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Sex differences have been observed in mania phenotypes in humans. However the mechanisms underlying this difference are poorly understood. Activating the lateral hypothalamus is implicated in manic-like behaviors in rodents. Using newly established lateral hypothalamus kindled (LHK) rat mania model, we investigated sex differences of manic-like behaviors and its correlation with voluntary ethanol intake. We stimulated the lateral hypothalamus bilaterally in the male and female Wistar rats over five consecutive days. We recorded and quantified kindling-induced behaviors for each individual animal. We also assessed ethanol consumption using a two-bottle choice ethanol drinking as well as circadian locomotor activity counts daily throughout the experiment. We found notable sex differences in several aspects of manic-like behaviors during kindling. Males exhibited a significantly increased locomotor activity during the light phase, and reduced rest interval. On the other hand, females displayed significantly higher ethanol consumption and more frequent rearing behavior. However, no sex differences were present in the duration of sexual, feeding or grooming behaviors or in dark-phase activity counts. The excessive alcohol intake in LHK female rats is reminiscent of clinically reported sex differences in bipolar patients while the other phenotypic sex differences such as rearing and locomotor activity are less clearly described in clinical studies. Overall, our results lend further evidence for the validity of the LHK rat as a useful model to study brain region-specific molecular changes during mania and its correlation with alcohol use disorders.

Sex differences in mania phenotype and ethanol consumption in the lateral hypothalamic kindled rat model