Females develop features of an addiction-like phenotype sooner during withdrawal than males

Towers, Eleanor Blair; Bakhti-Suroosh, Anousheh; Lynch, Wendy J.

doi:10.1007/s00213-021-05846-3

Cited by 22 publications

(37 citation statements)

References 51 publications

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“…For example, female rats self-administer higher levels of cocaine, show greater escalation of cocaine intake over time, and have a more significant disruption of diurnal control over drug intake than males under extended-access cocaine self-administration conditions, which supports an enhanced vulnerability to transition from controlled to dysregulated cocaine use in females (Lynch andTaylor, 2004, 2005;Roth and Carroll, 2004;Smith et al, 2011;Kawa and Robinson, 2019;Algallal et al, 2020). Additionally, our more recent study showed that two addiction-like features, an enhanced motivation for cocaine and compulsive cocaine use despite negative consequences, developed sooner during withdrawal from extended-access cocaine self-administration in females compared to males (following 7 versus 14 days; Towers et al, 2021). Our previous study and work from others has also shown that these addiction-like features increase, rather than decrease, in magnitude over withdrawal (Gancarz-Kausch et al, 2014;Towers et al, 2021).…”

Section: Introductionsupporting

confidence: 60%

“…Additionally, our more recent study showed that two addiction-like features, an enhanced motivation for cocaine and compulsive cocaine use despite negative consequences, developed sooner during withdrawal from extended-access cocaine self-administration in females compared to males (following 7 versus 14 days; Towers et al, 2021). Our previous study and work from others has also shown that these addiction-like features increase, rather than decrease, in magnitude over withdrawal (Gancarz-Kausch et al, 2014;Towers et al, 2021). This incubation effect has been extensively described for cue-induced cocaine-craving, which increases progressively, or incubates, over protracted withdrawal in both humans and animals tested following extended-access drug self-administration (Grimm et al, 2001;Li et al, 2015).…”

Section: Introductionmentioning

confidence: 97%

“…While this increased risk in women may be due to sociocultural factors , results from preclinical studies indicate that biological factors also contribute given that female animals develop addiction-like features more readily than male animals (Lynch and Taylor, 2004;Kerstetter et al, 2012;Perry et al, 2013Perry et al, , 2015Kawa and Robinson, 2019;Towers et al, 2021). For example, female rats self-administer higher levels of cocaine, show greater escalation of cocaine intake over time, and have a more significant disruption of diurnal control over drug intake than males under extended-access cocaine self-administration conditions, which supports an enhanced vulnerability to transition from controlled to dysregulated cocaine use in females (Lynch andTaylor, 2004, 2005;Roth and Carroll, 2004;Smith et al, 2011;Kawa and Robinson, 2019;Algallal et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

Towers

Kilgore

Bakhti-Suroosh

et al. 2023

Front. Behav. Neurosci.

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IntroductionWomen have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).MethodsCocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.ResultsIn males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.DiscussionThese findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

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Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

Towers

Kilgore

Bakhti-Suroosh

et al. 2023

Front. Behav. Neurosci.

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“…In any case, this piece of data is yet another study reinforcing the particular vulnerability of administering cocaine in rats during this age window of adolescence (PND 33–39; García-Cabrerizo et al 2015 ) on increasing negative affect (García-Cabrerizo and García-Fuster 2019 ; Bis-Humbert et al 2021a ) and addictive-like responses (e.g., Parsegian et al 2016 ; García-Fuster et al 2017 ), but with the novelty of providing the impact for female rats. Thus, early-life stressed female rats exposed to adolescent cocaine showed enhanced negative affect in adulthood (during abstinence and drug re-exposure), highlighting the risk of early cocaine initiation for the progression toward cocaine addiction, in the context that negative reinforcement during abstinence could likely increase this vulnerability (e.g., Towers et al 2021 ).…”

Section: Discussionmentioning

confidence: 98%

Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress

Bis-Humbert

García-Fuster

2021

Psychopharmacology

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Rationale The combination of several risk factors (sex, a prior underlying psychiatric condition, or early drug initiation) could induce the emergence of negative affect during cocaine abstinence and increase the risk of developing addiction. However, most prior preclinical studies have been centered in male rodents, traditionally excluding females from these analyses. Objectives To ascertain the behavioral and neurochemical consequences of adolescent cocaine exposure when the combination of several risk factors is present (female, early-life stress). Methods Whole litters of Sprague–Dawley rats were exposed to maternal deprivation for 24 h on postnatal day (PND) 9. Cocaine was administered in adolescence (15 mg/kg/day, i.p., PND 33–39). Negative affect was assessed by several behavioral tests (forced swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal cell fate markers were evaluated by western blot (FADD, Bax, cytochrome c) or immunohistochemistry (Ki-67; cell proliferation). Results Maternal deprivation is a suitable model of psychiatric vulnerability in which to study the impact of adolescent cocaine in female rats. While adolescent cocaine did not alter affective-like behavior during adolescence, a pro-depressive–like state emerged during adulthood, exclusively in rats re-exposed to cocaine during abstinence. FADD regulation by cocaine in early-life stressed female rats might contribute to certain hippocampal neuroadaptations with some significance to the observed induced negative affect. Conclusions Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress, highlighting the risk of early drug initiation during adolescence for the emergence of negative reinforcement during abstinence likely driving cocaine addiction vulnerability, also in female rats.

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“…Following acquisition, rats with ( n = 10) and without ( n = 9) a history of exercise were tested on motivation for fentanyl (0.25 µg/kg/infusion) using a PR schedule [ 42 ]. PR sessions began at approximately postnatal-day 53 and were conducted as described for acquisition testing except that the number of responses required to obtain an infusion increased throughout each session in the following steps: 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, etc; ref.…”

Section: Methodsmentioning

confidence: 99%

Impact of high-access exercise prior to and during early adolescence on later vulnerability to opioid use and relapse in male rats

2022

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Middle- and high-school athletes participating in certain team sports are at greater risk of opioid misuse and addiction than those who do not. While this risk is thought to be due to increased access to opioids, in this study we explored the possibility that the sensitizing effects of discontinued high-intensity exercise may also contribute. Specifically, using male rat models with fentanyl, we tested the hypothesis that high-access exercise (24 h/day access to a running wheel) during pre/early adolescence (two weeks, postnatal-day 24–37) would enhance vulnerability to opioid use and relapse during late adolescence/adulthood. Rats with a history of high-access exercise showed stronger fentanyl-associated lever discrimination during acquisition, greater motivation to obtain infusions of fentanyl following acquisition, and had an enhanced sensitivity to the reinstating effects of fentanyl-associated cues following extended (24 h/day), intermittent-access self-administration and protracted abstinence (14 days) compared to sedentary controls. In contrast, sedentary rats had greater overall responding (active- and inactive-lever) during acquisition and greater non-specific (inactive-lever) responding during extended-access self-administration. Molecular markers associated with opioid seeking/relapse were also differentially expressed in the nucleus accumbens core of rats with versus without a history of high-access exercise following relapse testing (e.g., Bdnf-IV and Drd2 expression). Together, these findings demonstrate that high-access exercise prior to and throughout early-adolescence enhances vulnerability to the reinforcing and cue-induced reinstating effects of opioids during later adolescence/adulthood. Thus, it is possible that the discontinuation of high intensity exercise contributes to the enhanced vulnerability observed in middle- and high-school athletes.

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Females develop features of an addiction-like phenotype sooner during withdrawal than males

Cited by 22 publications

References 51 publications

Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress

Impact of high-access exercise prior to and during early adolescence on later vulnerability to opioid use and relapse in male rats

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