Reduced nucleus accumbens SK channel activity enhances alcohol seeking during abstinence.
The cellular mechanisms underlying pathological alcohol seeking remain poorly understood. Here, we show an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol but not sucrose self-administration. Increased firing is associated with reduced small-conductance calcium-activated potassium channel (SK) currents and decreased SK3 but not SK2 subunit protein expression. Furthermore, SK activation ex vivo produces greater firing suppression in NAcb core neurons from alcohol- versus sucrose-abstinent rats. Accordingly, SK activation in the NAcb core significantly reduces alcohol but not sucrose seeking after abstinence. In contrast, NAcb shell and lateral dorsal striatal firing ex vivo are not altered after abstinence from alcohol, and SK activation in these regions has little effect on alcohol seeking. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence.
Hopf
F Woodward
FW
Ernest Gallo Clinic and Research Center, University of California, San Francisco, San Francisco, CA 94608, USA. woody@gallo.ucsf.edu
Bowers
M Scott
MS
Chang
Shao-Ju
SJ
Chen
Billy T
BT
Martin
Miguel
M
Seif
Taban
T
Cho
Saemi L
SL
Tye
Kay
K
Bonci
Antonello
A
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000187:drug effects; D000081410:Germinal Center Kinases; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration / Q000379:methods; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D000099317:Hippo Kinases
D001030:Apamin; D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002492:Central Nervous System Depressants; D000431:Ethanol; D000081410:Germinal Center Kinases; D024681:Potassium Channels, Calcium-Activated; D017346:Protein Serine-Threonine Kinases; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013395:Sucrose; D013549:Sweetening Agents; C496901:Kcnn3 protein, rat; C481222:Slk protein, rat; D000099317:Hippo Kinases; C102635:1-ethyl-2-benzimidazolinone