Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency

• Published in: Alcoholism, clinical and experimental research Vol. 45; no. 5; pp. 1013 - 1027
• Main Authors: Kipp, Brian T., Nunes, Polliana T., Savage, Lisa M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-05-2021
• Subjects: Acetylcholine; Acetylcholine - metabolism; Alcohol; Alcoholism - complications; Alcoholism - metabolism; Alcoholism - physiopathology; Animal models; Animals; Antimetabolites - toxicity; Attention - drug effects; Behavior, Animal - drug effects; Brain injury; Case-Control Studies; Central Nervous System Depressants - pharmacology; Cognition; Cognitive ability; Drug abuse; Epidemiology; Ethanol; Ethanol - pharmacology; Female; Females; Gender differences; Hippocampus - drug effects; Hippocampus - metabolism; Latency; Male; Males; Memory; Microdialysis; Operant conditioning; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Pyrithiamine; Pyrithiamine - toxicity; Rats; Rodents; Sex differences; Sex Factors; Short term memory; Spatial memory; Spontaneous alternation; Thalamus; Thiamine; thiamine deficiency; Thiamine Deficiency - chemically induced; Thiamine Deficiency - complications; Thiamine Deficiency - metabolism; Thiamine Deficiency - physiopathology; Toxicity; Vitamin B; Vitamin deficiency; thiamine deficiency; acetylcholine; cognition; ethanol; spatial memory
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14594

Background
Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol‐related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models.
Methods
Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine‐induced thiamine deficiency (PTD), combined CET‐PTD, or pair‐fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant‐based attentional set‐shifting task (ASST) for the analysis of behavioral flexibility.
Results
Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET‐PTD‐treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET‐PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET‐PTD‐treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET‐PTD and PTD treatment conditions, but no sex‐specific effects were observed.
Conclusions
Although the CET and CET‐PTD‐treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.