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Try out PMC Labs and tell us what you think. Learn More. Sex differences and gender are not solely determined by biology, nor are they entirely sociocultural. The interactions among biological, environmental, sociocultural and developmental influences result in phenotypes that may be more masculine or more feminine.

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These gender-related sex differences in the brain can influence the responses to drugs of abuse, progressive changes in the brain after exposure to drugs of abuse and whether addiction from drug-taking experiences. The theme of this special issue is sex differences in the brain. This article will discuss the topic of gender and sex differences in drug addiction, our field of study, but there are similar gender and sex differences in compulsive behaviors such as gambling Potenza et al. We define addiction as the chronic, compulsive use of a substance or engagement in a behavior, regardless of negative consequences.

We use sex to refer to the characterization of an individual as female or male from biological and morphological features. As discussed below, there are similar sex differences in humans and rodents in addiction or addiction-like behaviors respectively.

This suggests that there are some basic biological differences between females and males that influence how each responds to drugs of abuse and engage in addictive behaviors Becker et al. Gender is defined as a system of social organization with a set of behavioral prescriptions that are believed to follow from biological sex characteristics.

These perceptions of gender are socially constructed and shaped by sociocultural structures and processes over time Fausto-Sterling Researchers in the social and natural sciences have demonstrated that addictions and consequences of addictions differ by biological sex and also by gender Becker et al. A thesis of this article is that gender and sex differences in addiction are a complicated interaction between sociocultural factors and neurobiological sex differences.

When a scientist describes findings of sex differences that result in women becoming addicted more rapidly than men Anglin et al. While it is likely that some individuals are more vulnerable for addiction, as will be discussed below, it is not an inevitable outcome that a vulnerable person will necessarily become an addict. It is important to do so. Scientific findings need to be presented in a way that does not attribute sex differences in addiction entirely to the brain, and this message conveyed to the media as well.

This idea will be revisited at the conclusion of this article. These two types of sex differences differ in the extent to which they may be modified by environmental and sociocultural factors, with cognitive sex differences being affected to a greater extent by learning.

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First, some evidence for sex differences in addiction, in both animals and humans will be briefly reviewed. This has been the topic of a of detailed reviews recently Becker and Koob ; Carroll and Lynch ; Perry et al. This section provides a brief overview of the state of current knowledge regarding gender, and sex differences in addiction. As a result, findings remain incomplete and sometimes contradictory, particularly when the LGBT community is considered Hughes et al. Nevertheless, humans, monkeys and rodents exhibit similar sex differences in addiction-like behavior Carroll et al.

Effects of the environment and positive or negative experience can also affect the brain and influence vulnerability to addiction differently in males and females Bowman et al. For centuries it has been known that the phenomenon we now call addiction is a progressive condition. The initial stage involves engagement with the drug, when the person or animal experiences its rewarding aspects after sampling the drug.

It is important to note that some individuals never progress past this point, indefinitely using the drug occasionally or even stopping use. During acquisition the individual is not addicted, but for some individuals engagement and drug taking escalates and addiction follows, while others maintain moderate intake indefinitely or even stop using altogether Deroche-Gamonet et al. Using drugs can be related to social roles; for most of American history, men were much more likely than women to drink alcohol and use illicit drugs recreationally, while women were more likely to be prescribed drugs as medicine McClellan ; Kandall ; McClellan Today, however, in adolescents equal s of boys and girls ages 12—17 use illegal drugs Substance Abuse and Mental Health Services Administration Within the general population, individuals differ in their risk for addiction due to a range of factors including genetic and personality traits Heinrich et al.

Physicians, psychiatrists and social workers have believed since early in the 20 th century that women escalate alcohol use rapidly once they start McClellan ; McClellan ; Kandall Still, we do not know what makes some individuals at greater risk for addiction. For those women and men who are vulnerable to addiction i. In contrast, a recent analysis of data from two U. More rapid escalation after initiation of drug use in women compared with men has been replicated for other drugs of abuse Richmond-Rakerd et al.

Thus, we are defining vulnerable as those who show rapid escalation of drug taking. During attempts to quit drug use abstinencewomen exhibit greater unpleasant symptoms than men do Hogle and Curtin ; Becker and Koob When trying to quit smoking, women also go through more severe withdrawal than men Hogle and Curtin Women report greater effects on mood and anxiety as well as a greater stress response, compared to men Hogle and Curtin On the other hand, males exhibit greater withdrawal symptoms when quitting alcohol consumption than females do Devaud et al.

Most data suggest that women and men have similar outcomes after treatment for substance use disorders Greenfield et al.

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What has been reported to differ between women and men are the factors related to relapse, which is reported to be more sporadic occurring without apparent trigger or intent and related to negative affect as well as physical and sexual abuse among women Greenfield et al. This propensity to relapse associated with negative affect could be related to the greater withdrawal responses that women exhibit for some drugs Hudson and Stamp ; Sinha et al.

Alternatively, women might experience greater sensitivity to stress or the cues associated with the drug, as relapse can be triggered by these variables Hudson and Stamp Greater stress or cue-induced reinstatement of drug taking by females after abstinence is seen in animal models of drug self-administration Feltenstein et al. All of these factors have been reported to be related to relapse in studies of men and women who are addicted and are trying to quit Becker and Koob There are also issues related to social support for maintaining abstinence, with men tending to receive more social support at home and on the job and women tending to be more isolated or not supported by their partners in their decision to be abstinent Gallop et al.

Additionally, women who are addicted experience greater stigma than do men; this combined with less social support means more isolation and greater risk for relapse for women than men Becker et al. Sex and gender differences in addiction and relapse can be seen in humans and in animal models. Among the vulnerable populations, females escalate drug use more rapidly than males and relapse is more likely to be triggered by stressful events or drug-related cues.

But these differences are not solely determined by biology: sociocultural influences also differentially affect men and women and how they respond to drugs of abuse. In humans, stigma, on-going interpersonal violence, many more barriers to treatment-seeking and engagement, lack of social support for recovery among girls and women.

The animal models as well as the clinical research need to take into consideration how contextual and social factors may influence the processes of addiction and relapse differentially in males and females. For this very brief discussion of the neurobiology of sex differences in addiction we will focus on the nucleus accumbens and the dorsal striatum, but other areas of the brain are also involved in the neurobiology of addiction and the reader is referred to recent reviews for more details Becker and Koob, ; Becker et al.

One current model for the development of addiction is that the nucleus accumbens is important for engaging in behaviors that are initially rewarding, while the dorsal striatum is involved in escalated drug taking and compulsive behaviors Clark et al. In this model of addiction, when dopamine activation of the dorsal striatum becomes greater than the response to the drug in the nucleus accumbens, there is a loss of pleasure associated with drug taking even though drug taking increases DiFeliceantonio and Berridge ; Castro and Berridge The dorsal striatum is important for well-learned patterns of behavior that can operate in the background without intentional control, which is usually exerted by the prefrontal cortex.

For some habits such as learning to drive a car with manual transmission, this is an advantage for being able to shift gears when needed without conscious thought.

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The pattern of behavior, once learned, can be executed without thinking about it and it transfers from one car to another even when the gearshift is in a different position. This flexible pattern of automatic behavior also characterizes addiction.

When intake progresses from being a casual pleasure to avid and compulsive intake, the pattern of activation in the brain has also shifted from dopamine activation in the nucleus accumbens to dopamine activation in dorsolateral striatum Willuhn et al. Among female rats and humans that become compulsive drug takers, there is the tendency to experience the shift in loss of voluntary control of drug intake to compulsive drug intake more rapidly than for males Becker et al. Female rats tend to exhibit a smaller response in the nucleus accumbens to drug stimulation initially, compared with males, and have a relatively greater and more rapid initial response in the dorsal striatum to drugs, coupled with a decrease in the accumbens response after cocaine taking is well established Cummings et al.

This brain pattern may underlie the sex difference in escalation of drug taking that le to addiction. Supporting this notion, women who are smokers exhibit a lower response in the ventral striatum than in the dorsal striatum to nicotine stimulation compared with male smokers Cosgrove et al.

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Investigators have considered whether the long-term changes in the brain induced by exposure to the drug of abuse are what cause an individual to become addicted to that drug. Even though all individuals, both human and animal, will exhibit changes in the brain after receiving a drug of abuse Leyton ; Wegener and Koch ; Willuhn et al.

In these studies animals are considered to exhibit addiction-like behavior if they continue to take a drug when receiving an aversive mild shock, exhibit high levels of responding on a progressive ratio schedule and continue to respond for the drug under conditions when drug is not available. A few studies have examined the proportion of female rats that develop addiction-like behavior in the laboratory; in these studies where males and females are allowed to choose cocaine or a food reward, more females than males choose cocaine and females exhibit higher responding for cocaine than do males Perry et al.

Not many studies have examined the neural mechanisms for sex differences in drug-taking behavior, and more research is clearly needed. In the studies that have investigated sex differences in addiction-like behavior in the laboratory, female rats tend to exhibit similar patterns of drug taking behavior to those seen for women.

For example, female rats acquire drug self-administration more readily than males Carroll et al. This is true for all classes of drugs studied and for both rats and monkeys Carroll et al. Female rats also escalate their drug use more rapidly than males, take more drug when they get to maintenance dose and females will work harder to get a dose than male rats will Roth and Carroll ; Westenbroek et al.

There are changes in the brain of all individuals who get a drug, but the changes in the brains of individuals who become addicted are different from those who do not. This is assumed because the behavior of an addict is different from the behavior of a non-addict — if the behavior is different the brains are different.

Why the changes in the brain are not the same between addicts and non-addicts is not yet completely known. Individual differences in genetics, personality traits, extent of social support, experiences or trauma during development, and in whether one is male or female are all thought to contribute to how someone responds to drugs of abuse and whether one develops compulsive behaviors associated with an addiction Cummings et al.

This means that even though individuals can be categorized as male or female, or brought up in an impoverished vs. Studies of rodents show that females exhibit enhanced drug- cue- and stress-induced reinstatement in alcohol, cocaine and morphine seeking, compared to males Feltenstein et al. The laboratory evidence supports the idea that there are biological components to the sex differences.

But this does not mean that all women are going to be addicts or that women cannot quit once they have started. In fact, studies document many barriers for women in traditional treatment programs, and that treatment programs tailored for women tend to be more successful Campbell and Ettore The hormone condition of a woman needs to be considered when thinking about sex differences in addiction. The human menstrual cycle consists of follicular, periovulatory, and luteal phases.

During the 10—12 day follicular phase, the hormone estradiol is secreted from the ovary as the follicle develops, with concentrations of estradiol increasing daily. Next, during the 2—4 day peri-ovulatory phase, a rapid increase in estradiol triggers the release of luteinizing hormone from the pituitary that induces ovulation. This is followed by the luteal phase that lasts 10—12 days and is characterized by the release of relatively high concentrations of both estradiol and progesterone from the remnant of the follicle that is retained by the ovary the corpus luteum.

Menstruation occurs at the end of the luteal phase, unless pregnancy occurs. During menstruation hormone levels are at their lowest point, indicating the beginning of the next follicular phase Becker et al. Rats and mice do not have a spontaneous luteal phase Becker et al.

The acute subjective effects of drugs of abuse can vary over the menstrual cycle in humans. For example, in women the subjective effects of cocaine and amphetamine tend to be more intense during the follicular phase when estradiol is elevated, relative to the luteal phase of the menstrual cycle when both estradiol and progesterone increase Justice and de Wit ; Justice and De Wit ; Evans et al. It is not clear, however, that these subjective effects of estradiol and progesterone moderate intake in the cocaine-addicted woman, as exogenous progesterone did not decrease the self-administration of cocaine in this population of women Reed et al.

Most of the research on how ovarian hormones influence drug taking behavior in females has been done in rats and mice. In ovariectomized OVX female rats, estradiol administration affects behaviors that are induced by cocaine, amphetamine or methamphetamine, including drug self-administration. For example, OVX decreases cocaine-taking behavior. If an OVX rat is given estradiol, the rat will take more cocaine and work harder to get cocaine, just as an intact rat during estrus will work harder for cocaine Becker and Hu ; Roberts et al.

On the other hand, in males neither testicular hormones nor estradiol affects cocaine-taking Jackson et al. This sex difference is attributable to sexual differentiation of the brain during early life Perry et al. Estradiol also enhances the acquisition of opioid self-administration in OVX rats, and intact females acquire morphine and heroin self-administration faster and will work harder to get cocaine, morphine and heroin than will males Jackson et al.

Most laboratory studies are conducted with rats isolated in the testing chamber for hours. The chamber contains a lever or nose poke hole. The rat may receive an intravenous injection of a drug, such as cocaine, by pressing the lever or poking its nose into the hole. The rats learn to lever press or nose poke and start receiving drug. Most rats self-administer the drug, but not all rats will be highly motivated to get the drug under these conditions as determined by a progressive ratio schedule where the of responses increases exponentially to get a single dose.

When criteria are applied that are analogous to the DSM-IV criteria responding for drug in the presence of adverse consequences; exhibiting high rates of responding for the drug on a progressive ratio schedule; responding for drug even when not available; and loss of motivation for ly valued rewards such as highly palatable foodonly a small percentage of male rats exhibit characteristics of addiction Perry et al.

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