Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

Kerstetter, Kerry A.; Aguilar, Valerie R.; Parrish, Aaron B.; Kippin, Tod E.

doi:10.1007/s00213-008-1089-8

Cited by 125 publications

(152 citation statements)

References 66 publications

(98 reference statements)

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“…Our finding that E 2 treatment enhanced extinction of cocaine seeking even in ovariectomized rats that were perseverating for up to 5 wk suggests a potentially vital role for E 2 in the recovery from cocaine abuse. The importance of E 2 is underscored by our finding that female rats in the absence of E 2 failed to suppress cocaine seeking during extinction, and may explain why gonadally intact female rats in estrus (low E 2 levels) are more resistant to extinction of drug seeking than are male rats (Kerstetter et al 2008;Anker et al 2010). Therefore, low E 2 levels may increase the risk of relapse in some women, and this risk may be exacerbated by cocaine-induced menstrual cycle disorders (Mello and Mendelson 1997).…”

Section: Discussionmentioning

confidence: 93%

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

et al. 2013

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Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17b-estradiol (E 2 ) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E 2 treatment followed by 2 d of vehicle treatment, or were injected with E 2 daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E 2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E 2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E 2 -treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E 2 could rescue extinction in these rats, half were given daily E 2 treatment and half were given vehicle. E 2 -treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E 2 is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E 2 levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts.Gonadal hormones render women more susceptible than men to developing compulsive patterns of psychostimulant use. Natural fluctuations in levels of the primary ovarian hormones, estrogens and progesterone, account for this increased abuse liability. Higher levels of estrogens, and lower levels of progesterone, are associated with greater sensitivity to the euphorigenic properties of cocaine in women (Evans 2007). This increased sensitivity may contribute to why women, compared with men, start using cocaine regularly at a younger age (Chen and Kandel 2002), transition from use to abuse more quickly (McCance-Katz et al. 1999), experience greater craving in response to drug-associated cues (Robbins et al. 1999) and stress (Potenza et al. 2012;Waldrop et al. 2012), and exhibit more severe drug-seeking behavior upon relapse (Gallop et al. 2007). In contrast, more women than men remain abstinent after treatment (Weiss et al. 1997). Thus, women are both more susceptible to cocaine abuse and, paradoxically, more responsive to treatment.A substantial literature supports that estrogens mediate the enhancement of drug seeking observed in females (Febo et al. 2002;Larson et al. 2007;Segarra et al. 2010; Kerstetter and Kippin 2011), but little is known regarding the role of estrogens during treatment. Preclinically, treatment is modeled through ext...

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Section: Discussionmentioning

confidence: 93%

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

et al. 2013

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“…In humans, levels of cocaine craving vary across the menstrual cycle (Fox et al 2008) with evidence to suggest that these levels are influenced by the ratio of estradiol to progesterone (Sinha et al 2007). Similar findings have been observed in animal models in which levels of cocaine-seeking vary across the estrous cycle with the highest levels observed during estrus (Kippin et al 2005;Kerstetter et al 2008;Feltenstein and See 2007;Feltenstein et al 2011), a period when there are higher levels of estradiol compared to progesterone (Feltenstein et al 2009). Results have also shown that the incubation effect, the progressive increase in cocaine-seeking over protracted abstinence (Grimm et al 2001), is heightened and prolonged in estrus females compared to males and to females in non-estrus phases (Kersetter et al 2008).…”

Section: Dose-dependent Efficacy Of Exercise To Attenuate Cocaine-seesupporting

confidence: 80%

“…Consistent with findings in humans, the enhanced biological vulnerability seen in female laboratory animals is believed to be mediated by ovarian hormones, particularly estrogen which has been shown to increase vulnerability at each of the phases of the addiction process (Kerstetter et al 2008;Lynch 2006;Roth and Carroll 2004;Larson et al 2007). Although females in all phases of their estrous cycle exhibit incubation of cocaine craving (Kerstetter et al 2008), females tested during estrus (defined as high levels of estrogen relative to progresterone; Feltenstein et al 2009) maintain a potentiation in cocaine-seeking longer than those in other phases (Kippin et al 2005;Feltenstein and See 2007;Kersetter et al 2008).…”

Section: Animal Models Of Cocaine Addiction and Relapsesupporting

confidence: 57%

“…Although females in all phases of their estrous cycle exhibit incubation of cocaine craving (Kerstetter et al 2008), females tested during estrus (defined as high levels of estrogen relative to progresterone; Feltenstein et al 2009) maintain a potentiation in cocaine-seeking longer than those in other phases (Kippin et al 2005;Feltenstein and See 2007;Kersetter et al 2008). These findings are consistent with reports in ovariectomized rats supplemented with estradiol that displayed increased vulnerability during reinstatement testing conditions (for reviews see Anker and Carroll 2010;Anker 2009, andEvans 2007) and adds further support to the idea that hormonal status influences relapse vulnerability.…”

Section: Animal Models Of Cocaine Addiction and Relapsementioning

confidence: 99%

“…In laboratory animals, sex differences in the efficacy of exercise on cocaine-seeking are largely unknown, with only one study demonstrating an effect of unlimited wheel running on cocaine-primed reinstatement responding in both males and females . Given findings indicating a critical role of hormone levels influencing relapse vulnerability and treatment outcome (Kippin et al 2005;Kerstetter et al 2008;Feltenstein and See 2007;Feltenstein et al 2011), hormonal status may possibly affect the efficacy of wheel running to reduce cocaine-seeking. Further work is needed to determine whether the efficacy of wheel running to attenuate relapse vulnerability differs by sex and hormonal status (see Chapter IV).…”

Section: Gender and Sex Differences In The Efficacy Of Exercisementioning

confidence: 99%

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The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

Peterson

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Exercise is a potential intervention for cocaine addiction that has shown promise in both human and animal studies. However, the conditions that produce the most efficacious response have yet to be determined. Thus, the goal of this dissertation is to determine the exercise conditions that produce the most efficacious response in a preclinical model of cocaine addiction. The overall hypothesis is that exercise will be an effective intervention that reduces cocaine relapse vulnerability and blocks subsequent neuroadaptations that develop over an abstinence period. Although exercise is known to induce widespread effects in the brain and act on many different signaling pathways (e.g., norepinephrine, opioid, serotonin, endocannabinoid, cortisol); this dissertation will focus on its effects on brain derived neurotrophic factor (Bdnf) exon IV expression in the prefrontal cortex (PFC) as potential mechanism given that it is a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise.Chapter I of this dissertation provides background on the behavior and underlying neurobiology (i.e. epigenetic regulation of Bdnf) of cocaine addiction. This chapter also provides evidence to support the hypothesis that the efficacy of exercise for preventing relapse vulnerability is associated with alterations in Bdnf expression. Chapter II demonstrates that the efficacy of wheel running, an animal model of exercise, is dosedependent, with greatest effects following longer access, and is associated with epigenetic regulation of Bdnf exon IV expression in the PFC. Chapter III demonstrates that early, but not late, access to a running wheel during abstinence attenuates subsequent cocaine-seeking. Chapter IV demonstrates that the efficacy of wheel running is iii influenced by sex, estrous cycle phase, and dose conditions. In this chapter I demonstrate that males are more sensitive to the beneficial effects of wheel running, while in females longer access conditions is required to override estrus-induced vulnerability. Overall, the data presented in this dissertation establishes exercise as a promising intervention that has the ability to reduce cocaine relapse vulnerability likely by blocking cocaine-induced neuroadaptations (e.g. Bdnf) that develop over an abstinence period.

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Age and sex differences in reward behavior in adolescent and adult rats

Hammerslag

Gulley

2013

Developmental Psychobiology

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Compared to adults, adolescents are at heightened risk for drug abuse and dependence. One of the factors contributing to this vulnerability may be age-dependent differences in reward processing, with adolescents approaching reward through stimulus-directed, rather than goal-directed, processes. However, the empirical evidence for this in rodent models of adolescence, particularly those that investigate both sexes, is limited. To address this, male and female rats that were adolescents (P30) or adults (P98) at the start of the experiment were trained in a Pavlovian approach (PA) task and were subsequently tested for the effects of reward devaluation, extinction, and re-acquisition. We found significant interactions between age and sex: females had enhanced acquisition of PA and poorer extinction, relative to males, while adolescents and females were less sensitive to reward devaluation than male adults. These results suggest that females and adolescents exhibit reward behavior that is more stimulus-directed, rather than goal-directed.

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Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

Abstract: The effects of reproductive cycle and withdrawal duration on cocaine-seeking behavior are additive and time-dependent increases in cocaine-seeking behavior are more enduring in females than in male rats.

Cited by 125 publications

References 66 publications

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

Age and sex differences in reward behavior in adolescent and adult rats

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