Different Sensitivity to Ethanol and Sucrose in DAT and SERT Knockout Rats

BackgroundDopamine and serotonin are key regulators of reward sensitivity, yet their distinct roles in motivating natural (e.g., sucrose) versus drug (e.g., ethanol) rewards remain unclear. Understanding these mechanisms could help explain individual variability in reward processing relevant to substance use vulnerability. MethodsWe assessed reward sensitivity in dopamine transporter (DAT) and serotonin transporter (SERT) knockout (KO) rats using both home cage (two-bottle choice for sucrose and ethanol) and operant paradigms (Pavlovian and instrumental learning). ResultsDAT KO rats showed lower sucrose preference (-27% for 2%, -13% for 4%) and intake (-42% for 4%), diminished Pavlovian responding for sucrose (-68%), and slower acquisition of sucrose-taking behavior ([~]+30 days) compared to WT rats. DAT KO rats also showed reduced ethanol preference in the home cage (-16%) despite an unchanged intake. Furthermore, operant performed was markedly reduced operant performance after the sucrose-to-ethanol transition (-83%), with no increase in ethanol-taking following sucrose exposure (0% change), unlike WT controls (+41%). SERT KO rats presented reduced sucrose preference (-5%) and intake (-46%) for the 4% solution only. In addition, SERT KO rats also showed reduced Pavlovian sucrose responding (- 28%) and slower acquisition of sucrose-taking ([~]+30 days) but intact responding and learning for ethanol. In the home cage, they displayed lower ethanol preference (-35%) without significant change in operant ethanol performance. A modest overall increase in ethanol-taking was seen post-sucrose in both SERT KO and WT, but without genotype-specific effects. Conclusion and ImplicationsDAT deletion broadly impaired sensitivity for both natural sucrose and ethanol rewards, particularly under effortful or devalued conditions. In contrast, SERT deletion produced more selective impairments by disrupting sucrose operant responding and moderately reducing ethanol reward preference. These findings reveal distinct but overlapping roles of DAT and SERT in regulating reward sensitivity, with implications for understanding individual vulnerability to substance use.