Withdrawal from intermittent ethanol exposure increases probability of burst firing in VTA neurons in vitro.
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.
Hopf
F Woodward
FW
Ernest Gallo Clinic and Research Center, University of California San Francisco, Department of Neurology, Emeryville, CA 94608, USA.
Martin
Miquel
M
Chen
Billy T
BT
Bowers
M Scott
MS
Mohamedi
Maysha M
MM
Bonci
Antonello
A
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D000431:Ethanol / Q000009:adverse effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D017557:Ventral Tegmental Area / Q000502:physiology*
D002492:Central Nervous System Depressants; D018765:Dopamine Uptake Inhibitors; D024681:Potassium Channels, Calcium-Activated; D000431:Ethanol; D003042:Cocaine; D004298:Dopamine