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

George, Brianna; Barth, Samuel H.; Kuiper, Lindsey B.; Holleran, Katherine M.; Lacy, Ryan T.; Raab‐Graham, Kimberly F.; Jones, Sara R.

doi:10.1038/s41386-021-01035-0

Cited by 37 publications

(40 citation statements)

References 94 publications

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“…Our group has recently shown that extended heroin self-administration leads to increased dopamine release under 'burst-like' stimulation in female, but not male, rats [30]. While these previous results may appear contradictory when compared to current findings, some methodological differences may account for differing results.…”

Section: Discussioncontrasting

confidence: 83%

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Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens

Dawes

Peck

2022

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Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-hrs, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. After one day of withdrawal, male rats exhibited lower basal extracellular levels of dopamine as well as reduced dopaminergic responses to a heroin challenge (0.1 mg/kg/inf, IV). Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats have reduced stimulated dopamine release during tonic-like, single-pulse stimulations but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor activity was increased following heroin self-administration. These results reveal a marked low dopamine state following heroin-exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.

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Section: Discussioncontrasting

confidence: 83%

“…and xylazine (10 mg/kg, i.p.) and implanted with a chronic indwelling jugular catheter as described previously [30,31]. Immediately following the surgery, rats were administered meloxicam (1 mg/kg, s.c.) as a postsurgical anesthetic and single housed in custom chambers that functioned as both a housing cage and operant chamber.…”

Section: Methodsmentioning

confidence: 99%

Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens

Dawes

Peck

2022

Preprint

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“…Furthermore, sex differences have been observed across a variety of dopamine-dependent behaviors in mice and rats ( Zachry et al, 2019 ; Kutlu et al, 2020 ; Chen et al, 2021 ). For example, female rats display a faster acquisition rate and elevated responding during drug self-administration ( Lynch and Carroll, 1999 ; George et al, 2021 ). Female mice also exhibit higher levels of conditioned freezing relative to males during fear conditioning ( Dubroqua et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…The aforementioned research was primarily performed in male subjects; however, increasing evidence highlights sex differences in behavioral responding. Across studies, female subjects display augmented behavioral responses compared with males, including higher locomotor activity, faster latency, and elevated conditioned responding ( Lynch and Carroll, 1999 ; Dubroqua et al, 2011 ; Eubig et al, 2014 ; Scholl et al, 2019 ; Stringfield et al, 2019 ; Zachry et al, 2019 ; Kutlu et al, 2020 ; Bishnoi et al, 2021 ; Chen et al, 2021 ; George et al, 2021 ; Knight et al, 2021 ). Furthermore, prior research has identified sex differences in dopamine neuron activity and release ( Xiao and Becker, 1994 ; Walker et al, 2000 ; McArthur et al, 2007 ; Becker and Chartoff, 2019 ; Brundage et al, 2021 ; Zachry et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, prior research has identified sex differences in dopamine neuron activity and release ( Xiao and Becker, 1994 ; Walker et al, 2000 ; McArthur et al, 2007 ; Becker and Chartoff, 2019 ; Brundage et al, 2021 ; Zachry et al, 2021 ). These differences in dopamine transmission between males and females could account for the observed sex differences in dopamine-dependent behaviors ( Lynch and Carroll, 1999 ; Dubroqua et al, 2011 ; Eubig et al, 2014 ; Pitchers et al, 2015 ; Stringfield et al, 2019 ; Zachry et al, 2019 ; Kutlu et al, 2020 ; Chen et al, 2021 ; George et al, 2021 ). However, it is not known whether sex differences during Pavlovian learning are accompanied by distinct patterns of dopamine signaling.…”

Section: Introductionmentioning

confidence: 99%

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