title: Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice.
abstract: BACKGROUND
  The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol (EtOH) exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons.
  
  
  METHODS
  We induced alcohol dependence in mice via chronic intermittent EtOH (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices.
  
  
  RESULTS
  Chronic EtOH exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic EtOH exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor function. Moreover, CIE treatment lowered input resistance, and decreased the threshold and the after hyperpolarization of action potentials, suggesting chronic EtOH exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these EtOH-induced changes cellular function.
  
  
  CONCLUSIONS
  Acamprosate improved attentional control of EtOH exposed animals, but did not alter the concurrent changes in synaptic transmission or membrane excitability of mPFC neurons, indicating that these changes are not the pharmacological targets of acamprosate in the recovery of mPFC functions affected by chronic EtOH exposure.
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas.
authors.forename: Brett
authors.initials: B
authors.lastname: Morris
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas.
authors.forename: Angelique
authors.initials: A
authors.lastname: Carrasco
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas.
authors.forename: Sven
authors.initials: S
authors.lastname: Kroener
mesh_terms: D000077443:Acamprosate; D000200:Action Potentials / Q000187:drug effects; D000428:Alcohol Drinking / Q000503:physiopathology; D000437:Alcoholism / Q000503:physiopathology* / Q000523:psychology*; D000818:Animals; D001288:Attention / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D013654:Taurine; D000431:Ethanol; D000077443:Acamprosate
keywords: Acamprosate; Alcohol Addiction; Attentional Set-Shifting; Patch Clamp; Prefrontal Cortex