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Try out PMC Labs and tell us what you think. Learn More. Sex differences are present for all of the phases of drug abuse initiation, escalation of use, addiction, and relapse following abstinence. While there are some differences among specific classes of abused drugs, the general pattern of sex differences is the same for all drugs of abuse. Females begin regularly self-administering licit and illicit drugs of abuse at lower doses than do males, use escalates more rapidly to addiction, and females are at greater risk for relapse following abstinence.

In this review, sex differences in drug abuse are discussed for humans and in animal models. The possible neuroendocrine mechanisms mediating these sex differences are discussed. Drug abuse begins with acquisition or initiation of drug taking and in vulnerable individuals can eventually progress through phases Women want sex Cave increased drug taking until an individual is addicted. Sex differences are present for all of the phases of drug abuse, which includes initiation, then escalation of use and the progression to addiction, with subsequent withdrawal followed by relapse [ 2782, ].

The rates Women want sex Cave drug abuse are currently lower in women than in men. Nevertheless, the of women using and abusing prescription and illegal drugs is on the rise. If one looks at rate of escalation of drug use, however, women tend to increase their rate of consumption of alcohol, marijuana, opioids and cocaine more rapidly than do men [ 1954828699 ].

Furthermore, once addicted to a drug, women can find it more difficult to quit than men do. This is true for nicotine, as well as many other drugs of abuse [ 6212682 ]. Most of the research on sex differences in drug abuse, in both clinical and pre-clinical studies, has investigated the psychomotor stimulants, so opiates, nicotine, and alcohol are grouped together in this overview for convenience.

In humans, whether there is a sex difference in the pattern of opiate use has been questioned [ 82 ]. Nevertheless, some studies of addicts indicate that women tend to escalate their use of heroin more rapidly, become addicted in a shorter period of time, and seek treatment earlier than men do [ 359 ]. Women report shorter intervals between cigarettes, and find it more difficult to quit smoking cigarettes than men reviewed in [ 82].

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In a review of 13 studies that looked at the effect of menstrual cycle on smoking cessation, women tend to have a more difficult time quitting depending on the phase of menstrual cycle, with greater craving and dysphoria during the late luteal phase when estrogen and progesterone are declining than during the follicular phase of the cycle when estradiol is low and increasing and progesterone is low [ 26 ].

Women also exhibit a greater negative affective response to a cue that predicts electric shock during nicotine withdrawal, than do men [ 55 ]. One possibility for the menstrual cycle effects on smoking cessation is that during the follicular phase estradiol decreases anxiety and negative affect, thereby alleviating some of the negative consequences of smoking cessation.

Support for this idea comes from clinical and pre-clinical research showing that estradiol decreases anxiety and enhances positive affect [ ]. Yet, the frequency that young women are becoming intoxicated on alcohol on a regular basis is rising, and the medical consequences of chronic alcohol consumption are more severe for women than for men.

For example, women become addicted to alcohol more rapidly than do men [ ], and brain atrophy develops more rapidly in women than in men other negative medical consequences involve the heart, muscle and liver which are also compromised more rapidly in women than in men [ 86 ]. Cocaine abuse in particular has increased in the last decade among women so that of the 1. According to this recent report, among users years old The use and dependence among women of stimulant drug use is a Women want sex Cave public health concern in the USA [ 2782] and in other countries [ 2223 ].

As with other drugs of abuse, evidence suggests that women are more vulnerable to some aspects of psychostimulant abuse. Women begin using cocaine or amphetamine AMPH and enter treatment at earlier ages than men [ 5190 ] and have more severe cocaine use at intake than men [ 70 ].

Thus, the progression to dependence may differ between men and women, with women progressing through the landmark stages from initial use to dependence at a faster rate [ 1871 ].

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In women, the subjective effects of stimulants vary across the menstrual cycle [ 66 - 68 ]. For example, several of the positive subjective effects of d -AMPH such as euphoria, desire, increased energy and intellectual efficiency are potentiated during the follicular phase when estradiol levels are low at first Women want sex Cave rise slowly; progesterone levels are low relative to the luteal phase when estradiol levels are moderate and progesterone levels are high.

Additionally, administration of estradiol during the follicular phase further increases the subjective effects of d-AMPH [ 67 ]. In contrast, the subjective effects of psychomotor stimulant drugs are negatively correlated with salivary progesterone levels in women [ ], and progesterone administered during the follicular phase has been reported to attenuate the subjective response to repeated self-administered cocaine [ 4445]. Abstinent women report higher levels of craving following exposure to cocaine-related cues than do men [ ], and women have longer periods of use after abstinence than do men [ 49 ].

Such differences may be due to sociocultural factors as well as biological factors. Collectively, these suggest that women may be more sensitive to the addictive properties of cocaine than men. However, this evidence is based primarily on retrospective reports, and relatively little is known about Women want sex Cave neurobiological basis for sex differences in motivational processes in general.

Basic research on the role of sex and ovarian hormones in the neurochemical and behavioral responses to acute and repeated exposure to drugs of abuse also finds sex differences and may provide insight into the biological causes of sex differences in drug abuse. While there are sex differences in opiates, nicotine and alcohol, most of the pre-clinical research has been done with cocaine and other psychomotor stimulants primarily AMPHand so this review will focus on the psychomotor stimulants.

In laboratory animals there are sex differences in acquisition, maintenance, and relapse seen with opiates, nicotine and alcohol. The reader is referred to recent reviews for additional information [ 82]. Not all studies find a sex difference in self-administration of opiates heroin, morphine, and fentanyl. When there is a sex difference, however, females tend to acquire self-administration more rapidly and take more drug during the maintenance phase see Table in [ ]. Female rats also acquire nicotine self-administration more rapidly than males, and will work harder to receive nicotine than males reviewed in [ 82].

So, acquisition of self-administration of opiates and nicotine occurs more rapidly in females than in males. In laboratory animals, there are sex differences in the development of and recovery from ethanol dependence. Female rats have decreased seizure threshold following withdrawal and have a more rapid return to the control level of seizure susceptibility [ 36 ]. Devaud and colleagues have found that ethanol administration affects GABA-A and NMDA receptor subtypes differently in male and female rat brain, and the direction of the sex difference varies among brain regions [ 35 ].

Whether the sex differences in the effects of alcohol and GABA-A and NMDA receptors mediate sex differences in the long-term consequences of alcohol dependence is not known. In mice, sex differences in seizure threshold during ethanol withdrawal is modulated to some extent by ovarian hormones, but there are also inherent sex differences independent of gonadal hormones [ 1 ].

It is difficult to characterized sex differences in acquisition of ethanol taking behavior, as rats and mice don't readily self-administer alcohol. Acquisition of ethanol consumption usually involves training animals to self-administer a saccharine sweetened mixture and then fading out the saccharine until animals are taking a pure ethanol solution.

This process can take 30 days, making it difficult to parse out factors that influence acquisition. Further research in the clinical setting and the laboratory is needed to clarify the causes and extend our understanding of the nature of these sex differences in alcohol use and abuse.

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The acute behavioral response to psychomotor stimulants in rodents can reflect both the sex difference and the modulatory role of gonadal hormones in males and females e. With repeated exposure to psychomotor stimulants there is an increase in the psychomotor activating effects of the drug, known as behavioral sensitization.

Behavioral sensitization can be different in males and females, and can be differentially affected by gonadal steroid hormones, as we now discuss. Sensitization of AMPH- or cocaine-induced psychomotor behavior can be defined as the absolute increase in the behavioral response exhibited when two tests are compared.

Under such comparisons, intact females exhibit more robust sensitization than do intact males [ 242546,]. Following ovariectomy OVX of female rats the expression of sensitization to AMPH is attenuated [ 242546, ] or suppressed all together []. These demonstrate that the neurobiological response to Women want sex Cave drugs is sexually dimorphic, but they do not address how this biological difference impacts sex differences in the motivation to take drugs.

The animal model of human drug taking behavior that has the most face validity is self-administration. In self-administration studies, animals are trained to bar-press or nose poke in order to receive access to a drug usually by i. The animal's pattern of drug taking can be studied during acquisition, maintenance and relapse.

It is also possible to manipulate the schedule of reinforcement in order to determine motivation to take a drug. Sex differences have been reported during all phases of the addiction process as assessed using various self-administration paradigms see [ 2782]. When a low dose of drug is used, intact or ovariectomized OVX female rats acquire cocaine self-administration at a faster rate than do intact of castrated CAST males [ 28627880 ]. Estradiol treatment enhances acquisition of cocaine self-administration in OVX female rats [ 6283 ], but not males [ 64 ] and the estradiol antagonist, tamoxifen, when given to intact females inhibits acquisition in intact females [ 78 ].

So, there are inherent sex differences independent of circulating gonadal hormones in the acquisition of cocaine self-administration, with females being more vulnerable than males. Furthermore, Women want sex Cave enhances acquisition in females, but not in males. During maintenance conditions, when given a choice between two doses of cocaine, female rats in estrus preferred higher doses of cocaine compared with females in other phases of the estrous cycle or male rats [ 7879 ]. revealed that following a 1-day abstinence period, motivation to obtain cocaine was decreased in OVX rats treated with vehicle, but not in OVX rats treated with EB.

In another experiment under extended access conditions, using the discrete trial procedure, OVX rats treated with estradiol consumed more cocaine than vehicle treated controls [ 78 ]. These show that estradiol influences both cocaine self-administration under high access conditions and that there are subsequent motivational changes resulting from such access. When responding for low doses of cocaine is assessed under a schedule in which the of responses required in order to obtain a cocaine infusion progressively increases, motivation for access to a drug can be assessed.

Females also worked harder for access to cocaine during the phase of the estrous cycle when estradiol was elevated, suggesting that ovarian hormones modulate the motivation to obtain cocaine [ ].

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In a recent study from our lab we investigated the involvement of ovarian hormones in the motivation to obtain cocaine. We found that estradiol treatment given to OVX rats enhances responding on a progressive ratio schedule at some doses of cocaine Figure 1. Thus, there are sex differences in the motivation to take cocaine, and estradiol enhances the motivation to take cocaine.

Ovariectomized OVX female rats were prepared for self-administration as ly described [ 62 ]. Rats were trained on an FR1 and then an FR2 schedule of reinforcement while receiving 0. During the first week the cocaine dose received was 0. Analysis of variance with repeated measures was conducted at each dose.

There were no group differences in the of nose pokes in the inactive hole during any test sessions. Sex differences have also been observed under reinstatement testing conditions deed to parallel relapse in humans [ 6981] but see [ 47 ]. In a recent study Figure 2we investigated the effect of estradiol in OVX female rats on reinstatement of responding for cocaine. In a similar experiment, Carroll and colleagues found that acute or chronic estradiol enhanced reinstatement of responding for cocaine [ 73 ]. Thus, estradiol rapidly enhances the subjective effects of cocaine to reinstate responding for access to cocaine, but estradiol does not reinstate responding on its own.

OVX rats were trained to self-administer cocaine with 0. Animals received 0. Daily 3-hour sessions of self-administration training Women want sex Cave given for 5 consecutive days followed by 2 days off for 2 weeks, animals were required to earn at least 50 infusions per day for the last two consecutive sessions to continue in the experiment.

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The extinction training was under an FR1 schedule on days 2, 9, 16 and 30 post-training. There were no ificant differences in the of infusions received by the different groups during self-administration training and there were no differences among the groups during extinction. There were no ificant differences in the of active responses made by animals in these groups after EB priming.

On day 30 of extinction, animals received OIL or EB same groups as above and were returned to the test chamber. In contrast to estradiol, progesterone treatment given concurrently with estradiol counteracts the effect of estradiol on acquisition of cocaine self-administration behavior [ 64 ].

We have recently confirmed this finding, and shown that progesterone alone does not affect cocaine self-administration, but that progesterone enhances cocaine intake in EB primed OVX rats [ ]. Taken together, a wealth of data now indicate that ovarian hormones contribute to sex differences in cocaine self-administration and that estradiol in particular is a key factor influencing the reinforcing effects of cocaine in female rats.

So, over the course of the estrous cycle and menstrual cycle, there are peaks and valleys during which females are more or less susceptible to the reinforcing properties of cocaine. The effect of progesterone to counteract the effects of estradiol in some hormone treatment regimens may reflect hormonal influences on maternal behavior, where estradiol and progesterone Women want sex Cave elevated during pregnancy and withdrawal from progesterone is necessary for the rapid onset of maternal behavior at parturition.

This is not the case, however, as testosterone treatment has not been found to affect behavioral sensitization in CAST males [ 46 ].

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Furthermore, there is no effect of CAST on acquisition of cocaine self-administration behavior and a dose of estradiol that enhances self-administration in female rats has no effect on cocaine self- administration behavior in male Women want sex Cave [ 64 ]. Thus, the effects of estradiol on the acquisition of cocaine self-administration are sexually dimorphic. The female rat has a day estrous cycle. Circulating estradiol is low during diestrus 1 and increases gradually during diestrus 2 and may persist for a third day of diestrus.

The estradiol on these days induces genes needed for initiation of sexual behavior, including induction of progesterone receptors [ 89 ]. On the next day, proestrus, there is an endogenous surge of estradiol that occurs around noon, which triggers ovulation about 12 hours later.

The surge of estradiol is followed in the afternoon by a surge of progesterone which induces behavioral estrus hours later, coincident with ovulation. Progesterone initially acts synergistically with estradiol to induce sexual activity and is subsequently responsible for the termination of sexual receptivity [ 89 ]. Female rats are more responsive to AMPH on the evening of behavioral estrus than 24 hr later on diestrus. Intact female rats also tend to show a greater behavioral response to cocaine on estrus compared to other days of the estrous cycle [ ] or to males [ ].

The basal extracellular concentrations of DA in the striatum, determined by quantitative microdialysis, are greater on estrus than on diestrus [ ]. There is also estrous cycle-dependent variation in striatal DA receptors [ 3775 ]. In contrast, in males, there are no differences between intact and CAST males in the efficacy of AMPH, cocaine or even stimulation of the nigrostriatal pathway to induce rotational behavior or stereotyped behavior [ 1216].

In studies with acute and repeated cocaine treatment we do not see an effect of CAST on the behavioral response to cocaine or cocaine self-administration [ 6062 ].

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In females, however, estradiol rapidly down regulates D2 DA receptor binding in striatum [ 8 ]. In vitrothe AMPH-stimulated increase in striatal DA release is comparable for tissue from intact male rats and intact female rats in estrus [ 17 ].

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Sex Differences in Drug Abuse