA (Hopf et al, 2007), nucleus accumbens (Hopf et al, 2010), hippocampus (Mulholland et al, 2011), dorsal raphe (Lowery-Gionta et al, 2014), and ventral BNST (Pleil et al, 2015). Several of these studies also reported decreases in SK channel function (Hopf et al, 2007(Hopf et al, , 2010Mulholland et al, 2011;Padula et al, 2015), suggesting that these channels are particularly sensitive to chronic ethanol exposure. Although downregulation of SK channel function would be expected to alter AP firing, AHPs are also generated by KCNQ channels that mediate M-currents and HCN channels that underlie the I H current (Gu et al, 2005;Hansen et al, 2008).…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…Recent work has identified SK-type (small conductance) calcium-activated potassium channels (SK) as a novel therapeutic intervention for alcoholism (Hopf et al, 2007(Hopf et al, , 2010a(Hopf et al, , 2011Mulholland et al, 2010). Long-term alcohol intake, either operant or under intermittent-access twobottle choice, is associated with reduced SK function in the Nacc core but not Nacc shell or dorsal striatum (Hopf et al, 2010a(Hopf et al, , 2011.…”

Chronic ethanol exposure leads to divergent control of dopaminergic synapses in distinct target regions

“…The reason for this change still remains to be determined, however a recent study (Hopf et al, 2007) demonstrated that VTA neurons exhibit increased NMDA-induced bursting during ethanol withdrawal, suggesting that the alteration in DAT expression could be a homeostatic change in response to increasing amounts of dopamine released. Interestingly, we found that DAT levels in the nucleus accumbens were decreased following chronic continuous ethanol exposure.…”

“…Currently less is known of the participation of dopamine in chronic actions of ethanol, or conversely, what effects chronic ethanol exposure has on dopaminergic systems. Chronic ethanol exposure has been reported to alter dopaminergic function via modulation of the activity of VTA dopaminergic cells (Brodie, 2002;Shen, 2003;Hopf et al, 2007). In addition to somatic effects on dopaminergic neurons, a number of studies have suggested that chronic ethanol administration can alter dopaminergic function at the level of the dopamine synapse (Casu et al, 2002;Budygin et al, 2003;Budygin et al, 2007).…”