The effects of histone deacetylase inhibitors on the attentional set-shifting task performance of alcohol-dependent rats

Abstract Objectives Alcohol dependence causes extensive damage to the central nervous system, resulting in impaired brain structure and behavioral changes. Moreover, histone deacetylase (HDAC) inhibitors restrain the activity of HDAC and cause increased histone acetylation, which may be related to alcohol dependence. Methods Ethanol dependence was modelled in animals by persistent alcohol exposure and tested in the conditioned place preference (CPP) paradigm. To induce CPP, the alcohol-treated rats were given orally gradient concentration (3%, 6%, and 9% v/v) alcohol administration for 20 consecutive days. The sodium butyrate (NaB)-treated rats were injected daily. Cognitive flexibility was evaluated using an attentional set-shifting task (ASST) in which the rats performed a series of seven consecutive discriminations after the final CPP paradigm. Results Ethanol administration induced alcohol dependence behaviors, with more time spent in the ethanol-paired compartment. Compared with the CPP scores of the control group, the scores of the ethanol- and NaB-treated groups were significantly higher. In the ASST, alcohol-treated rats had significantly increased number of trials to reach criteria (TTC) in most phases, higher error rate, and lower cognitive levels compared to the control group. Moreover, the present findings demonstrated that NaB combined with ethanol caused cognitive deficits as the result of an increased number of TTC during the ASST. Conclusions The attentional/cognitive flexibility of the prefrontal cortex of alcohol-dependent rats was damaged and the NaB administration procedure itself did not produce cognitive deficits, but instead exacerbated cognitive impairment in alcohol-dependent rats.