Age differences in brain structural and metabolic responses to binge ethanol exposure in fisher 344 rats.

Natalie M Zahr, Edith V Sullivan, Kilian M Pohl, Adolf Pfefferbaum

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2021 Jan

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An overarching goal of our research has been to develop a valid animal model of alcoholism with similar imaging phenotypes as those observed in humans with the ultimate objective of assessing the effectiveness of pharmacological agents. In contrast to our findings in humans with alcohol use disorders (AUD), our animal model experiments have not demonstrated enduring brain pathology despite chronic, high ethanol (EtOH) exposure protocols. Relative to healthy controls, older individuals with AUD demonstrate accelerating brain tissue loss with advanced age. Thus, this longitudinally controlled study was conducted in 4-month old (equivalent to ~16-year-old humans) and 17-month old (equivalent to ~45-year-old humans) male and female Fisher 344 rats to test the hypothesis that following equivalent alcohol exposure protocols, older relative to younger animals would exhibit more brain changes as evaluated using in vivo structural magnetic resonance imaging (MRI) and MR spectroscopy (MRS). At baseline, total brain volume as well as the volumes of each of the three constituent tissue types (i.e., cerebral spinal fluid (CSF), gray matter, white matter) were greater in old relative to young rats. Baseline metabolite levels (except for glutathione) were higher in older than younger animals. Effects of binge EtOH exposure on brain volumes and neurometabolites replicated our previous findings in Wistar rats and included ventricular enlargement and reduced MRS-derived creatine levels. Brain changes in response to binge EtOH treatment were more pronounced in young relative to older animals, negating our hypothesis. Higher baseline glutathione levels in female than male rats suggest that female rats are perhaps protected against the more pronounced changes in CSF and gray matter volumes observed in male rats due to superior metabolic homeostasis mechanisms. Additional metabolite changes including low inositol levels in response to high blood alcohol levels support a mechanism of reversible osmolarity disturbances due to temporarily altered brain energy metabolism.

Citation

Natalie M Zahr, Edith V Sullivan, Kilian M Pohl, Adolf Pfefferbaum. Age differences in brain structural and metabolic responses to binge ethanol exposure in fisher 344 rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2021 Jan;46(2):368-379