Studying Sex Differences in Rodent Models of Addictive Behavior

Radke, Anna K.; Sneddon, Elizabeth A.; Monroe, Sean C

doi:10.1002/cpz1.119

Cited by 34 publications

(18 citation statements)

References 240 publications

(247 reference statements)

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“…There are sex differences in the role of the IL in renewal of appetitive Pavlovian conditioned responding (Anderson and Petrovich, 2018a,b). Sex differences in behavioral strategies could lead to differential effects of neural manipulations (Radke et al, 2021;Shansky and Murphy, 2021). We observe similar levels of renewal (Brown and Chaudhri, 2021) and reinstatement (LeCocq and Chaudhri, 2021) of appetitive Pavlovian conditioned responding in male and female rats.…”

Section: Discussionsupporting

confidence: 52%

Corticostriatal Suppression of Appetitive Pavlovian Conditioned Responding

2021

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The capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic (IL) cortex to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behavior. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown, and the psychological mechanisms involved in response suppression following extinction are unclear. We trained male Long Evans rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 ml per CS) in a specific context, and then following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilateral, optogenetic stimulation of the IL-to-NAcS circuit selectively during CS trials suppressed renewal. In a separate experiment, IL-to-NAcS stimulation suppressed CS responding regardless of prior extinction and impaired extinction retrieval. Finally, IL-to-NAcS stimulation during the CS did not suppress the acquisition of Pavlovian conditioning but was required for the subsequent expression of CS responding. These results are consistent with multiple studies showing that the IL-to-NAcS neural circuit is involved in the suppression of operant cocaine-seeking, extending these findings to appetitive Pavlovian cues. The suppression of appetitive Pavlovian responding following IL-to-NAcS circuit stimulation, however, does not appear to be an extinction-dependent process.

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Section: Discussionsupporting

confidence: 52%

Corticostriatal Suppression of Appetitive Pavlovian Conditioned Responding

2021

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“…If the interaction is significant, then a claim can be made that the sexes responded differently to the treatment. Comparing the treated and control groups within each sex, in other words disaggregating the data by sex and testing for effects of treatment separately in females and males, does not test whether the sexes responded differently; that is, it does not test whether the magnitude of the response differs between females and males ( Gelman and Stern, 2006 ; Makin and Orban de Xivry, 2019 ; Maney, 2016 ; Nieuwenhuis et al, 2011 ; Radke et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Reporting and misreporting of sex differences in the biological sciences

Garcia-Sifuentes

Maney

2021

eLife

157

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As part of an initiative to improve rigor and reproducibility in biomedical research, the U.S. National Institutes of Health now requires the consideration of sex as a biological variable in preclinical studies. This new policy has been interpreted by some as a call to compare males and females with each other. Researchers testing for sex differences may not be trained to do so, however, increasing risk for misinterpretation of results. Using a list of recently published articles curated by Woitowich et al. (eLife, 2020; 9:e56344), we examined reports of sex differences and non-differences across nine biological disciplines. Sex differences were claimed in the majority of the 147 articles we analyzed; however, statistical evidence supporting those differences was often missing. For example, when a sex-specific effect of a manipulation was claimed, authors usually had not tested statistically whether females and males responded differently. Thus, sex-specific effects may be over-reported. In contrast, we also encountered practices that could mask sex differences, such as pooling the sexes without first testing for a difference. Our findings support the need for continuing efforts to train researchers how to test for and report sex differences in order to promote rigor and reproducibility in biomedical research.

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“…There has been a recent surge of interest in characterizing aversion-resistant drinking in male and female rodents across different paradigms (Radke et al, 2021b). Although the current study is the first to characterize sex differences in footshock-resistant responding in an operant task, one study examining EtOH conditioned place preference (CPP) found that experience with a footshock on the EtOH-paired side reduced preference in male but not female mice (Xie et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

Sneddon

Fennell

Bhati

et al. 2022

Preprint

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Background: One characteristic of alcohol use disorder (AUD) is compulsive drinking, or drinking despite negative consequences. When quinine is used to model such aversion resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol (EtOH) mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in EtOH than males. Here, we aimed to determine if this female vulnerability to aversion resistant drinking behavior is similarly observed when footshock punishment is used. Methods: Male and female C57BL/6J mice were trained to respond for 10% EtOH in an operant task on a fixed ratio 3 schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 mA footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 to 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock. Results: Males and females continued to respond for 10% EtOH when paired with a 0.25 mA footshock. Females alone continued to respond for EtOH when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Finally, footshock sensitivity in the flinch, jump, vocalize test did not differ by sex. Conclusions: Females continue to respond for 10% EtOH despite a 0.35 mA footshock and this behavior is not due to differences in footshock sensitivity between males and females. These results suggest that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. These results add to the literature characterizing aversion resistant alcohol drinking behaviors in females.

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Studying Sex Differences in Rodent Models of Addictive Behavior

Cited by 34 publications

References 240 publications

Corticostriatal Suppression of Appetitive Pavlovian Conditioned Responding

Corticostriatal Suppression of Appetitive Pavlovian Conditioned Responding

Reporting and misreporting of sex differences in the biological sciences

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

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