This study examined the effects of Acamprosate, Naltrexone, and CaCl2 on cognitive flexibility and synaptic function in mice following chronic-intermittent ethanol (CIE) exposure or operant alcohol self-administration. Mice exposed to CIE exhibited deficits in attentional set-shifting tasks and novel object recognition that were recovered with treatment of Acamprosate, CaCl2, or Naltrexone. Operant drinking mice also showed deficits in attentional set-shifting that were prevented by Acamprosate. Following operant drinking, mice had increased NMDA:AMPA ratios in neurons that were reversed by Acamprosate. The study suggests these drugs can help recover cognitive

1. Effects of Acamprosate, Naltrexone and CaCl2 on cognitive flexibility and synaptic function in mice following
chronic-intermittent ethanol (CIE) exposure or operant alcohol self-administration
Aarron Phensy, Grishma Pradhan, Rohith Kandunuri, Hannah Fang, Amogh Singhal, Sven Kroener
School of Behavioral and Brain Sciences, The University of Texas at Dallas
SUMMARY
Operant - Electrophysiology
548.21
CIE -
Attentional
Set-Shifting –
Digging Task
CIE –
Attentional
Set-Shifting
Visual Cue-Based
CIE - Novel Object
Recognition
Operant - Attentional Set-Shifting
Animals required significantly more
trials to meet criterion for an
attentional set-shifting task following
CIE treatment. Acamprosate, CaCl
and Naltrexone were all successful in
recovering this deficit
CIE animals show deficits
during IDR2 as well as EDR,
suggesting additional
cognitive deficits.
These changes were
prevented by both
Acamprosate and CaCl
treatment
CIE has no effect on
normal patterns of
social interaction
CIE treatment resulted in a deficit in novel
object recognition which was recovered with
treatment of Acamprosate, CaCl and
Naltrexone
Animals who went through operant
drinking showed deficits in their
ability to shift their attention to a
visual cue during an attentional set-
shifting task. Treatment with
acamprosate prevented this deficit.
Following operant drinking and 3
or 4 days of withdrawal, animals
show increased in NMDA:AMPA
ratios in layer 5 pyramidal cells.
This is reversed by acamprosate
The frequency or amplitude o spontaneous
EPSCs is not affected by moderate levels of
alcohol drinkingCIE – Social Interaction
Alcohol addiction is a downward spiral in which loss of cognitive control over decision making can
result in repeated abuse. Mice that have been given chronic-intermittent ethanol (CIE) exposure
exhibit a decrease in performance in PFC-dependent tasks such as attentional set-shifting tasks.
Acamprosate is one of the leading drugs prescribed in order to maintain abstinence of alcohol and
can prevent these cognitive deficits in mice. Here we examine if CaCl, a suspect active moiety in
Acamprosate as well as the opioid-antagonist Naltrexone can also prevent cognitive deficits in
CIE exposed mice.
Evidence suggests that loss of cognitive control is due to maladaptive synaptic plasticity in the
prefrontal cortex. We have previously shown that following chronic-intermittent ethanol (CIE)
treatment, mice exhibit increased NMDA function in layer 5 pyramidal neurons as well as
increased excitability. However treatment with Acamprosate did not correct this change.
Importantly, alcohol dependence is usually a learned behavior. Here we examine cognitive as well
as synaptic changes following an operant alcohol exposure paradigm as well as the effects of
Acamprosate in this paradigm.
 C57 mice began alcohol exposure on one of the two timelines described below starting at PND 80
 Mice were food restricted to 85% of their baseline weight for the attentional set-shifting task
 During the treatment period mice were given injections of either saline, 200mg/kg Acamprosate, 147mg/kg
CaCl, or 10mg/kg Naltrexone twice a day for three days
 Following treatment, mice went through a battery of behavioral tests or were sacrificed for
electrophysiological recordings
 Whole cell patch clamp recordings in layer 5 pyramidal cells of the mPFC layer 2/3 were performed in the
presence of picrotoxin to study alterations in glutamatergic synaptic transmission
METHODS
INTRODUCTION
Chronic-Intermittent Ethanol (CIE) Timeline
Operant Drinking Timeline
• Chronic-intermittent ethanol exposure results in cognitive deficits in mice as revealed through
two different attentional set-shifting tasks, as well as a novel object recognition task.
Performance in all three tasks was able to be restored if either Acamprosate, CaCl or Naltrexone
were given during withdrawal.
• CIE did not impact the normal pattern of social interactions in mice
• Operant alcohol drinking also resulted in cognitive deficits as measured via the attentional set
shifting (shift-to-cue) task. This deficit was ameliorated with Acamprosate treatment.
• Operant alcohol exposure lead to an increase in NMDA function which, unlike previously
demonstrated shifts induced by CIE (Hu et al., 20015), was reversed by treatment with
Acamprosate.