Sex differences in conditioned orienting and the role of estradiol in addiction-related behaviors.

Abstract

Conditioned orienting response (OR) is a form of cue-directed behavior thought to indicate increased attentional and/or motivational processing of reward-associated stimuli. OR as a phenotype has been shown to predict both direct drug proclivity in female rats and behaviors indirectly related to drug proclivity in male rats, but no extant research has compared males and females in terms of their OR behavior or its notable substrates. As females are at increased risk for substance abuse, and the ovarian hormone estradiol is often cited as a driving factor for this predilection, it is important to characterize sex differences between males and females and explore what, if any, contribution estradiol has in behaviors which predict substance abuse. In these experiments, male and female rats [intact or ovariectomized (OVX) with/without estradiol replacement] were compared on a battery of behavioral tasks, including OR, novelty-seeking, attentional set-shifting, and ultrasonic vocalizations (USVs) to amphetamine treatment. Female rats, regardless of estradiol replacement, had higher OR scores than males. OR score was a predictor of attention impairments, and estradiol availability contributed to this relationship in females. Sex differences were not observed in novelty-seeking, attentional set-shifting, or USV response to amphetamine; however, estradiol replacement did alter the presentation of these behaviors.

Sex differences in cognitive flexibility are driven by the estrous cycle and stress-dependent

“…We also expected a poor performance in the light discrimination task by the control proestrus female rats, as a previous study demonstrated impaired set-shifting performance in ovariectomized female rats with 17β-estradiol treatment (Hilz et al, 2022 ). It is important to note that our results contradict two other studies, which are carried out on female rhesus monkeys and female rats, respectively, and showed that estradiol treatment improves set shifting (Voytko et al, 2009 ; Lipatova et al, 2016 ).…”

“…It is important to consider where women are in their cycle when exposed to stress and cognitive flexibility testing, as gonadal hormones can contribute to sex differences in response to stress (Becker et al, 2005 ; Oyola and Handa, 2017 ; Heck and Handa, 2019 ). Although previous studies have separately examined sex differences in cognitive flexibility (LaClair et al, 2019 ; Hilz et al, 2022 ), stress effects on cognitive flexibility (Thai et al, 2013 ; Hurtubise and Howland, 2016 ; Shields et al, 2016 ; Goldfarb et al, 2017 ; Grafe et al, 2017a ; Sullivan et al, 2019 ), and the effect of gonadal hormones on cognitive flexibility (Wallin and Wood, 2015 ; Lipatova et al, 2016 ; Hilz et al, 2022 ), many of the findings were inconsistent, and the role of the estrous cycle in stress-induced impacts on cognitive flexibility is still unknown. This study explored sex differences in cognitive flexibility using an operant strategy-shifting paradigm after either control conditions or restraint stress in freely cycling female and male rats (with estrous cycle tracking in the female rats).…”

“…Thus far, there have been limited studies exploring sex differences in cognitive flexibility, with the majority of research indicating that women require more trials for reversal learning compared to men, but that there were no sex differences in ED shifts (LaClair et al, 2019 ; Hilz et al, 2022 ). Moreover, studies exploring the effects of stress on cognitive flexibility tend to only include male subjects and are equivocal in their findings.…”

“…There have been inconsistent findings on the impacts of gonadal hormones on cognitive flexibility. For example, one rodent study has found that 17β-estradiol treatment in females leads to worse set-shifting performance compared to both males and ovariectomized control females (Hilz et al, 2022 ). However, another rodent study has shown that in ovariectomized female rats, 17β-estradiol treatment results in poorer learning in simple discrimination but improved learning in extradimensional set-shifting (Lipatova et al, 2016 ).…”

Hormonal contraceptives alter amphetamine place preference and responsivity in the intact female rat.

“…USVs were recorded throughout CPP procedures for a subset of rats ( n = 28; 5 rats did not have USV recording) and digitized with UltraSoundGate system (Avisoft Bioacoustics) using methods described in Hilz et al, 2021. USVs were recorded and analyzed using Avisoft-RECORDER and Avisoft-SASlab Pro software (Avisoft Bioacoustics).…”