Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

Abstract

Rationale Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT+/+ (regular functioning), SERT+/− (50% transporter reduction) and SERT−/− (complete reduction). Objectives We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption. Methods An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s. Results F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT−/− females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype. Conclusions These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.

Investigating social housing: The effects of isolation on rodent ethanol consumption

“…While anxiety and hyperactivity are not mutually exclusive, we chose to refrain from forming a specific hypothesis related to housing on the SAT, and leave this largely exploratory. We did expect to see greater exploration, and less anxiety in the female animals compared to the males, as previous research has shown that female rats tend to be more active (Healy et al, 2022;Hussain et al, 2022;Nelson et al, 2019;).…”

“…We also expected that the female rats would consume more ethanol overall (and show a higher preference) than the male rats during the IATBCP, owing to the previous findings of the literature above (Hussain et al, 2022;Moore & Lynch, 2015).…”

“…A review of sex bias in rat research found that female rats are overwhelmingly under-researched in many areas of neuroscience, and that this holds significant implications for the findings (or perhaps the lack thereof) that these studies have claimed (Thorne et al, 2022). Female rats show consistently different patterns of behaviour to male rats, in a variety of tasks including ethanol consumption (Moore & Lynch, 2015), locomotor activity (Healey et al, 2022;Hussain et al, 2022), and anxiety paradigms (Domonkos et al, 2017;Healey et al, 2022;Kinley et al, 2021). The dismissal of using female rats in experimental samples is a detriment to research for much the same reasons as described above; by obfuscating one half of the potential sample, we are deliberately muddying conclusions drawn for the sake of data and experimental 'cleanliness'.…”

“…Based on such literature as detailed above, we would expect that the male rats housed individually would consume more ethanol compared to their pair-housed counterparts (Anacker et al, 2010;Cortes-Patino et al, 2016;Hussain et al, 2022;Lesscher et al, 2015).…”

“…These findings would support both the animal literature (Anacker et al, 2010), and the human literature (Creswell, 2021;Hamilton et al, 2021;Keough et al, 2016;, that isolation increases alcohol consumption, and peer/socialised drinking moderates it. There is no specific literature to inform whether this hypothesis is appropriate for female rats, but previous general literature supports the hypothesis of a sex effect in the IATBCP (Hussain et al, 2022;Thorne et al, 2022).…”