title: Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice.
abstract: BACKGROUND
  Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown.
  
  
  OBJECTIVE
  This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2).
  
  
  METHODS
  Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9% ethanol + 2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0-1.7 μg/side) in PFC, NAC, or AMY prior to self-administration.
  
  
  RESULTS
  pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions.
  
  
  CONCLUSIONS
  Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, CB #7178, Thurston Bowles Building, Chapel Hill, NC, 27599, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Faccidomo
authors.forename: Michael C
authors.initials: MC
authors.lastname: Salling
authors.forename: Christina
authors.initials: C
authors.lastname: Galunas
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Hodge
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage* / Q000494:pharmacology; D003216:Conditioning, Operant; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration
chemical_list: D002492:Central Nervous System Depressants; D011480:Protease Inhibitors; C424127:SL 327; D000607:Aminoacetonitrile; D000431:Ethanol; D048049:Extracellular Signal-Regulated MAP Kinases