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Females Are More Vulnerable to Drug Abuse than Males: Evidence from Preclinical Studies and the Role of Ovarian Hormones

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Abstract

Human and animal research indicates the presence of sex differences in drug abuse. These data suggest that females, compared to males, are more vulnerable to key phases of the addiction process that mark transitions in drug use such as initiation, drug bingeing, and relapse. Recent data indicate that the female gonadal hormone estrogen may facilitate drug abuse in women. For example, phases of the menstrual cycle when estrogen levels are high are associated with enhanced positive subjective measures following cocaine and amphetamine administration in women. Furthermore, in animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. This chapter discusses sex differences in and hormonal effects on drug-seeking behaviors in animal models of drug abuse. The neurobiological basis of these differences and effects are also discussed.

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... While the above data strongly support the assertion that the Oxt system can affect alcohol use and dependency, as has been mentioned previously, most of this work has been performed in males, due in part to men having higher prevalence rates of AUD compared to women (Abuse & Administration, 2016). Females, however, should not be ignored because they tend to have a different alcohol metabolism, increased blood alcohol levels, and greater neurotoxic effects compared to males (Anker & Carroll, 2011). In preclinical studies, female rodents often self-administer greater volumes of alcohol and maintain a longer preference for alcohol compared to males (Almeida et al., 1998;Juarez & Barrios de Tomasi, 1999;Lancaster, Brown, Coker, Elliott, & Wren, 1996;Sneddon, White, & Radke, 2019;Vetter-O'Hagen, Varlinskaya, & Spear, 2009). ...
... Generally speaking, females tend to have higher expression levels of Oxt and Oxtr as compared to males (Dumais, Bredewold, Mayer, & Veenema, 2013;Uhl-Bronner, Waltisperger, Martinez-Lorenzana, Condes Lara, & Freund-Mercier, 2005). Given that males and females differ in their physiological and behavioral responses to alcohol and that there are sex differences in the Oxt system (Anker & Carroll, 2011;Heather K. Caldwell, 2018), it is reasonable to predict that the Oxt system may have differing effects on alcohol consumption in males and females. ...
... The goal of this study was to understand how a dysfunctional Oxt system affected alcohol consumption in both males and females, rather than directly evaluating sex differences. Taking into account previous research that suggests Oxt is able to offer some protection against excessive alcohol consumption, through its actions on the Oxtr (Bahi et al., 2016;King et al., 2017;Schuckit & Hesselbrock, 1994), and female vulnerability to alcohol abuse (Anker & Carroll, 2011), we sought to investigate how genetic disruption of the Oxtr affected stress-induced alcohol consumption in female and male Oxtr knockout (−/−) mice. We hypothesized that female and male Oxtr −/− mice would have increased voluntary alcohol consumption compared to wild-type littermates. ...
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Introduction The oxytocin (Oxt) system, while typically associated with the neural regulation of social behaviors, also plays a role in an individual's vulnerability to develop alcohol use disorders (AUD). In humans, changes to the Oxt system, due to early life experience and/or genetic mutations, are associated with increased vulnerability to AUD. While a considerable amount is known about Oxt's role in AUD in males, less is known or understood, about how Oxt may affect AUD in females, likely due to many clinical and preclinical studies of AUD not directly considering sex as a biological variable. This is unfortunate given that females are more vulnerable to the effects of alcohol and have increased alcohol consumption, as compared to males. Therefore, in the current study we wanted to determine whether genetic disruption of the Oxt receptor (Oxtr), that is, Oxtr knockout (−/−) mice, affected stress‐induced alcohol consumption in males and females. We hypothesized that genetic disruption of the Oxtr would result in increased stress‐induced alcohol consumption in both males and females compared to wild‐type (+/+) controls. Though, we predicted that these disruptions might be greater in female Oxtr −/− mice. Methods To test this hypothesis, a two‐bottle preference test was utilized along with the forced swim test (FST), and pre‐ and poststress alcohol consumption and preference measured within each sex (males and females were run separately). As a follow‐up experiment, a taste preference test, to control for possible genotypic differences in taste, was also performed. Results In males, we found no significant genotypic differences in alcohol consumption or preference. However, in females, we found that genetic disruption of the Oxtr resulted in a greater consumption of alcohol both pre‐ and poststress compared to controls. Conclusion These data suggest that in females, disruptions in Oxt signaling may contribute to increased vulnerability to alcohol‐associated addiction.
... Weitere Studien konnten andererseits zeigen, dass soziale Netzwerke auf Frauen im Vergleich zu Männern eine höhere Anziehung ausüben (Andreassen et al. 2017;Turel 2015) und Frauen mit einer höheren Wahrscheinlichkeit SND-Symptome entwickeln (Turel et al. 2014 (Griffin et al. 1989), einem stärker ausgeprägten Craving (Verlangen nach der Droge) während der Abstinenz (Robbins et al. 1999;Tonn Eisinger et al. 2018) und einem erschwerten Aufhören mit dem Drogenkonsum (Carpenter et al. 2006;Lynch et al. 2002;Tonn Eisinger et al. 2018) (Evans et al. 2002;Justice und de Wit 1999;Tonn Eisinger et al. 2018). Diese bei Frauen beobachteten Unterschiede in der Reaktion auf Kokain in Abhängigkeit des Estradiol-Levels konnten bei Ratten reproduziert werden (Anker und Carroll 2011;Becker und Hu 2008;Tonn Eisinger et al. 2018). Die Entfernung der endogenen Ovarialhormone mittels Ovariektomie oder Verabreichung eines Rezeptorantagonisten hob diesen Unterschied im Verhalten bezüglich Kokain auf (Carroll et al. 2004;Jackson et al. 2006;Lynch et al. 2001;Sircar und Kim 1999;Tonn Eisinger et al. 2018 (Becker und Hu 2008;Tonn Eisinger et al. 2018;Yoest et al. 2014 (Becker und Rudick 1999;Dluzen und Ramirez 1984). ...
... Bei männlichen Individuen wurde, meines Wissens nach, dieser Die hier aufgeführten Transmittersysteme sind an verschiedenen wichtigen Prozessen im Gehirn beteiligt und wirken sich auf Genussregulation, Belohnung und Motivation, Sucht, Entscheidungen, motorische Koordination (Sealfon und Olanow 2000), Gedächtnis und Lernen (Riedel et al. 2003), Sexualverhalten, autonome Funktionen, Stimmung und kognitive Funktion (Bethea et al. 2002;Portas et al. 2000), Angst und Anxiolyse (Bitran et al. 1995) (Evans et al. 2002;Justice und de Wit 1999). Diese bei Frauen beobachteten Unterschiede in der Reaktion auf Kokain in Abhängigkeit des Estradiol-Levels konnten bei weiblichen Ratten reproduziert werden (Anker und Carroll 2011;Becker und Hu 2008). Die Entfernung der endogenen Ovarialhormone mittels Ovarektomie oder Verabreichung eines Rezeptorantagonisten hob diesen Unterschied im Verhalten bezüglich der Kokainverabreichung auf (Carroll et al. 2004;Jackson et al. 2006;Lynch et al. 2001;Sircar und Kim 1999 (1) Früherer Beginn des Konsums von Psychostimulantien (Griffin et al. 1989) (2) Telescoping effect: Schnellere Entwicklung einer Sucht und schnellere Inanspruchnahme von professioneller Hilfe nach kürzeren Konsumzeiten (Griffin et al. 1989;Hernandez-Avila et al. 2004;Lynch 2018;Randall et al. 1999) (3) Stärker ausgeprägte Craving Symptomatik während der Abstinenz (Robbins et al. 1999) (4) Erschwertes Beenden des Drogenkonsums (Carpenter et al. 2006;Lynch et al. 2002) (5) Erhöhte Rückfalltendenz (Ignjatova und (Thaler et al. 2009). ...
Thesis
ZUSAMMENFASSUNG Hintergrund und Ziele: Internetspiele und Soziale Netzwerke (Social Network Sites = SNSs) bergen ein hohes Suchtpotential. Es ist wichtig die passionierte Nutzung der genannten Medien von der pathologischen Nutzung zu unterscheiden. Die Internet Gaming Disorder (IGD) und die Social Network Use Disorder (SND) gehen mit verschiedenen negativen Auswirkungen auf das Individuum und sein Umfeld einher, die denen in substanzgebundenen Süchten beobachteten Effekten gleichen. Jungen und Männer spielen mehr Internetspiele und haben ein größeres Risiko eine IGD zu entwickeln. Für Mädchen und Frauen scheint das Gleiche für SNSs und SND zu gelten. Es bestehen Geschlechtsunterschiede in verschiedenen Bereichen der Suchtentwicklung und -Aufrechterhaltung. Frauen haben beispielsweise eine höhere Tendenz den Substanzgebrauch oder das Glückspiel zu nutzen, um negative Emotionen zu modulieren, entwickeln nach im Vergleich zu Männern kürzeren Konsumzeiten ein süchtiges Verhalten und weisen höhere Rückfalltendenzen auf. Ein Ansatz die auch bei SND und IGD 2 beobachteten geschlechtsspezifischen Unterschiede zu erklären, sind die bereits in substanzbasierten Süchten und in der Glücksspielsucht (die bereits als Verhaltenssucht klassifiziert ist) beobachteten Effekte der weiblichen Sexualhormone Östrogen und Progesteron auf das Suchtverhalten und das mesolimbische Dopaminsystem. Östrogen hat bei Frauen und weiblichen Individuen eine das Suchtverhalten (Eskalation, Craving u.a.) fördernde Wirkung. Progesteron hingegen scheint in beiden Geschlechtern eine das Suchtverhalten hemmende Wirkung zu haben. Erklärt werden diese Effekte unter anderem über den Einfluss der Hormone auf das dopaminerge Belohnungssystem und GABA-erge Synapsen. Ziel dieser Arbeit ist es zu untersuchen, ob die von anderen Autoren beobachteten Geschlechterunterschiede bezüglich IGD und SND reproduziert werden können und ob ein Zusammenhang zwischen den Östrogen- und Progesteronkonzentrationen im Serum und der IGD und SND besteht. Methoden: Über einen Zeitraum von drei Jahren wurden insgesamt 192 Probanden rekrutiert (99 Frauen und 93 Männer). Die Rekrutierung erfolgte in drei Schritten. Im Onlinescreening (1), Telefonscreening (2) und der Testung vor Ort in der Psychiatrischen und Psychotherapeutischen Klinik (3). Es erfolgte jeweils die Erhebung des Internetnutzungsverhaltens mittels DSM-5 Kriterien für IGD und von uns adaptiert für SND, der Compulsive Internet Use Scale (CIUS), der Internetnutzungszeiten und ein vor Ort durchgeführtes Craving Experiment. Die Ausschlusskriterien waren u.a. Substanzsüchte, Hinweise auf eine Schizophrenie oder schwere körperliche Erkrankungen. Die Testung vor Ort und die Blutentnahme fanden immer zur gleichen Zeit zwischen 09:00 und 12:00 Uhr am Vormittag statt. Die Bestimmung der Hormone im Serum erfolgte nach Abschluss der Rekrutierung für alle Proben zum gleichen Zeitpunkt. Für die verschiedenen Formen des Estradiols Gesamtestradiol (E2), freies Estradiol (fE2) und bioverfügbares Estradiol (bE2) wurde eine ELISA und für Progesteron die Massenspektrometrie verwendet. Ergebnisse und Beobachtungen: Für die Auswertung der Hormonkonzentrationen im Serum erfolgte die Einteilung der Kohorte in drei Gruppen: Frauen mit hormoneller Kontrazeption (FmH), Frauen ohne hormonelle Kontrazeption (FoH) und Männer. Frauen beider Gruppen erfüllten mehr SND-Kriterien (Männer vs. FmH p = 0,016; Männer vs. FoH p = 0,001), wählten signifikant häufiger SNSs für das Craving-Experiment (Männer vs. FmH p < 0,001; Männer vs. FoH p < 0,001) und FoH verbrachten signifikant mehr Zeit in SNSs (Männer vs. FoH p = 0,004) als Männer. Diese hingegen erfüllten mehr IGD-Kriterien (Männer vs. FmH p = 0,001; Männer vs. FoH p = 0,002) wählten häufiger das Internetspielen für das Craving-Experiment (Männer vs. FmH p < 0,001; Männer vs. FoH p < 0,001) und verbrachten signifikant mehr Zeit mit dem Spielen im Internet als Frauen (Männer vs. FmH p < 0,001; Männer vs. FoH p < 0,001). Insgesamt erfüllten wenige Proband:innen fünf oder mehr IGD-/ bzw. SND-Kriterien. Die 3 Werte für Östrogen und Progesteron waren bei FoH am höchsten und bei FmH am niedrigsten, die Männer lagen dazwischen. Die Estradiolkonzentrationen bei den Männern lagen über den angenommenen Referenzwerten. Bei Männern korrelierte die Estradiolkonzentration signifikant negativ mit den erfüllten SND-Kriterien (bE2) (p = -0,046) und dem maximalen Craving für das Spielen im Internet in den letzten 7 Tagen (E2, fE2, bE2) (p = -0,013; -0,008; -0,007). In der Gruppe FmH zeigte sich eine signifikant positive Korrelation der Estradiolkonzentrationen und der maximalen mit dem Spielen im Internet verbrachten Zeit (p = 0,049), sowie eine signifikant positive Korrelation der Progesteronkonzentration und den erreichten Punkten in der CIUS (p = 0,027). FoH wiesen keinerlei signifikante Korrelationen der untersuchten Parameter auf. Praktische Schlussfolgerungen: Die bereits durch andere Autoren beschriebenen Geschlechterunterschiede bezüglich IGD und SND konnten reproduziert werden. Die Männer erfüllten mehr IGD-Kriterien und verbrachten mehr Zeit mit dem Internetspielen, während die Frauen mehr SND-Kriterien erfüllten und mehr Zeit mit SNSs verbrachten. Höhere Estradiolkonzentrationen scheinen bei Männern im Hinblick auf SND und Craving für Internetspielen protektiv zu sein, während sie bei FmH mit längeren maximalen Internetspielzeiten korrelieren. FoH zeigten in unserer Kohorte keinen Zusammenhang zwischen den Serumkonzentrationen von Östrogen und Progesteron und der IGD bzw. SND. Ursächlich hierfür können unter anderem die geringe Stichprobengröße und die Schwankungen der Hormonkonzentrationen während des Zyklus in dieser Gruppe sein. Insgesamt werden größere Kohorten mit ≥ 5 Kriterien für IGD und SND unter gleichzeitiger Berücksichtigung des hormonellen Status bei weiblichen Probandinnen benötigt. Aufgrund der geringen Stichprobengröße und der bei multipler Testung bestehenden Gefahr falsch positiver Ergebnisse bedürfen unsere Ergebnisse der Replikation.
... Over the past 20 years, evidence has accumulated indicating that the fluctuation of ovarian hormones may be a prominent mediator of gender differences observed in substance abuse [6,33,54]. Specifically, E 2 is noted to enhance reactions to rewarding stimuli [51] and amplify the hedonic effects of psychostimulants [5,34]. For instance, elevated levels of E 2 correlate with enhanced positive subjective moods following psychostimulant exposure in women [54,55]. ...
... E 2 levels are highest during proestrus, decline during estrus, and remain relatively low during metestrus and diestrus [57]. In agreement with clinical reports, increased E 2 levels also correlate with enhanced drug-seeking behaviors in female rodents [33]. Thus, the following sections provide selective summaries of clinical studies and findings from animal research comparing the subjective and behavioral effects of cocaine, METH, and nicotine between the sexes. ...
Article
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Substance abuse is a chronic pathological disorder that negatively affects many health and neurological processes. A growing body of literature has revealed gender differences in substance use. Compared to men, women display distinct drug-use phenotypes accompanied by recovery and rehabilitation disparities. These observations have led to the notion that sex-dependent susceptibilities exist along the progression to addiction. Within this scope, neuroadaptations following psychostimulant exposure are thought to be distinct for each sex. This review summarizes clinical findings and animal research reporting sex differences in the subjective and behavioral responses to cocaine, methamphetamine, and nicotine. This discussion is followed by an examination of epigenetic and molecular alterations implicated in the addiction process. Special consideration is given to histone deacetylases and estrogen receptor-mediated gene expression.
... Unfortunately, female animals are often excluded from research, which leaves large gaps in our knowledge of addiction development, treatment, and neurobiological mechanisms. Studies show that sex is one of the factors that could influence the liability to drug abuse (Festa et al. 2004) and that the pattern of drug seeking and taking is expressed differently in males and females, showing that females are more vulnerable to drug overuse (see Anker and Carroll 2011;Bobzean et al. 2014, for reviews). Data from animal studies suggest analogous sex-dependent drug-seeking and -taking behaviours. ...
... The animal studies are consistent with those performed in humans showing that the pattern of drug seeking and taking can be expressed differently in males and females, making sex a vulnerability factor in drug abuse (see Anker and Carroll 2011;Bobzean et al. 2014, for reviews). In clinical reports, women were reported to initiate drug use at an earlier age than men (Chen and Kandel 2002) and were more likely to transit from casual to binge-like patterns of drug taking (Lynch et al. 2002;Mann et al. 2005). ...
Article
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Rationale Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood. Objectives The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress — CMUS) on the liability to mephedrone-induced reward in Wistar rats. Methods The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively. Results Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats’ prefrontal cortex and hippocampus. Conclusions Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.
... Substances such as alcohol are more rewarding during the FP, perhaps due to increased neural excitability [12,15] which may mean that alcohol's positive effects are experienced more quickly. For instance, higher oestrogen levels during the FP have been associated with enhanced positive effects during substance use [20]. Such effects of ovarian hormones may also explain the finding that during the FP, females may be at greater risk of relapse to alcohol use [21]. ...
... Research would benefit from larger sample sizes as, although we used a power calculation to determine the sample size for both studies, the sample was still relatively small for the lab-based study which reduces the reliability of the findings [53]. Additionally, the sample for study one was homogeneous and self-selected (e.g. the age range of [18][19][20][21][22][23][24][25]. This was beneficial to control for potential heterogeneous factors that influence the relationship between the menstrual cycle and alcohol use, such as age (as shown in study two). ...
Article
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Background and aims: Although alcohol research often comments on observed sex differences (i.e. patterns of consumption), there is a lack of investigation into the reasons for these differences. For females, the regular hormonal fluctuations across the menstrual cycle are a potential influencing factor for alcohol consumption. In this pilot we aimed to investigate the relationship between menstrual cycle phase (follicular-phase [FP] and luteal-phase [LP]) and status (naturally-cycling [NC] and hormonal-contraception [HC]) on alcohol consumption and craving of casual drinkers, and identify potential influencing factors in this relationship. Methods: Study One: participants (n = 28; 15 HC, 13 NC) were either NC or HC (between subject factor: hormonal status) and attended two lab-based sessions corresponding with their FP and LP (within factor: cycle phase [NC] or time [HC]). Participants completed a mock alcohol taste-test, in addition to pre- and post-consumption measures of craving, anxiety, stress, and mood. Study Two: participants (n = 262; 144 HC, 118 NC) were either NC or HC (between subject factor) and completed an online study assessing menstrual cycle phase, alcohol use, craving, impulsivity, and stress. Results: Study One: A significant effect of cycle phase was found on alcohol craving (p = .019): craving was higher during the FP compared to the LP for NC participants, with HC participants showing no difference across sessions. There was no effect of phase or status on alcohol consumption, stress, or mood (ps > .05). Study Two: Regression analyses showed that age, craving, impulsivity and stress were significantly associated with alcohol consumption for NC participants (ps < .05), however only age and craving were associated with consumption for the HC participants (ps < .001). Conclusions: Alcohol craving was higher during the follicular, compared to the luteal, phase for the naturally cycling group, and different factors may be associated with drinking behaviour across women who are NC and those using HC. Future alcohol research should consider the menstrual cycle and contraceptive status for females.
... Preclinical models present a unique opportunity to identify the underlying mechanisms of these behaviours. Indeed, many excellent reviews have been published on the topic of sex differences in animal models of SUD in the last 20 years (Anker and Carroll, 2010a;Becker, 2016;Becker et al., 2017;Becker and Chartoff, 2019;Becker and Koob, 2016;Bobzean et al., 2014a;Hudson and Stamp, 2011;Kokane and Perrotti, 2020;Lynch, 2006;McHugh et al., 2018;Quigley et al., 2021a;Roth et al., 2004;Segarra et al., 2010;Yoest et al., 2018). We seek to add to the current understanding of sex differences in vulnerability to specific components of CUD by discussing the neuropharmacological and behavioural effects of E2 and P4 in the psychomotor stimulant, behavioural sensitization, place conditioning, and reinstatement rodent models of CUD for the purpose of identifying pharmacological targets for future CUD treatment strategies. ...
... We seek to add to the current understanding of sex differences in vulnerability to specific components of CUD by discussing the neuropharmacological and behavioural effects of E2 and P4 in the psychomotor stimulant, behavioural sensitization, place conditioning, and reinstatement rodent models of CUD for the purpose of identifying pharmacological targets for future CUD treatment strategies. Regarding cocaine self-administration specifically, we recommend to readers any of the following excellent reviews discussing the role of gonadal hormones in sex differences in cocaine self-administration (Anker and Carroll, 2010a;Becker and Koob, 2016;Kokane and Perrotti, 2020;Lynch, 2006). ...
Article
Women are more sensitive to cocaine craving elicited by stimuli associated with relapse. Ovarian hormones modulate cocaine craving and may therefore function as risk factors or therapeutic agents for the development and treatment of cocaine use disorder, respectively. We review herein the neuropharmacological effects of the steroid hormones 17ß-estradiol, progesterone, and allopregnanolone, a progesterone metabolite, in relation to their effects on cocaine-induced locomotion, behavioural sensitization, conditioned place preference, and reinstatement of cocaine seeking. In general, the literature suggests that female rats are more sensitive to these cocaine-induced behaviours than males and that 17ß-estradiol facilitates the expression of these sex differences. Alternatively, in females, exogenous progesterone attenuates cocaine conditioned place preference, reinstatement, and possibly behavioural sensitization, either on its own or after conversion to allopregnanolone. These opposing effects of 17ß-estradiol and progesterone/allopregnanolone involve endocannabinoid, γ-aminobutyric acid, dopamine, and glutamate transmission in the medial prefrontal cortex and striatum. We conclude that 17ß-estradiol may be a risk factor for various components of cocaine use disorder in women, whereas progesterone and allopregnanolone may be potential treatment options.
... Sex 2.1.1. Behavioral findings ( Fig. 2A and Fig. 2B)-Several clinical and preclinical studies have investigated sex differences in all stages of SUD [for comprehensive reviews, refer to (Anker and Carroll, 2011;Becker, 2016;Becker and Chartoff, 2019;Becker and Hu, 2008;Becker et al., 2012;Bobzean et al., 2014;Carroll and Anker, 2010;Lynch et al., 2002;Riley et al., 2018)] including drug craving and relapse. The emerging picture is complex, due to the large inconsistencies 1) within clinical or preclinical studies, 2) between clinical and preclinical studies and 3) across drug classes (Fredriksson et al., 2021;Nicolas et al., 2021). ...
... (Fig. 3)-What contributes to the sex differences in incubation of cocaine craving? Key factors are ovarian hormones associated with the estrus cycle (Anker and Carroll, 2011). Kerstetter et al. (2008);Nicolas et al. (2019) and Corbett et al. (2021) report that females rats during estrus exhibit stronger incubation of craving than during non-estrus or males, which is consistent with findings in cocaine-induced reinstatement (Feltenstein et al., 2009;Feltenstein and See, 2007;Kippin et al., 2005). ...
Article
It was suggested in 1986 that cue-induced cocaine craving increases progressively during early abstinence and remains high during extended periods of times. Clinical evidence now supports this hypothesis and that this increase is not specific to cocaine but rather generalize across several drugs of abuse. Investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after abstinence from intravenous drug or palatable food self-administration. Incubation of craving is susceptible to variation in magnitude as a function of biological and/or the environmental circumstances surrounding the individual. During the last decade, the neurobiological correlates of the modulatory role of biological (sex, age, genetic factors) and environmental factors (environmental enrichment and physical exercise, sleep architecture, acute and chronic stress, abstinence reinforcement procedures) on incubation of drug craving has been investigated. In this review we summarized the behavioral procedures adopted, the key underlying neurobiological correlates and clinical implications of these studies.
... 1 Recent research demonstrates that alcohol use and high-risk alcohol drinking behaviours among women are rapidly rising. 2 Further, women may progress from initial alcohol experience to alcohol dependence more quickly than men 3 and work harder for alcohol following a period of abstinence. 4 Paralleling the effects observed in humans, female rodents are known to be more vulnerable to a range of addictive behaviours. 5 For example, female rodents consume more ethanol (EtOH) than males [6][7][8][9] and are more likely to consume EtOH despite the risk of punishment. [10][11][12] The neurobiological mechanisms contributing to these behavioural differences are still relatively unknown. ...
Article
Alcohol use and high‐risk alcohol drinking behaviours among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the four core genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours. FCG mice were given access to escalating concentrations of EtOH in a two‐bottle, 24‐h continuous access drinking paradigm to assess consumption and preference. Relapse‐like behaviour was measured by assessing escalated intake following repeated cycles of deprivation and re‐exposure. Twenty‐four‐hour EtOH consumption was greater in mice with ovaries (Sry−), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX versus XY mice. For both consumption and preference, the influences of the Sry gene and sex chromosomes were concentration dependent. Escalated intake following repeated cycles of deprivation and re‐exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry− FCG mice and C57BL/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviours is warranted. We used the FCG mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours, including the alcohol deprivation effect. Escalated intake following repeated cycles of deprivation and re‐exposure emerged only in XX mice (vs. XY). These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes. We used the four core genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours, including the alcohol deprivation effect. Escalated intake following repeated cycles of deprivation and re‐exposure emerged only in XX mice (vs. XY). These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes.
... It is possible that changes in mood are not driving fluctuations in addictive behaviors across the menstrual cycle. Alternative mechanistic explanations include, but are not limited to, the interplay between hormones and neurotransmitters (Anker and Carroll 2011), evolutionary theory (Saah 2005), and relations between the immune system and inflammatory processes (Pehlivanoglu et al. 2001). We need more research on potential mechanistic explanations underlying menstrual cycle phase-addictive behavior relations, particularly for nicotine use which has accumulated a strong evidence base for increases premenstrually and menstrually. ...
Article
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Research examining relations between menstrual cycle phase and female addictive behaviors is accumulating. Theories suggest addictive behaviors may increase during specific phases of the menstrual cycle resulting from cyclical fluctuations in hormones and affect. In line with self-medication theory, we predicted that addictive behaviors would increase premenstrually and menstrually, phases marked by elevations in negative affect, relative to the follicular and luteal phases. We also hypothesized, coinciding with reward-sensitivity theory, that addictive behaviors may increase during ovulation, a phase characterized by increased positive affect, compared to the same phases. This systematic review summarizes extant literature examining the menstrual cycle phase-addictive behavior relationship and underlying motivations. Articles pertaining to menstrual cycle phase and addictive behaviors within the PsycINFO, CINAL, and PubMED databases were screened to determine eligibility following PRISMA guidelines (n = 1568). Thirty-four articles examining alcohol use, cannabis use, nicotine use, caffeine use, and gambling behavior across menstrual cycle phase met inclusion criteria. Consistent with self-medication theory, strong evidence indicated that nicotine use increased premenstrually and menstrually. Other factors increasing both nicotine and alcohol use premenstrually and menstrually include having a premenstrual dysphoric disorder diagnosis or having premenstrual syndrome. Motivations for using alcohol and nicotine may too vary by menstrual cycle phase. Results were less consistent or understudied for other addictive behaviors and thus conclusions cannot be drawn. Menstrual cycle phase appears to be a female-specific factor affecting some addictive behaviors, particularly nicotine use, and should be considered when conducting addictive behavior research or clinical interventions for reproductive-aged females with addictive disorders.
... Additionally, endocannabinoid receptors participate in estradiol-potentiated cocaine-induced locomotor activity (Peterson et al., 2016). The interactions among endocannabinoid, opioid and hormonal systems may represent female-specific mechanisms underlying addiction vulnerability (Anker and Carroll, 2011;Carroll and Anker, 2009;Chartoff and McHugh, 2016;Lynch et al., 2002). In contrast, only male rats showed enrichment of genes in neuroinflammatory pathways, adding to an emerging literature on the role of neuroinflammatory processes in sex differences in the effects of opioids (Averitt et al., 2019;Doyle et al., 2017). ...
Article
Background Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied. Methods We employed Next-Generation RNA-sequencing (RNA-seq) followed by quantitative chromatin immunoprecipitation to investigate changes in gene expression and their regulation in adult male and female rats’ dorsomedial prefrontal cortex (dmPFC) after a regimen of daily injection of morphine (5.0 mg/kg; 10 days). Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. A complementary behavioral study evaluated the effects of the same morphine injection regimen on locomotor activity, pain sensitivity, and somatic withdrawal signs. Results Behaviorally, repeated morphine injection induced locomotor hyperactivity and hyperalgesia in both sexes. 90% of differentially expressed genes (DEGs) in morphine-treated rats were upregulated in both males and females, with a 35% overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Chromatin immunoprecipitation revealed enrichment of H3 acetylation, a transcriptionally activating chromatin mark. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males. Conclusions Our results cohere with findings from previous studies based ona priori gene selection. Our results also reveal novel genes and molecular pathways that are upregulated by repeated morphine exposure, with some common to males and females and others that are sex-specific.
... For example, access to a running wheel significantly decreased cocaine self-administration in female rats but not in males [136], and access to saccharin reduced phencyclidine intake to a greater extent in female compared to male monkeys [137]. Further studies have shown consistent findings that many aspects of drug abuse are reduced in female rats, monkeys, and humans by treatment with progesterone or its metabolite allopregnanolone, and there are no effects in males, as these are ovarian steroid hormones (see reviews in [19,[138][139][140]). While the scope of individual differences in these examples is limited to sex, together, they offer an experimentally tractable link between neurobiological differences that underpin both addiction severity and treatment sensitivity. ...
Chapter
Overall, this review focuses mainly on the behavioral overlap and interaction between drug abuse and excessive behavior directed toward natural rewards. In recent years, rats selectively bred for high (HiS) or low (LoS) saccharin intake and tested for all phases of drug addiction have provided valuable information regarding vulnerability to drug (Carroll et al., Behav Pharmacol 19:435–60, 2008) and food (Avena, Appetite 55:734–7, 2010; Yakovenko et al., Appetite 57:397–400, 2011) dependence/addiction, related affective disorders, and impulsive behavior. The neurobiological bases for this interaction between drug and food rewards have been reviewed by others (Deadwyler, Ann N Y Acad Sci 1187:140–7, 2010; Volkow and Wise, Nat Neurosci 8:555–60, 2005; Olsen, Neuropharmacology 61:1109–22, 2011). The HiS and LoS rats are models of the heritability of maladaptive behaviors, including hallmarks of drug dependence, bingeing, and withdrawal that serve equally well for the understanding of binge eating. The purpose of this chapter is to review recent developments in this area of research, emphasizing that several commonalities between food and drug addiction have been revealed, and to highlight similar connections between other individual differences and their relationships to sweet preference and drug abuse. Impulsivity will also be discussed as a major marker of addiction vulnerability that covaries with sweet preference, as well as other vulnerability factors, such as age (adolescents vs. adults) and sex. New evidence is presented regarding the importance of reactivity to aversive events in predicting drug abuse in HiS and LoS rats and on the importance of other addiction-prone and addiction-resistant phenotypes. Recent data from animal models also suggest that the addiction-prone and addiction-resistant groups (e.g., HiS, LoS) respond in opposite ways when treated for drug abuse. Finally, new evidence shows the importance of self-initiated and self-maintained treatments to reduce vulnerability to behavioral excesses and incubation of craving after termination of their use.
... Both staining intensity and number of PNNs, as well as a c-Fos expression in BLA neurons phenotyped for Ca 2+ /calmodulin kinase II (CaMKII), calbindin (CB), and parvalbumin (PV) immunoreactivity, were examined in female rats. Females were used in the initial study because they display greater vulnerability to drug abuse than males [31,32], thus allowing for greater translational value for understanding trait-based risk. ...
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Negative urgency is a facet of impulsivity associated with negative affect and risky behavior that may involve the amygdala. The current study determined if social isolation during development alters negative urgency and c-Fos activity in the basolateral amygdala (BLA). Female Sprague-Dawley rats were raised in an isolated condition (IC), a standard social condition (SC), or an enriched condition (EC) and then were tested for locomotor activity, novelty place preference, and negative urgency using a reward omission task. Following performance on the reward omission task, the brains were analyzed for c-Fos expression in Ca2+/calmodulin kinase II (CaMKII) and calbindin (CB) neurons, as well as in parvalbumin (PV) neurons associated with perineuronal nets (PNNs) in BLA. IC rats exhibited enhanced locomotion compared with both SC and EC rats, as well as enhanced novelty place preference compared with EC rats; only IC rats showed increased responding following omission of an expected reward (negative urgency). Following completion of the reward omission task, IC rats also displayed increased percent of c-Fos neurons in BLA associated with CaMKII, CB, and PV neurons compared with SC and EC rats. In IC rats, c-Fos activation in BLA occurred following the omission of an expected reward. Finally, IC rats displayed reduced PNN intensity associated with PV neurons compared with EC rats, but the percent of these neurons co-expressing c-Fos was greater in IC rats; SC rats were intermediate between IC and EC rats. Negative urgency was observed in IC rats, but not SC or EC rats. While multiple mechanisms are likely involved, this behavioral effect was associated with an isolation-induced increase in activity of excitatory neurons in BLA, as well as decreased PNN intensity surrounding GABAergic neurons in the same region.
... Women's heightened vulnerability to stages of substance use disorder, such as acquisition, escalation and relapse, has been extensively investigated in animal models. Female rodents self-administered the drug at a faster rate, showed enhanced bingeing patterns of drug intake, and were also more vulnerable to relapse of drug-seeking behavior compared with male rodents (for reviews see Anker and Carroll, 2011;Becker and Hu, 2008;Becker et al., 2012;Carroll and Anker, 2010). Based on the findings from rodent studies, one could speculate that women may be at higher risk for these behavioral dysregulations due to underlying neurobiological mechanisms related to ovarian hormones (Becker and Hu, 2008;Carroll and Anker, 2010). ...
Article
Women and men exhibit differences in behavior when making value-based decisions. Various hypotheses have been proposed to explain these findings, stressing differences in functional lateralization of the brain, functional activation, neurotransmitter involvement and more recently, sex hormones. While a significant interaction of neurotransmitter systems and sex hormones has been shown for both sexes, decision-making in women might be particularly affected by variations of ovarian hormones. In this review we have gathered information from animal and human studies on how ovarian hormones affect decision-making processes in females by interacting with neurotransmitter systems at functionally relevant brain locations and thus modify the computation of decision aspects. We also review previous findings on impaired decision-making in animals and clinical populations with substance use disorder and depression, emphasizing how little we know about the role of ovarian hormones in aberrant decision-making.
... With respect to medication compliance and substance use, women were more likely to adhere to medication treatment, yet test positive for benzodiazepines and amphetamines, a finding consistent with previous research (Back et al., 2011). Evidence exists that women are more vulnerable to the rewarding effects of stimulants and that estrogen is possibly a factor in this sensitivity (Anker & Carroll, 2011;NIDA, 2018f). ...
Thesis
In 2017, more than 70,000 people in the United States died due to drug overdoses; of that number, approximately 68% involved prescription or illicit opioids (CDC, 2019). Presently, insurance companies and physicians require all opioid use disorder (OUD) patients to receive counseling during medication treatment for OUD, despite the lack of evidence it is necessary for all patients. This requirement restricts access and creates hardship for those who may benefit from medication alone. In an effort to inform policy and improve quality of treatment, this nonexperimental, correlational study examined the relationship between individual counseling status and treatment outcomes in patients receiving medication treatment for OUD. Treatment outcome variables (treatment utilization, medication use, and opioid use) were extracted from the electronic health records of 11,551 adults who received treatment between January 2016 and January 2018. The impact of individual counseling on outcome variables was examined while controlling for confounding variables (gender, age, race, ethnicity, PTSD/trauma, anxiety, and criminal justice involvement). Bivariate analyses suggested women in OUD treatment were prone to have experienced PTSD/trauma and anxiety, while males were more likely to have CJS involvement. Women were more often retained in care and were in treatment for longer periods of time than males. In addition, older patients used OUD medication more often than younger patients; however, older patients were also more prone to use benzodiazepines and alcohol. Multivariate analyses revealed patients with increased rates of treatment utilization were more likely to utilize medication treatment and demonstrate reduced opioid use. In addition, higher rates of treatment utilization were related to reduced opioid use. Patients with more frequent interruptions in OUD treatment more often tested positive for opioids. This study revealed very little evidence that counseling during OUD treatment had a positive impact on treatment utilization. Yet, it found no evidence that counseling while active in treatment had an impact on medication utilization or opioid use. Although counseling may have some benefit for some patients in OUD treatment, these findings do not support mandating counseling during OUD treatment.
... Further, women may progress from initial alcohol experience to alcohol dependence more quickly than men 3 . Paralleling the effects observed in humans, female rodents are known to be more vulnerable to a range of addictive behaviors 4 . For example, female rodents consume more ethanol (EtOH) than males [5][6][7][8] and are more likely to consume EtOH despite the risk of punishment [9][10][11] . ...
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Alcohol use and high-risk alcohol drinking behaviors among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the Four Core Genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement to EtOH drinking behaviors. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behavior was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX vs. XY mice but not influenced by gonad type. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). These results demonstrate that aspects of EtOH drinking behavior may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviors is warranted.
... The widely accepted sex differences observed in the pharmacological and mood-altering effects of substances can be attributed to hormonal differences between men and women (Newman & Mello, 2009). Research using both animal models and human participants has shown that females have a heightened vulnerability to addiction because estrogen enhances rewarding properties of substances and progesterone protects against aversive effects (Anker & Carroll, 2011;Carroll & Anker, 2010). Women are also especially likely to use addictive behaviours to cope with negative affect (Weatherly, 2013), and individuals who use addictive behaviours to manage their emotions report more severe problems than those who use addictive behaviours for other reasons, such as to socialize or increase excitement (Stewart, Zack, Collins, & Klein, 2008). ...
Preprint
To elucidate similarities and differences between binge eating and a behavioral addiction, this prospective study compared facets of emotion regulation that were associated with problem gambling, the only formally recognized behavioral addiction, and binge eating. Community-based women (N = 202) who engaged in at-risk binge eating (n = 79), at-risk gambling (n = 36), or both (n = 87) completed four online assessments over six months. Baseline and six-month surveys assessed self-reported emotion dysregulation (using the DERS and UPPS-P), binge eating (using the EDE-Q), and gambling (using the PGSI); abbreviated two- and four-month surveys assessed only binge eating and gambling. Binge eating and problem gambling were both associated with emotion dysregulation, and greater positive urgency was correlated with more severe problem gambling but less frequent binge eating. Negative urgency explained no unique variance in binge eating or problem gambling changes over time, once other facets of emotion dysregulation (i.e., positive urgency and facets assessed by the DERS) were included. Thus, previous cross-sectional research may have overestimated the association of negative urgency with both binge eating and problem gambling. Overall, these findings suggest that binge eating and problem gambling are associated with common as well as distinct emotion regulation deficits.
... Des protocoles d'extinction et de réinstallation de recherche de drogue ont été développés à partir des modèles d'auto-administration intraveineuse de drogue, et de conditionnement de préférence de place, afin de modéliser la rechute (Anker et Carroll 2011). ...
Thesis
Malgré de nombreuses données cliniques montrant une forte comorbidité entre les troubles dépressifs et addictifs, les mécanismes physiopathologiques à la base de cette association demeurent mal connus. Le but de cette thèse est de déterminer les mécanismes neurobiologiques par lesquels des états de type dépressifs favorisent les conduites addictives. Pour cela, nous avons utilisé un modèle génétique de dépression chez la souris, le modèle des souris H/Rouen. Ces souris ont été sélectionnées, par reproduction dirigée, sur la base de leur comportement d'immobilité dans l'épreuve de suspension par la queue, beaucoup plus prolongé que chez les souris non résignées (NH/Rouen) ou que chez les souris témoins (I/Rouen) présentant un phénotype intermédiaire. Les souris H/Rouen présentent par ailleurs de nombreuses caractéristiques reflétant un phénotype dépressif. Nous avons tout d'abord poursuivi la caractérisation phénotypique de ces trois lignées de souris et montré que les souris H/Rouen manifestent également un comportement anxieux plus prononcé que les deux autres lignées dans une batterie de tests comportementaux classiques. Nous avons ensuite testé l'influence de ce phénotype mixte d'anxiété et de dépression sur la vulnérabilité à la cocaïne. Nous avons montré que les souris H/ et I/Rouen sont moins sensibles aux effets psychomoteurs aigus de la cocaïne que les souris NH/Rouen ; par contre, toutes les lignées de souris expriment une sensibilisation comportementale à la cocaïne semblable, indiquant que les changements neuroadaptatifs qui se développent au cours des injections répétées de cocaïne estompent les différences de réactivité initiales. Nous avons ensuite montré que les souris femelles H/Rouen présentent une préférence de place conditionnée induite par la cocaïne (CPP) robuste, durable et plus élevée que chez les souris NH/ et I/ Rouen, indiquant une plus grande sensibilité aux indices contextuels associés aux effets de cette drogue. Cette observation nous a conduits à rechercher les mécanismes neuronaux qui interviennent dans la vulnérabilité accrue à la cocaïne observée chez les souris femelles H/Rouen. Notre étude neuroanatomique, basée sur l'expression de la protéine Fos lors du test de CPP, a permis de mettre en évidence une activation plus forte de la partie cingulaire du cortex préfrontal, du noyau accumbens shell, de l'amygdale basolatérale et du subiculum ventral chez les souris femelles H/Rouen par rapport aux souris NH/ et I/Rouen, qui pourrait refléter leur plus forte propension à la recherche conditionnée de drogue. Finalement, comme le BDNF (ou Brain Derived Neurotrophic Factor) présent au niveau du noyau accumbens pourrait être impliqué à la fois dans la dépression et la vulnérabilité aux drogues, nous avons commencé l'étude de son expression par la technique de western blot chez les trois lignées de souris, dans des conditions basales et après conditionnement à la cocaïne
... One important caveat is that a large majority of this work was conducted in male animals, despite seminal work showing significant local effects of gonadal hormones within mesolimbic systems (Anker & Carroll, 2011;Bazzett & Becker, 1994;Becker, 1999;Carroll & Smethells, 2015;Cummings, Jagannathan, Jackson, & Becker, 2014;Lynch, Roth, & Carroll, 2002;Walker, Ray, & Kuhn, 2006;Walker, Rooney, Wightman, & Kuhn, 2000;Yoest, Quigley, & Becker, 2018). It should be noted that much of the work in males was conducted in ex vivo preparations which isolates the local circuits, and as such is advantageous for investigating direct mechanisms without confounding influences of long-range projection systems and other whole animal systems such as circulating hormones. ...
Article
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Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward‐related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms ‐ such presynaptic dopamine autoreceptors and dopamine transporters ‐ as well heterosynaptic mechanisms such as retrograde signaling from postsynaptic cholinergic and dynorphin systems, among others. Additionally, modulation of dopamine release via diffusible messengers such as nitric oxide and hydrogen peroxide, allows for various metabolic factors to quickly and efficiently regulate dopamine release and subsequent signaling. Here we review how these mechanisms work in concert to influence the timing and magnitude of striatal dopamine signaling, independent of action potential activity at the level of dopaminergic cell bodies in the midbrain, thereby providing a parallel pathway by which dopamine can be modulated. Understanding the complexities of local regulation of dopamine signaling is required for building comprehensive frameworks of how activity throughout the dopamine system is integrated to drive signaling and control behavior.
... Since ovarian hormones can influence drug seeking [48], we hypothesized that CORT effects may have covaried with estrous phase. In support of this possibility, CORT-potentiated cocaine seeking was only observed during diestrus and proestrus. ...
Article
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Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite comparable self-administration and extinction, females displayed a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock, tested across a range of intensities, failed to potentiate cocaine-primed reinstatement in females. However, restraint potentiated reinstatement in both sexes. While sex differences in stressor-induced plasma corticosterone (CORT) elevations and defensive behaviors were not observed, differences were evident in footshock-elicited ultrasonic vocalizations. CORT administration, at a dose which recapitulates stressor-induced plasma levels, reproduced stress-potentiated cocaine-primed reinstatement in both sexes. In females, CORT effects varied across the estrous cycle; CORT-potentiated reinstatement was only observed during diestrus and proestrus. As in males, CORT-potentiated cocaine seeking in females was localized to the PrL-PFC and both CORT- and restraint-potentiated cocaine seeking required PrL-PFC CB1R activation. In addition, ex vivo whole-cell electrophysiological recordings from female layer V PrL-PFC pyramidal neurons revealed CB1R-dependent CORT-induced suppression of inhibitory synaptic activity, as previously observed in males. These findings demonstrate that, while stress potentiates cocaine seeking via PrL-PFC CB1R in both sexes, sensitivity to cocaine priming injections is greater in females, CORT-potentiating effects vary with the estrous cycle, and whether reactivity to specific stressors may manifest as drug seeking depends on biological sex.
... Human studies have shown that women are more vulnerable to drug abuse compared with men (Bobzean et al. 2014). Likewise, studies with rodents show that females are more sensitive to the reinforcing effects of drug abuse than males (Anker and Carroll 2011;Calipari et al. 2017). Westenbroek et al. (2013) found that isolated females were more motivated to seek cocaine than their male siblings (Westenbroek et al. 2013). ...
Article
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Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words “social isolation” and “adolescence” and “drug” or “cocaine” or “amphetamine” or “nicotine”, resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.
... 31 Female rats also have shown to be more sensitive to amphetamine, cocaine and are found to be more vulnerable to addiction than males. 32 Few studies have revealed that females and males have a difference in their extent of the response to nicotine, cocaine, and methamphetamine. 12,33 For instance, the adverse effects of methamphetamine were found to be more pronounced in females than in males. ...
Article
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Background: Burden of substance abuse is becoming a worldwide problem. One of the psychostimulant plants widely consumed in Ethiopia and other East African countries is Catha edulis Forsk (khat). Most of the users claim that its stimulatory effect is the determinant factor that makes them use. However, its rewarding and reinforcing potential and variation between sexes have not been investigated. This study was, therefore, designed to measure the rewarding effect of khat extract (ke) in the addiction mice model of both sexes. Materials and methods: Forty-eight Swiss albino mice of both sexes (age 6-7 weeks) weighing 21-33 gm were used. The mice were conditioned to ke (100 mg/kg, 200 mg/kg and 300 mg/kg b.w). The control group was conditioned to tween 80 (2%, v/v) in distilled water. The reinforcing effect of khat was evaluated using the conditioned place preference paradigm. The classical pairing to the extract was made using the place conditioning box. Post-conditioning tests have been conducted four times and the average values were taken for analysis using SPSS version 21.0. Results: Time spent in the khat-paired compartment was significantly higher for mice conditioned to ke 200 mg/kg (p<0.05) and ke 300 mg/kg (p<0.001). The rewarding effect of khat was strong in females at a higher dose when compared to the same sex of mice conditioned to the vehicle (p<0.001) or male mice conditioned to the same dose of khat extract (p<0.05). Repeated administration increased khat rewarding sensitization at all doses. Though the crude khat extract did not affect the food consumption and total body weight, water consumption was significantly less in mice received ke 100 mg/kg (p<0.01), where it was significantly higher in mice received ke 300 mg/kg (p<0.01). Sniffing (p<0.05) and climbing (p<0.05) psychomotor activities of mice were also affected by the crude khat extract. Conclusion: Mice showed place conditioning to khat extract, and the response was significantly higher in female mice. The crude khat extract did not affect food consumption and total body weight. The mechanisms behind the rewarding response of khat extract and sexual differences should be investigated.
... It remains unknown if loss of non-drug reward produces resurgence of punishment-suppressed alcohol seeking. Further, there is considerable evidence that females show greater drug-, stress-, and cue-induced relapse to extinguished drug seeking than males [see 16,17,18]. Only a single J o u r n a l P r e -p r o o f study [11] has examined potential sex differences in relapse to drug seeking (i.e., cocaine) following suppression by punishment, finding that females were somewhat overrepresented (63%) in a subgroup of punishment-resistant rats that also showed greater cue-induced relapse. ...
Preprint
To better approximate the human condition, animal models of relapse to drug and alcohol seeking have increasingly employed negative consequences to generate abstinence. Here we report the first demonstration of relapse to punishment-suppressed alcohol seeking induced by loss of non-drug reward (i.e., resurgence). We also report the first examination of potential sex differences in any form of relapse to alcohol seeking following suppression by punishment. Male and female rats first pressed a lever for 20 % oral alcohol. Next, lever pressing for one group continued to produce alcohol, but also produced occasional footshock. For another group, lever pressing similarly produced alcohol and occasional footshock, and a nose-poke response produced alternative non-drug reward (i.e., food). Males showed similar suppression of alcohol seeking by punishment alone and punishment + alternative non-drug reward, whereas females showed less suppression by punishment alone. Finally, when alternative reinforcement and punishment were suspended, resurgence occurred for both sexes in the group that previously had access to non-drug reward. Exposure to and then removal of punishment alone did not produce relapse for males, but it did for females. These results suggest that loss of alternative non-drug reward can generate relapse to alcohol seeking following abstinence induced by negative consequences. Future research should further examine the role of potential sex differences in sensitivity to punishment and how such differences may contribute to relapse more broadly.
... The growing research on sex differences has also revealed significant sex differences in both depression prevalence and the effect of CB and alcohol use. In fact, clinical and preclinical studies show that females have greater vulnerability toward drug abuse at all stages of the addiction cycle including drug initiation, binging, withdrawal, and relapse (5,6). Also, female substance users show an increase in sexual risk-taking (7); and an increased risk of depression and anxiety (8,9). ...
Article
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Objective The current study examined the impact of the use of hormonal birth control, cannabis (CB), and alcohol on depression symptoms. Study Design Survey data from 3,320 college-aged women collected over a 2-year period. Depression symptoms were assessed using the PHQ-9. Results Individuals taking hormonal birth control ( N = 998; age = 19.1 ± 1.6 years) had lower overall depression scores than did those not taking birth control ( N = 2,322; age = 19.1 ± 1.8 years) with 15.2% of those not taking hormonal birth control had depressive symptoms while 12.1% of those in the birth control group had depressive symptoms. Additionally, those taking hormonal birth control had higher scores on the alcohol and CB use assessment. A between-subjects ANOVA with depression score as the dependent variable found significant effects hormonal birth control use, CB and alcohol use, as well as a significant interaction between CB use and hormonal birth control use. Conclusions While there are some limitations (e.g., the between subjects design makes it such that there may be uncontrolled differences between groups), the results suggest that hormonal birth control use may help to reduce depressive symptoms. Implications More studies examining the impact of hormonal birth control and substance use on depression are required. The results suggest a potential interaction between CB and hormonal birth control use on depression symptoms that is not observed for alcohol. This implies that alcohol and CB may be linked to depression via different mechanisms.
... Apparently, amphetamines are the drugs with the smallest gender gap, although women represent only 26% of amphetamine clients. Women may be more vulnerable to the reinforcing effects of stimulants (NIDA, 2020), with estrogen possibly being a mediating factor for this increased sensitivity (Anker & Carroll, 2011). To date, there are few studies on treatment outcomes in patients using psychostimulants (Soyka et al., 2017;Kamp et al., , 2020Simpson et al., 2016). ...
Article
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Methamphetamine use disorder is associated with severe psychiatric symptoms and psychosocial problems. Women seem to be more affected than men. Therefore, this study examined psychiatric comorbidities and psychopathology, drug use patterns, and treatment outcomes in women addicted to methamphetamine compared to men. Data on methamphetamine-dependent inpatients were collected in two centers specialized for addiction treatment at admission (T0) and discharge (T1, after treatment for 24 weeks). Sociodemographic and clinical measures were collected with the semi-structured clinical interview I at baseline; the self-reported standardized questionnaire (SCL-90-R) was administered at admission and discharge and after 24 weeks. During the entire treatment procedure, treatment relevant aspects were monitored. Out of all 108 treatment-seeking participants (86 men, 22 women), 64 completed the study (51 men, 13 women; drop-out rate: 40.7% ( n = 44)). Methamphetamine-dependent women used other stimulants more often than men, while men used hallucinogens significantly more frequently than women. Female inpatients differed significantly from men in various sociodemographic variables (e.g., having children, single parenting) and were significantly more often affected by current ( p < 0.001) and lifetime mental stress disorders ( p < 0.001), as well as specific psychiatric disorders ( p < 0.001) (e.g., posttraumatic stress disorder). At discharge, mental symptoms decreased significantly in men but not in women. Both before and after treatment, women seem to be more vulnerable to psychiatric comorbidities and psychopathologic symptoms compared to men. Although this study only provides preliminary data on gender-specific characteristics of methamphetamine-dependent patients and their treatment, it seems appropriate to discuss the development of gender-specific treatment options. Further studies in this field are needed.
... The second step was to assess the measurement invariance of the scale so as to make comparisons between groups valid (Deng et al., 2008;Putnick and Bornstein, 2016). Studies have shown that females are more sensitive than males to physical and psychological effects of drugs (Anker and Carroll, 2011;Simmler et al., 2011) and present more severe negative drugrelated problems related to ecstasy (Allott and Redman, 2007), ketamine (Li et al., 2017), methamphetamine (Kogachi et al., 2017), and other substance use (Fattore et al., 2009;van der Plas et al., 2009), indicating the importance of understanding sex differences to better guide drug investigation and clinical treatment. In Belarus, compared with people over 30 years old, young drug users under 30 years old had a higher prevalence of the use of hallucinogens and amphetamine-type stimulants (Lelevich et al., 2016), and the rates of substance use disorder are highest in individuals younger than 30 years, for both the cocaine users and hallucinogen users (American Psychiatric, 2013). ...
Article
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Objective: In contrast to the drug situation in the rest of the world, synthetic drugs, rather than traditional drugs, have been the dominant abused drugs in China since 2019. However, the public misconception that synthetic drugs are not as addictive as traditional drugs, such as opioids and the scarcity of specific measurement instruments, have hindered the clinical diagnosis and treatment of synthetic drug abusers, thus the development of a localized instrument to evaluate dependence on synthetic drugs is in urgently needed. Method: Using a sample of 618 Chinese synthetic drug abusers (Mean age = 34.69 years; 44.17% female), the present study developed and examined the psychometric properties of a self-reporting instrument, the Synthetic Drug Dependence Scale (SDDS), which consists of four subscales: physical dependence, psychological dependence, health injury, and social function injury. Results: The SDDS revealed a three-factor model structure (weighted root mean square residual (WRMR) = 0.876, comparative fit index (CFI) = 0.965, Tucker–Lewis index (TLI) = 0.953, and Root mean square error of approximation (RMSEA) = 0.070), with good internal consistency (composite reliability = 0.912, alfa = 0.801) and convergent validity. Elevated scores on the SDDS were associated with a higher level of reward sensitivity, punishment sensitivity, and stronger impulsivity. Interestingly, psychological dependence was the only significant predictor ( p < 0.05) of criterion variables compared with the other three subscales, implying the important role of psychological factors in synthetic drugs dependence. Adequate measurement equivalence across sex, age (18–30 and 31–57 years old), and employment group (employed and unemployed) was also established. Conclusion: The SDDS appears to be an effective and reliable instrument that could be used to further investigate the characteristics of synthetic and traditional drug dependence, promoting a deeper understanding of the physical and psychological roles in drug dependence.
... These underlying biological mechanisms may help explain why human females find alcohol more rewarding during the FP relative to the LP when levels of estrogens are highest (3,9). Higher levels of estrogens can also increase the risk of relapse to drinking during recovery (11,12). An additional point of consideration is hormonal contraception. ...
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... An additional limitation comes from the fact that estrous cycle was not examined in the female treatment groups. While estrous cycle has been determined to alter behavior in certain preclinical models of addiction (Lacy et al. 2016;Anker and Carroll 2011) and cognition (Cordeira et al. 2018;Broestl et al. 2018), data from both our lab (Smiley et al. 2020) and others (Maeng et al. 2015) establishes the fact that estrous cycle phase does not have an effect on freezing behavior during extinction. Therefore, we do not see estrous cycle as a factor that could serve to alter fear behaviors during extinction in these studies. ...
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... Cocaine abuse disorders are observed in both men and women; however, compared to men, women have a higher likelihood of becoming addicted at a younger age [35], take higher doses [36], require less time to become addicted [37], experience more cravings [38,39], and have a greater difficulty remaining abstinent [40][41][42]. Sex differences in response to cocaine are also seen in experimental animals [39]. It was proposed that the differential efficacy of cocaine across sexes is driven by circulating estrogens, which affect DAT activity [43]. ...
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... It remains unknown if loss of non-drug reward produces resurgence of punishment-suppressed alcohol seeking. Further, there is considerable evidence that females show greater drug-, stress-, and cue-induced relapse to extinguished drug seeking than males [see [16][17][18]. Only a single study [11] has examined potential sex differences in relapse to drug seeking (i.e., cocaine) following suppression by punishment, finding that females were somewhat overrepresented (63 %) in a subgroup of punishment-resistant rats that also showed greater cue-induced relapse. ...
... Females may also be particularly sensitive to the subjective effects of cannabis, which increases a female's vulnerability to dependence on this substance (Cooper and Haney, 2014). This is consistent with ample preclinical evidence indicating that females are more susceptible to all stages of substance use, from initiation to relapse (Anker and Carroll, 2011). ...
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Chapter
Psychostimulant drugs, such as cocaine and amphetamines, of the indirect sympathomimetic class have a long history as tonics and other preparations to allay fatigue and sustain performance. These drugs also have a long history of abuse and dependence. Abuse potential varies with the availability of the drug both environmentally and physiologically, with intravenous and smoked forms of both cocaine and amphetamines producing much more severe substance use disorder. Cocaine and amphetamines have a characteristic abuse cycle that involves binge administration, withdrawal dysphoria, paranoia, and psychosis-like symptoms as the cycle continues or intensifies. Significant advances have been made in our understanding of the mechanisms of action of psychomotor stimulant drugs at the behavioral, neuropharmacological, cellular, and molecular levels that can be heuristically framed in the three-stage cycle of addiction:  binge/intoxication, withdrawal/negative affect, and  preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain, basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain, extended amygdala), and preoccupation/anticipation (executive function, prefrontal cortex). Thus, the new revised book, Neurobiology of Addiction, is now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.
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The present experiments determined the effects of voluntary home-cage wheel running on the development (Experiments 1 and 2a) and expression (Experiment 2b) of conditioned hyperactivity and long-term sensitization in male, Swiss-Webster mice. Mice experienced 3 weeks of wheel running (exercise) or not (sedentary) either beginning prior to (Experiments 1 and 2a), or immediately following (Experiment 2b), the acquisition phase. During the acquisition phase, mice (n = 12–15/group) received injections (subcutaneous) of either vehicle (saline) or methamphetamine (0.5 or 1.0 mg/kg, Experiment 1; 1.0 mg/kg, Experiments 2a and 2b) immediately prior to 5 locomotor-activity sessions. The extinction phase began 48 hours (h) (Experiment 1) or 3 weeks (Experiments 2a and 2b) after acquisition and all mice received vehicle injections prior to 4 locomotor-activity sessions. Tests of long-term sensitization occurred 72 h after the last extinction session and involved an escalating, methamphetamine-dose regimen (0.25 ➔ 1.0 mg/kg), 1 dose/session for 3 sessions. While pre-acquisition wheel running failed to alter development of conditioned hyperactivity after training with the 0.5 mg/kg methamphetamine dose, it blunted the development of conditioned hyperactivity, and blocked (Experiment 1) or attenuated (Experiment 2a) induction of long-term sensitization after training with the 1.0 mg/kg methamphetamine dose. Furthermore, while post-acquisition wheel running retarded extinction of conditioned hyperactivity, it did not alter expression of conditioned hyperactivity or long-term sensitization (Experiment 2b). Collectively, the results suggest that the impact of voluntary exercise on context-drug associations and long-term sensitization is critically dependent on the timing of exercise relative to drug conditioning.
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RationaleCocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction.Objectives To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response.Methods One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min.ResultsGender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033).Conclusions Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.
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Noradrenaline and alpha-2 receptors are implicated in the neuroadaptive changes in alcohol dependence leading to increased alcohol seeking. Preclinical methods often used to induce dependence, such as alcohol vapor, require long exposure periods. Another method, gavage with alcohol, induces dependence in a shorter time frame (4-6 d), but its effects on relapse is less well understood. We examined the role of alpha-2 receptors on alcohol self-administration (ASA) and relapse in male and female rats made alcohol dependent by gavage. The influence of these variables on the inhibitory effects of the alpha-2 agonist guanfacine on ASA, and on reinstatement induced by the alpha-2 antagonist yohimbine were determined. We also extended this analysis to relapse induced by the kappa opioid receptor agonist U50,488. Male and female Sprague Dawley rats, trained to self-administer alcohol were treated with intragastric vehicle or alcohol (12 g/kg/d for 5 d). In Exp. 1 we examined the effects of alcohol gavage on reinstatement induced by yohimbine (0.625-1.25 mg/kg) and U50,488 (1.25-2.5 mg/kg). In Exp. 2 we determined the effects of a longer period of alcohol gavage on guanfacine (0.25-0.75 mg/kg)-induced reductions in ASA and on yohimbine (0.625-2.5 mg/kg)-induced reinstatement. Our key findings are that alcohol dependence induced by gavage produces sex-specific effects on reinstatement. Non-dependent females had greater reinstatement than males, but dependence reduced reinstatement in females. In males, dependence modestly enhanced yohimbine-induced reinstatement, while U50-induced reinstatement was absent irrespective of dependence condition. Alcohol dependence did not modify the inhibitory effects of guanfacine on ASA in males or females.
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There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.
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Exercise programs have shown great potential for both the prevention and treatment of substance use disorder (SUD). As exercise has been shown to have potent effects on physical and psychological health, it is reasonable to examine the mechanism of how exercise can be used as an adjunct treatment for addiction. The present study examined the effects of chronic aerobic (treadmill) exercise on both GABA(a) and mu-opioid receptor levels in the brains of male and female rats. GABA(a) receptor binding, measured by [³H] Flunitrazepam, was increased in the cingulate cortex following exercise, but only in females. Mu-opioid receptor expression, measured by [³H] ([D-Ala², N-MePhe⁴, Gly-ol]-enkephalin) (DAMGO), showed no effect of exercise while showing an effect of sex, with increased [³H] DAMGO binding in the brains of sedentary males compared to that of sedentary females. Our findings support the potential role for GABA(a) signaling in the cingulate cortex as part of the mechanism of action of aerobic exercise. These data, along with prior reports, aid our understanding of the neurochemical impact and mechanism of chronic aerobic exercise on neuropsychiatric disease, particularly regarding addiction.
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In recent years there has been an increase in the development of new synthetic drugs, among which the “bath salt” 3,4-methylenedioxypyrovalerone (MDPV), a psychostimulant with a mechanism of action similar to those of cocaine and amphetamine, stands out. Drugs of abuse have been consistently shown to affect memory function in male rodents. We have recently shown that amphetamine and MDPV induce generalization of fear memory in an inhibitory avoidance discrimination task in male rats. Although abuse of illicit drugs is more prevalent in men than in women, several studies have demonstrated that females are more vulnerable to the effects of drugs of abuse than males and the effects caused by substance dependence on memory in females are still under-investigated. Thus, we examined the effects of subchronic amphetamine or MDPV administrations on memory in a contextual fear conditioning/generalization paradigm in adult male and female rats. Animals were given daily subchronic injections of the drugs, starting 6 days prior the beginning of the behavioral procedures until the end of the paradigm. On day 1 of the experimental protocol, all rats were exposed to a safe context and, the day after, to a slightly different chamber where they received an unsignaled footshock. Twenty-four and forty-eight hours later, freezing behavior and emission of 22 kHz-ultrasonic vocalizations (USVs) were measured in the two different contexts to assess fear memory retention and generalization. Our results indicate that MDPV treatment altered freezing in both sexes, USVs were affected by amphetamine in males while by MDPV in females.
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Of the more than 100 studies that have examined relationships between excessive ethanol consumption and the brain transcriptome, few rodent studies have examined chronic consumption. Heterogeneous stock collaborative cross mice freely consumed ethanol vs. water for 3 months. Transcriptional differences were examined for the central nucleus of the amygdala, a brain region known to impact ethanol preference. Early preference was modestly predictive of final preference and there was significant escalation of preference in females only. Genes significantly correlated with female preference were enriched in annotations for the primary cilium and extracellular matrix. A single module in the gene co-expression network was enriched in genes with an astrocyte annotation. The key hub node was the master regulator, orthodenticle homeobox 2 (Otx2). These data support an important role for the extracellular matrix, primary cilium and astrocytes in ethanol preference and consumption differences among individual female mice of a genetically diverse population.
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Chapter
Women were underrepresented in clinical research for many decades, especially regarding the use of alcohol and other substances. This fact, associated with the stigma related to chemically dependent women, has caused public policies for the care of harmful alcohol use to exclude or not give due importance to this population. In this chapter we describe the female gender specificities regarding the consumption of alcohol, its effects and biological, subjective, and social consequences. Women are more vulnerable than men to the physical harm of alcohol. They are affected by hormone-related issues, pregnancy, and maternity and have a different social role from men in our culture. Finally, we discuss the particularities of alcohol treatment and prevention programs for women, which should not follow the same model as men’s or mixed gender programs, but should adapt to these differences and be concerned with the barriers that most commonly keep them away from services.
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Stimulant use disorder is associated with significant global health burden. Despite evidence for sex differences in the development and maintenance of stimulant use disorder, few studies have focused on mechanisms underpinning distinct trajectories in females versus males, including the effect of the ovarian sex hormones estrogen and progesterone. This review aimed to identify and synthesise the existing preclinical and clinical literature on the effect of ovarian sex hormones on stimulant consumption in females. A systematic search of peer-reviewed literature identified 1593 articles, screened using the following inclusion criteria: (1) adult female humans or animals, (2) using stimulant drugs, (3) ovarian sex hormones were administered exogenously OR were measured in a validated manner and (4) with stimulant consumption as an outcome measure. A total of 50 studies (3 clinical and 47 preclinical) met inclusion criteria. High-estrogen (low progesterone) phases of the menstrual/estrus cycle were associated with increased stimulant use in preclinical studies, while there were no clinical studies examining estrogen and stimulant consumption. Consistent preclinical evidence supported progesterone use reducing stimulant consumption, which was also identified in one clinical study. The review was limited by inconsistent data reporting across studies and different protocols across preclinical laboratory paradigms. Importantly, almost all studies examined cocaine use, with impact on methamphetamine use a significant gap in the existing evidence. Given the safety and tolerability profile of progesterone, further research is urgently needed to address this gap, to explore the potential therapeutic utility of progesterone as a treatment for stimulant use disorder.
Article
Background Childhood trauma is associated with the development of adult mental health and substance use disorders, with females generally being more at risk. Alcohol is commonly used for coping with trauma, and alcohol use disorder (AUD) affects ∼14.4 million adult Americans annually. Research investigating sex differences in the environmental modification of anxiety and alcohol use following childhood trauma will extend our understanding of the etiology of AUD. Here, we sought to model the interacting effects of a single-episode late childhood trauma with post-trauma environment on adult alcohol use using male and female mice. Methods C57Bl6/J mice (d22) exposed to predator odor (TMT) or water were reared in standard environments (SE) or environmental enrichment (EE). Mice were assessed for adolescent anxiety and conditioned fear, and for adult alcohol use in a limited access, response non-contingent, alcohol exposure paradigm. Results A single exposure to predator odor was an effective stressor, inducing long-term sex-dependent changes in conditioned fear and alcohol behaviors that interacted with post-trauma environment. Adolescent EE females showed more conditioned freezing to the trauma-associated context. Adult EE mice consumed less total alcohol than SE mice. However, alcohol use across time differed for males and females. Exposure to a childhood stressor increased alcohol use significantly in females, but not males. EE males, but not EE females, drank less than SE counterparts. Conclusions Findings from this model recapitulate greater vulnerability to childhood trauma in females and support sex differences in post-trauma development of conditioned fear and alcohol use that are modified by environment.
Article
Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032-0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0-17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.
Article
Investigations have shown that the circadian rhythm can affect the mechanisms associated with drug dependence. In this regard, we sought to assess the negative consequence of morphine withdrawal syndrome on conditioned place aversion (CPA) and lateral paragigantocellularis (LPGi) neuronal activity in morphine-dependent rats during light (8:00−12:00) and dark (20:00−24:00) cycles. Male Wistar rats (250−300 g) were received intraperitoneal 10 mg/kg morphine or its vehicle (Saline, 2 mL/kg/12 h) in 13 consecutive days for behavioral assessment tests. Then, naloxone-induced conditioned place aversion and physical signs of withdrawal syndrome were evaluated during light and dark cycles. In contrast to the behavioral part, we performed in vivo extracellular single-unit recording for investigating the neural response of LPGi to naloxone in morphine-dependent rats on day 10 of morphine/saline exposure. Results showed that naloxone induced conditioned place aversion in both light and dark cycles, but the CPA score during the light cycle was larger. Moreover, the intensity of physical signs of morphine withdrawal syndrome was more severe during the light cycle (rest phase) compare to the dark one. In electrophysiological experiments, results indicated that naloxone evoked both excitatory and inhibitory responses in LPGi neurons and the incremental effect of naloxone on LPGi activity was stronger in the light cycle. Also, the neurons with the excitatory response exhibited higher baseline activity in the dark cycle, but the neurons with the inhibitory response showed higher baseline activity in the light cycle. Interestingly, the baseline firing rate of neurons recorded in the light cycle was significantly different in response (excitatory/inhibitory) -dependent manner. We concluded that naloxone-induced changes in LPGi cellular activity and behaviors of morphine-dependent rats can be affected by circadian rhythm and the internal clock.
Article
Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G-protein-dependent feedback pathways, mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G-protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABABR-dependent and D2R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D2R and GABABR in VTA DA neurons. Ablation of GABABR or D2R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABABR or D2R activation. D2R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABABR ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D2R nor GABABR ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G-protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction.
Article
Abstract Background Opioid use disorders are rising among females. So, there is a need for more recognition of the various factors contributing to this trend in women, to help us to plan effective interventions to this group of patients. Hence, we conducted this research to identify risk factors associated with opioid use in females including mood regulation, alexithymia, and personality disorders. The study included 60 females ranging from 18 to 45 years [30 females diagnosed with opioid use disorder according DSM-IV (case group), and 30 females with no mental illness diagnosis according to general health questionnaire (control group)]. The subjects were recruited from inpatients and outpatient clinic of Al-Abbassia Hospital, Cairo, Egypt. Both groups were assessed by the Structured Clinical Interview for DSM-IV axis II disorders (SCID II) for personality, Trait Meta-Mood Scale (TMMS) for emotional regulation and Toronto Alexithymia Scale-20 (TAS-20) for alexithymia. Results Regarding sociodemographic data, cases were significantly different from controls as they are less educated (P < 0.001), more 73% (22) unemployed (P
Article
BACKGROUND Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats. METHODS Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29. RESULTS SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults. CONCLUSION Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age.
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Animal models of addictive behaviors are useful for uncovering neural mechanisms involved in the development of dependence and for identifying risk factors for drug abuse. One such risk factor is biological sex, which strongly moderates drug self‐administration behavior in rodents. Female rodents are more likely to acquire drug self‐administration behaviors, consume higher amounts of drug, and reinstate drug‐seeking behavior more readily. Despite this female vulnerability, preclinical addiction research has largely been done in male animals. The study of sex differences in rodent models of addictive behavior is increasing, however, as more investigators are choosing to include both male and female animals in experiments. This commentary is meant to serve as an introductory guide for preclinical investigators new to the study of sex differences in addiction. We provide an overview of self‐administration models, a broad view of female versus male self‐administration behaviors, and suggestions for study design and implementation. Inclusion of female subjects in preclinical addiction research is timely, as problem drug and alcohol use in women is increasing. With proper attention, design, and analysis, the study of sex differences in addiction has the potential to uncover novel neural mechanisms and lead to greater translational success for addiction research.
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Activation of the mesolimbic dopamine system is known to trigger relapse in animal models of cocaine-seeking behavior. We found that this "priming" effect was selectively induced by D2-like, and not by D1-like, dopamine receptor agonists in rats. Moreover, D1-like receptor agonists prevented cocaine-seeking behavior induced by cocaine itself, whereas D2-like receptor agonists enhanced this behavior. These results demonstrate an important dissociation between D1- and D2-like receptor processes in cocaine-seeking behavior and support further evaluation of D1-like receptor agonists as a possible pharmacotherapy for cocaine addiction.
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Intact female rats and ovariectomized (OVX) rats with different ovarian steroid replacement regimens were tested for changes in corticotropin-releasing factor (CRF)-enhanced startle (increased acoustic startle amplitude after intracerebroventricular infusion of 1 mug of CRF). OVX rats injected with estradiol (E) followed by progesterone (P) showed a blunted CRF-enhanced startle effect compared with OVX and E-injected rats. CRF-enhanced startle also was reduced significantly in lactating females (high endogenous P levels) compared with cycling rats (low to moderate P levels), as well as in non-E-primed rats when P was administered acutely (4 hr before testing) or chronically (7 d P replacement). The ability of P to attenuate CRF-enhanced startle was probably mediated by its metabolite allopregnanolone [tetrahydroprogesterone (THP)], because THP itself had a similar effect, and chronic administration of medroxyprogesterone, which is not metabolized to THP, did not blunt CRF-enhanced startle but instead slightly increased it. These data suggest that P blunts CRF-enhanced startle through a mechanism involving its neuroactive metabolite THP, although a role for the P receptor cannot be completely ruled out. Finally, neither chronic P replacement nor acute THP affected fear-potentiated startle, suggesting that P metabolites have an effect on the bed nucleus of the stria terminalis and anxiety rather than on the amygdala and stimulus-specific fear.
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Extensive research indicates that chronic substance abuse disrupts stress and reward systems of the brain. Gender variation within these stress-system alterations, including the impact of sex hormones on these changes, may influence sex-specific differences in both the development of, and recovery from, dependency. As such, gender variations in stress-system function may also provide a viable explanation for why women are markedly more vulnerable than men to the negative consequences of drug use. This article therefore initially reviews studies that have examined gender differences in emotional and biophysiological changes to the stress and reward system following the acute administration of drugs, including cocaine, alcohol, and nicotine. The article then reviews studies that have examined gender differences in response to various types of stress in both healthy and drug-abusing populations. Studies examining the impact of sex hormones on these gender-related responses are also reported. The implications of these sex-specific variations in stress and reward system function are discussed in terms of both comorbid psychopathology and treatment outcome.
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Classical estrogen receptor-signaling mechanisms involve estradiol binding to intracellular nuclear receptors [estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta)] to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K(+)-evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ERalpha located on the membrane of medium spiny GABAergic neurons. This experiment examined whether overexpression of ERalpha in the striatum would enhance the effect of estradiol on rotational behavior and the K(+)-evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ERalpha cDNA (AAV.ERalpha) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ERalpha in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared with controls and exhibited behavioral sensitization of contralateral rotations induced by a low-dose of amphetamine. ERalpha overexpression also enhanced the inhibitory effect of estradiol on K(+)-evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior.
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Previous research indicates that progesterone (PROG) decreased cocaine-seeking behavior in female rats. This effect of PROG may be in part due to its metabolite allopregnanolone (ALLO), which has been shown to decrease the sensitizing effects of cocaine and reduce lethality associated with cocaine overdose in mice. The purpose of the present study was to examine the effects of ALLO on the reinstatement of cocaine-seeking behavior in female and male rats. Rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg per infusion) during 2-h sessions, and once acquisition criteria were met, cocaine self-administration continued for 14 days. Cocaine was then replaced with saline, and lever pressing was allowed to extinguish over 21 days. After the extinction phase, rats received s.c. ALLO (15 or 30 mg/kg), PROG (0.5 mg/kg), PROG (0.5 mg/kg) plus the 5-alpha reductase inhibitor finasteride (25 mg/kg), or vehicle pretreatment for 3 days. Rats were then tested during reinstatement with three doses of cocaine (5, 10, and 15 mg/kg, i.p. in mixed order). PROG, and to a greater extent ALLO, decreased cocaine-primed reinstatement in females, while finasteride blocked the attenuating effects of PROG on reinstatement. ALLO had no effect on cocaine-primed reinstatement in males. These findings suggest that ALLO may explain part of PROG's inhibitory effect on cocaine-primed reinstatement, and it may serve as a novel approach for preventing relapse in female cocaine abusers.
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This article is an initial report from a review of alcohol and drug treatment studies with follow-ups of 2 years or more. The goals of the review are to examine the stability of substance use outcomes and the factors that moderate or mediate these outcomes. Results from 12 studies that generated multiple research reports are presented, and methodological problems encountered in the review are discussed. Substance use outcomes at the group level were generally stable, although moderate within-subject variation in substance use status over time was observed. Of factors assessed at baseline, psychiatric severity was a significant predictor of outcome in the highest percentage of reports, although the nature of the relationship varied. Stronger motivation and coping at baseline also consistently predicted better drinking outcomes. Better progress while in treatment, and the performance of pro-recovery behaviors and low problem severity in associated areas following treatment, consistently predicted better substance use outcomes.
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To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.
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The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats. Animals were bilaterally ovariectomized (OVX), and a Silastic capsule (0.5 cm) containing 17 beta-estradiol was sc implanted. Control animals received a blank capsule. Animals were killed 21 days later. In E-treated rats, we found significantly higher corticosterone (CORT) peak levels 20 min after a 5-sec footshock (1.0 mamp) or exposure to ether vapors (P less than 0.05) compared to those in OVX controls. In addition, the recovery of the ACTH and CORT responses to footshock stress was significantly prolonged (P less than 0.05) in the presence of E. Furthermore, the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback. Consequently, we examined the influence of E on mineralocorticoid and glucocorticoid receptor concentrations using in vitro binding assays. E did not alter mineralocorticoid or glucocorticoid receptor concentrations in any of the brain regions examined. The administration of RU 28362 (40 micrograms/100 g BW for 4 days) to OVX control or E-treated rats significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.02) in control rats only. In contrast, aldosterone administration (40 micrograms/100 g BW for 4 days) significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.0008) in both control and E-treated animals. Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback.
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Regulation of drug intake refers to the maintenance of relatively constant levels of drug over a specified time period. An understanding of regulation of drug intake may be critical in determining how drugs function as reinforcers and how their reinforcing effects may be modified. However, little is known about regulation of drug intake, and the mechanisms underlying it are poorly understood. Three mechanisms that have proposed to account for findings of regulation of drug intake were discussed to determine their relevance for drug-reinforced responding. These mechanisms include aversive effects, direct effects, and satiation. Although a greater role for satiation was supported in this review, drugs may vary on the degree to which they can produce satiation and whether satiation acts in concert with either the aversive effects or the direct effects of drugs is unclear.
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The recent cloning of a second estrogen receptor (ER) provided a new tool to investigate and clarify how estrogens are capable of communicating with the brain and influence gene expression and neural function. The purpose of the present study was to define the neuroanatomical organization of each receptor subtype using a side-by-side approach and to characterize the cellular population(s) expressing the ERβ transcript in the endocrine hypothalamus using immunohistochemistry combined with in situ hybridization. Axonal transport inhibition was accomplished to cause neuropeptide accumulation into the cytoplasm and thus facilitate the detection of all positive luteinizing hormone-releasing hormone (LHRH), corticotropin-releasing factor (CRF), vasopressin (AVP), oxytocin (OT), gastrin-related peptide (GRP), and enkephalin (ENK) neurons. The genes encoding either ERα or -β were expressed in numerous limbic-associated structures, and fine differences were found in terms of intensity and positive signal. Such phenomenon is best represented by the bed nucleus of the stria terminalis (BnST) and preoptic area/anterior hypothalamus, where the expression pattern of both transcripts differed across subnuclei. The novel ER was also found to be expressed quite exclusively in other hypothalamic nuclei, including the supraoptic (SON) and selective compartments (magnocellular and autonomic divisions) of the paraventricular nucleus (PVN). A high percentage of the ERβ-expressing neurons located in the ventro- and dorsomedial PVN are of OT type; 40% of the OT-ir cells forming the medial magnocellular and ventromedial parvocellular PVN showed a clear hybridization signal for ERβ mRNA, whereas a lower percentage (15–20%) of OT neurons were positive in the caudal parvocellular PVN and no double-labeled cells were found in the rostral PVN and other regions of the brain with the exception of the SON. Very few AVP-ir neurons expressing ERβ transcript were found throughout the rat brain, although the medial PVN displayed some scattered double-labeled cells (<5%). Quite interestingly, the large majority of the ERβ-positive cells in the caudal PVN were colocalized within CRF-ir perikarya. Indeed, more than 60–80% of the CRF-containing cells located in the caudolateral division of the parvocellular PVN exhibited a positive hybridization signal for ERβ mRNA, whereas very few (<5%) neuroendocrine CRF-ir parvocellular neurons of the medial PVN expressed the gene encoding ERβ. A small percentage of ERβ-expressing cells in the dorsocaudal and ventromedial zones of the parvocellular PVN were also ENK positive. The ventral zone of the medial parvocellular PVN also displayed GRP-ir neurons, but no convincing hybridization signal for ERβ was detected in this neuronal population. Finally, as previously described for the gene encoding the classic ER, LHRH neurons of both intact and colchicine-pretreated animals did not express the novel estrogen receptor. This study shows a differential pattern of expression of both receptors in the brain of intact rats and that ERβ is expressed at various levels in distinct neuropeptidergic populations, including OT, CRF, and ENK. The influence of estrogen in mediating genomic and neuronal responses may therefore take place within these specific cellular groups in the brains of cycling as well as intact male mammals. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 357–378, 1998
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5α-Pregnane-3α,21-diol-20-one (THDOC; 5 mg/kg) and the triazolobenzodiazepine alprazolam (1 mg/kg) attenuated mild stress-induced increase in plasma corticosterone concentrations via GABAergic mechanisms. Unlike alprazolam, THDOC failed to decrease corticotropin-releasing factor (CRF) concentrations in the locus ceruleus. While THDOC may plausibly act via endogenous GABAergic mechanisms to reduce stress-induced endocrine and behavioral responses that are likely mediated in part by CRF neurons, these preliminary findings suggest that, at the dose and time point studied, THDOC does not identically mimic the actions of alprazolam, another drug which potentiates GABAergiv activity.
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Sex differences in ethanol intake in rats suggest that there may be sex differences in brain dopamine systems believed to mediate ethanol’s reinforcing properties. To test this hypothesis, we used in vivo microdialysis to examine changes in nucleus accumbens and striatal dopamine, DOPAC and HVA following acute administration of several doses of ethanol in male and female Long-Evans rats. Following dialysis, rats were trained to bar press for oral ethanol reinforcement. In nucleus accumbens, females showed greater increases in dopamine than males at low to intermediate doses. In striatum, both sexes showed increased dopamine at the low to intermediate doses. In addition to showing increased responsiveness to ethanol-induced mesolimbic dopamine stimulation, females consumed more ethanol than males during behavioral testing. Correlations between neurochemical measures and subsequent ethanol consumption indicated that among males, both basal and peak ethanol-induced nucleus accumbens dopamine levels were inversely related to later ethanol intake. No such relationship was observed for females. Striatal neurochemical measures were not significantly related to ethanol intake. These findings supported the hypothesis of sex differences in mesolimbic responses to ethanol and suggested that the relationship of those responses to subsequent ethanol intake may differ for males and females.
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The effects of marijuana cigarette (1.8% THC) smoking on pulse rate and mood were studied under double-blind placebo-controlled conditions in 28 adult female volunteers during the follicular, luteal, and ovulatory phases of the menstrual cycle. Statistically significant increases in pulse rate, subjective levels of intoxication, and the POMS confusion factor occurred after marijuana smoking. However, no statistically significant differences for any measure were observed following marijuana smoking as a function of menstrual cycle phase. Subjects with a past history of intermittent marijuana use (five or less times weekly) had significantly higher pulse rates, subjective levels of intoxication, and POMS confusion factor scores than did subjects with a past history of regular (six or more times weekly) marijuana use. Persistence of marijuana-induced changes in pulse rate, intoxication, and confusion were also of longer duration for subjects with a past history of intermittent marijuana smoking. The influence of past history of marijuana use on marijuana-induced alterations in pulse rate, intoxication, and mood for females appears to be similar to males. These similarities are not attenuated as a function of the menstrualcycle phase of females.
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During normal development there is a perinatal sensitive period during which the male brain is exposed to high levels of gonadal steroids, resulting in permanent differentiation of neural substrates. The cellular mechanisms mediating hormonally induced sexual differentiation remain largely unknown. In the adult brain, steroids exert profound influences on the amino acid transmitters, GABA, and glutamate. We have found steroid regulation of amino acid neurotransmission during the perinatal sensitive period and propose this may be functionally related to sexual differentiation of the brain. Specifically, the mRNA coding for the rate-limiting enzyme in GABA synthesis, glutamic acid decarboxylase (GAD), is up to twice as high in some steroid-concentrating regions of the neonatal male brain compared to females, including the arcuate nucleus, dorsomedial nucleus, and the CA1 region of hippocampus. Sex differences in GABA tissue concentrations positively correlate with GAD mRNA differences in several brain regions. There are also sex differences in protein levels of GABAA receptor subunits. In parallel with these findings are significantly higher levels of binding to the non-NMDA glutamate receptor in steroid-concentrating regions of male brain. Given that GABA is an inhibitory transmitter and glutamate is an excitatory amino acid, these results initially appear paradoxical. However, in contrast to its inhibitory action in the adult brain, early in development GABA is actually excitatory and acts in a manner analogous to glutamate. Therefore, the combination of increased excitatory GABAergic and glutamatergic activity should result in substantially higher levels of neuronal excitation in the male brain. We speculate that an increased level of neuronal excitation is a potential mechanism mediating the permanent masculinization of the brain.
Article
Regional changes in striatal D2 dopamine (DA) receptor binding in castrated (CAST) or ovariectomized (OVX) rats were investigated following administration of a low dose of estradiol benzoate (EB), repeated treatment with EB followed by progesterone, or vehicle. In two separate experiments, there was a significant decrease in striatal D2 DA receptor binding in caudal striatum from OVX, but not CAST rats 30 min after a single injection of EB. In CAST rats, there was a significant increase in striatal D2 DA receptor binding in rostral striatum 4 h after injection of EB. There was no effect of EB plus progesterone treatment in either OVX or CAST rats. In addition, CAST rats had significantly lower D2 DA receptor binding in the lateral region of the rostral striatum than did OVX rats. These results show sexually dimorphic and regionally specific effects of estrogen on striatal D2 DA receptor binding, and a significant sex difference in striatal D2 DA receptor binding in the absence of circulating gonadal hormones. The present findings are discussed in light of previous reports of sex differences in gonadal hormone influences on striatal DA mediated behaviors.
Article
Experiments were conducted to examine sex differences in striatal dopamine function using in vivo microdialysis in freely moving rats. We report here a sex difference in basal extracellular striatal dopamine determined by quantitative microdialysis (the no net flux method) when castrated and ovariectomized rats were compared. There was no sex difference in dopamine uptake into synaptosomes. This indicates that the sex difference in extracellular dopamine is most likely due to sex differences in dopamine release, synthesis, and/or metabolism. Within 30 min after a single injection (s.c.) of either estradiol benzoate (2.0 μg/100 g) or 17β-estradiol (1.5 μg/100 g) the amphetamine-stimulated release of dopamine was enhanced in the striatum of ovariectomized rats, but there was no effect in castrated male rats. The enhanced amphetamine-induced striatal dopamine release in ovariectomized rats was associated with an enhanced frequency of stereotyped head and limb movements and an increased peak in extra 1/4 turns. There were also sex differences in stereotyped behavior and extra 1/4 turns whether or not animals received estrogen treatment. Thus, there are sex differences in striatal extracellular dopamine and in the effect of estrogen on the striatal dopamine neurochemical and behavioral responses to amphetamine.
Article
Ovariectomy (OVX) of female rats results in a decreased behavioral response to stimulation of the mesostriatal dopamine (DA) system and decreased striatal DA release in vitro. Estrogen replacement restores both behavioral and neurochemical responsiveness. In this report, microdialysis in freely moving rats is used to simultaneously study the behavioral and neurochemical effects of systemic estradiol. OVX rats received a unilateral 6-hydroxy-dopamine lesion of the substantia nigra and then underwent microdialysis of the intact striatum. Thirty min after a single injection of 5 μg estradiol benzoate, amphetamine-induced rotational behavior and striatal DA release are both potentiated, relative to the response of oil-treated control animals.
Article
In female rats the gonadal hormones estrogen and progesterone modulate dopamine (DA) activity in the striatum and nucleus accumbens. For example, there is estrous cycle-dependent variation in basal extracellular concentration of striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA-mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced striatal DA release, and behaviors mediated by the striatal DA system. Estrogen rapidly and directly acts on the striatum and accumbens, via a G-protein–coupled external membrane receptor, to enhance DA release and DA-mediated behaviors. In male rats, estrogen does not affect striatal DA release, and removal of testicular hormones is without effect. These effects of estrogen also result in gender differences in sensitization to psychomotor stimulants. The effects of the gonadal hormones on the striatum and ascending DA systems projecting to the striatum and nucleus accumbens are hypothesized to occur as follows: estrogen induces a rapid change in neuronal excitability by acting on membrane receptors located in intrinsic striatal GABAergic neurons and on DA terminals. The effect of these two actions results in enhanced stimulated DA release through modulation of terminal excitability. These effects of gonadal hormones are postulated to have important implications for gender differences in susceptibility to addiction to the psychomotor stimulants. It is suggested that hormonal modulation of the striatum may have evolved to facilitate reproductive success in female rats by enhancing pacing behavior.
Article
The release of endogenous dopamine (DA) from rat striatal tissue was studied in an in vitro superfusion system following hormonal manipulations in vivo. Progesterone treatment in estrogen-primed ovariectomized female rats potentiated DA release stimulated either by amphetamine or potassium (K+). In addition, the amount of striatal DA released in response to K+-stimulation was influenced by the light-dark cycle. We conclude that striatal DA release is modulated by ovarian hormones, and suggest that ovarian hormone modulation of presynaptic striatal DA activity may contribute to well-known estrous cycle dependent variations in some non-reproductive behaviors.
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Nicotine intake, menstrual and smoking withdrawal symptomatology, and baseline cortisol and MHPG were assessed in nine women smokers under conditions of ad lib smoking and overnight abstinence in three menstrual phases (early follicular, mid-to-late follicular, and late luteal). A trend towards higher nicotine intake p <0.100 was observed in the mid-to-late follicular phase. Although me menstrual symptomatology was not significantly elevated during the smoking abstinence condition overall, abstinence appeared to prevent the normal reduction in symptomatology during the mid-to-late follicular phase that occurred under conditions of ad lib smoking. Menstrual and withdrawal symptoms were highly correlated, and both were most pronounced during the late luteal/abstinence condition. The smoking-specific item “craving” reflected this pattern, though in attenuated form, suggesting that the observed exacerbation of withdrawal symptomatology was not simply due to generalized dysphoria, as queried in both instruments. MHPG was significantly elevated in the late luteal phase, whereas cortisol was significantly higher during ad lib smoking than during abstinence and tended to be highest in the mid-to-late follicular phase. Further investigation will be needed to determine the functional significance of these findings for understanding and treating smoking in women.
Article
The results of 3 experiments examining the influence of estrogen on the nigrostriatal dopamine (DA) system are reported. In two experiments the influence of hormonal manipulations on amphetamine (AMPH)-induced rotational behavior was investigated using rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. It was found that: (1) female rats in estrus make more rotations than ovariectomized (OVX) rats; and (2) estrogen treatment (5 μg estradiol benzoate, daily for 4 days) in OVX rats enhances AMPH-induced rotational behavior 4 h and 4 days after estrogen treatment. During the intervening period, at 24 h after cessation of estrogen treatment, control and hormone-treated animals did not differ. In a third experiment, the effect of estrogen treatment on the release of endogenous DA from striatal tissue slices in superfusion was examined. Estrogen enhanced AMPH-stimulated striatal DA release 4 h after the last treatment relative to OVX controls. However, 24 h and 4 days after estrogen treatment DA release had returned to control levels. It is suggested that estrogen has an immediate potentiating effect on striatal DA release, and this may be responsible for the increased behavioral response to AMPH 4 h after estrogen treatment. The previously demonstrated increase in postsynaptic striatal DA receptors may be responsible for the second increase in AMPH-induced rotational behavior, that occurs 4 days after estrogen treatment.
Article
Humans are routinely exposed to a vast array of environmental neurotoxicants, including pesticides, endocrine disrupters, and heavy metals. The long-term consequences of exposure have become a major human health concern as research has indicated strong associations between neurotoxicants and a variety of dopamine-related neurological disorders. Developmental exposure to pesticides including paraquat, organochlorines, and rotenone produce alterations in the dopaminergic system and has been linked to neurodegenerative disorders, including Parkinson's disease. Endocrine disrupters such as Bisphenol A, mimic estrogenic activity and impact various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse. A second class of endocrine disrupters, the polychlorinated biphenyls, may act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson-like symptoms. Exposure to the heavy metal lead enhances dopaminergic activity and has been associated with attention deficits, Alzheimer's disease, and increased drug sensitivity. Manganese exposure, in contrast, results in dopamine deficiencies and Parkinson-like symptoms. Therefore, this commentary will discuss the effects and consequences that exposure to these three classes of environmental neurotoxicants have on the dopamine system and related behaviors and disorders. Finally, the recent hypothesis that exposure to environmental compounds which have effects on dopaminergic neurotransmission, including 2,4-dichlorophenoxyacetic acid, Bisphenol A, and multiple heavy metals, may potentiate drug-induced behaviors and increase the brain's vulnerability to drug addiction will be discussed.
Article
The purpose of this experiment was to investigate the regulation of drug intake in rats (n = 20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions.
Article
Sex differences exist in several aspects of cocaine abuse, and recent research suggests that this may be due, in part, to differential sensitivity to stress. Women, compared to men, exhibit greater stress-induced cocaine craving and responses to both cocaine and stress fluctuate during phases of the hormonal cycle. The goal of the present study was to compare male and female rats on the maintenance and extinction of cocaine seeking and on an animal model of stress-induced relapse by administering the pharmacological stressor yohimbine. An additional goal was to examine possible sex-specific treatment effects of the progesterone metabolite, allopregnanolone, on yohimbine-induced reinstatement. Male and female rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg). Following a 14-day maintenance period, cocaine solutions were replaced with saline, and rats were allowed to extinguish lever pressing. Subsequently, rats were administered saline, yohimbine (2.5mg/kg), or allopregnanolone (15 mg/kg)+yohimbine (2.5mg/kg) priming injections on separate days using a within-subjects reinstatement procedure. The results indicated that females were more resistant to extinction than male rats and that both groups reinstated cocaine seeking following injections of yohimbine; however, female rats responded more than males to yohimbine-priming injections. Additionally, allopregnanolone blocked yohimbine's potentiating effect on responding in females but not males. These results suggest that females may be more sensitive than males to stress-induced reinstatement of cocaine-seeking behavior, and the progesterone metabolite, allopregnanolone, offers protection against this vulnerability.
Article
Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies.