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Enhanced heroin self-administration and distinct dopamine adaptations in female rats

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Abstract

Increasing evidence suggests that females are more vulnerable to the harmful effects of drugs of abuse, including opioids. Additionally, rates of heroin-related deaths substantially increased in females from 1999 to 2017 [1], underscoring the need to evaluate sex differences in heroin vulnerability. Moreover, the neurobiological substrates underlying sexually dimorphic responding to heroin are not fully defined. Thus, we evaluated male and female Long Evans rats on acquisition, dose-responsiveness, and seeking for heroin self-administration (SA) as well as using a long access model to assess escalation of intake at low and high doses of heroin, 0.025 and 0.1 mg/kg/inf, respectively. We paired this with ex vivo fast-scan cyclic voltammetry (FSCV) in the medial nucleus accumbens (NAc) shell and quantification of mu-opioid receptor (MOR) protein in the ventral tegmental area (VTA) and NAc. While males and females had similar heroin SA acquisition rates, females displayed increased responding and intake across doses, seeking for heroin, and escalation on long access. However, we found that males and females had similar expression levels of MORs in the VTA and NAc, regardless of heroin exposure. FSCV results revealed that heroin exposure did not change single-pulse elicited dopamine release, but caused an increase in dopamine transporter activity in both males and females compared to their naïve counterparts. Phasic-like stimulations elicited robust increases in dopamine release in heroin-exposed females compared to heroin-naïve females, with no differences seen in males. Together, our results suggest that differential adaptations of dopamine terminals may underlie the increased heroin SA behaviors seen in females.

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Fig. 1: Females show increased responding, intake, and seeking for heroin across doses, but similar rates of acquisition.
Fig. 2: Females exhibit increased responding and escalation for a low dose, 0.025 mg/kg/inf, of heroin during long access.
Fig. 3: Female rats also have increased responding for a high dose, 0.1 mg/kg/inf, of heroin on long access.
Fig. 4: Mu opioid receptor (MOR) protein levels do not differ between drug naïve or heroin-exposed male and female rats in the NAc or VTA.
Fig. 5: Heroin self-administration increased the rate of dopamine reuptake in both sexes and phasic-like dopamine release in the medial NAc shell of female rats.

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BEG, RTL, and SRJ were responsible for the study concept and design. BEG conducted all of the behavioral and voltammetry experiments and analyzed these data under the guidance of LBK and KMH. SHB conducted western blotting experiments and analyzed this data under the guidance of KRG, BEG, and SRJ drafted the manuscript. All authors provided critical revision of the manuscript for important intellectual content. All authors critically reviewed content and approved final version for publication.

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Correspondence to Sara R. Jones.

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George, B.E., Barth, S.H., Kuiper, L.B. et al. Enhanced heroin self-administration and distinct dopamine adaptations in female rats. Neuropsychopharmacol. 46, 1724–1733 (2021). https://doi.org/10.1038/s41386-021-01035-0

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