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

Abstract

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 difference in the progression of manic symptoms during acute hospitalization: A prospective pilot study

“…In our preclinical LHK rat model of mania, male rats showed a nonsignificant trend (p = .0516) toward increased sexual behavior compared with female rats (Abulseoud et al, 2015). Further studies are needed to investigate the phenomenology and neurobiological basis of sex differences in impulsive behaviors during manic episode.…”

“…In agreement with our findings, one cross‐sectional study reported that male manic patients scored significantly higher on the sexual interest item than female patients upon admission to inpatient unit (Young et al, ). In our preclinical LHK rat model of mania, male rats showed a nonsignificant trend ( p = .0516) toward increased sexual behavior compared with female rats (Abulseoud et al, ). Further studies are needed to investigate the phenomenology and neurobiological basis of sex differences in impulsive behaviors during manic episode.…”

“…We chose such a facility to collaborate with because of their expertise in diagnosis, symptom quantification and treatment of acute mania, and the large volume of patients, and equally important, because of the unrestricted hospital length of stay. We hypothesized, based upon past research on acute mania (Hendrick et al, ; Kumar & Ram, ; Viguera et al, ; Young et al, ) and our work (Abulseoud et al, ), that the presentation of acute manic symptoms is sex‐dependent. Specifically, males will exhibit more aggressive and sexual manifestations compared to females.…”

“…Sex differences, in general, stem from a complex interplay between neurobiological and psychosocial factors. To explore the neurobiological aspect, we used our newly established lateral hypothalamic‐kindled (LHK) rat mania model to examine sex differences in manic‐like behaviors during mania induction (Abulseoud et al, ) and we found that male rats exhibited more sexual behavior, significantly increased locomotor activity during the light phase, and reduced rest interval, while females displayed significantly higher ethanol consumption and more frequent rearing behaviors (Abulseoud et al, ). To test whether these results translate in a clinical model, we sought to examine sex difference in the progression of manic symptoms during acute hospitalization in an academic medical center in Turkey.…”

Antipsychotic-like effects of a neurotensin receptor type 1 agonist

“…Also, acute amphetamine treatment cannot represent the chronic symptoms of schizophrenia and bipolar disorder. Thus, it will be important to examine the effects of PD149163 in other rodent models of mania- and schizophrenia-like behaviors [65, 66]. …”