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► Dopamine neurotransmission mediates the reinforcing effects (reward system) of ► drugs of abuse and may underlie neuropsychiatric disorders such as ► schizophrenia, ► Parkinson's disease, and ► attention deficit disorder, where sex differences have been reported in incidence, prevalence, clinical course, and treatment outcome. Addiction to some abused ► psychostimulants such as ► cocaine and nicotine is more severe in women, the age of onset of schizophrenia is later in women than men and the prevalence of Parkinson's disease is lower in women than men. Sex differences in the baseline activity of the dopaminergic system may underlie these observed differences as well as responses to dopaminergic drugs.

Dopamine release and uptake rates, which regulate extracellular dopamine levels, are higher in females than males in some brain regions such as the striatum. Women have higher levels of ► dopamine transporters in the striatum, lower striatal dopamine D2 receptor affinity and higher dopamine 2 (D2) receptor levels in the frontal cortex compared to men; this may result in elevated levels of dopamine in these brain regions in women. In fact, postmortem and neuroimaging studies in human subjects suggest that dopamine release in women is higher relative to men. In human subjects, d-amphetamine-induced dopamine release in striatal and extrastriatal regions is higher in women suggesting sex differences in cognitive function and sensation-seeking behavior. The decline observed in DA receptor levels with age is also slower in women than men. In rats, indirect dopamine agonists like ► cocaine, which block the dopamine transporter, induce greater behavioral and neuroendocrine effects in females than males. Female rats acquire self-administration of cocaine faster than males. Responses to direct acting dopamine D2 ligands display sex differences with females being more sensitive than males.

Ovarian hormones underlie some, but not all sex differences observed in drug abuse, suggesting qualitative and quantitative sexual dimorphisms in neural systems. Estrogen enhances the response to the psychomotor stimulants ► amphetamine or cocaine; this effect is observed both during estrogen replacement following ovariectomy and during the estrus phase of the estrus cycle in rats.

In studies on rodents, estrogen is reported to increase dopamine synthesis, and baseline dopamine release in the striatum, and to increase neuronal firing in sub-stantia nigra. Estrogen inhibits gamma-aminobutyrate (► GABA) neurons in the striatum and accumbens, which subsequently increase dopaminergic activity. Another established effect of estrogens is the down regulation of dopamine receptors. Dopaminergic transmission varies with estrous cycle phase. For example, amphetamine-stimulated dopamine release is greatest during the estrus phase of the cycle, a time when the behavioral response is also greatest. Estrogen plays an important role in modulating sex differences in neurochemical responses to ► psy-chomotor stimulants.

► Stress, negative mood, and exposure to drug-related cues predict relapse in cocaine dependence. The effect of stress is more significantly associated with relapse in women and drug cues in men. Estrogen and progesterone have opposite effects on behavioral responses to cocaine, while the former increases the effects, the latter decrease it and the effects are more pronounced in females than males. Stress and cocaine enhance the stress response, mainly through the ► corticotrophin releasing factor (CRF) and central noradrenergic pathways, both of which activate the meso-limbic dopaminergic systems involved in the rewarding effects of cocaine. Progesterone also plays a key role in stress regulation and D2 receptor function, which results in an increase of DA release. On the other hand, in male rats, the density of dopamine D1 receptors is higher than in female rats in the ► nucleus accumbens, a brain region implicated in reward.

Sex differences observed in behavioral responses to one drug cannot be generalized to all behaviors because neuro-biological mechanisms controlling different behaviors can be dissociated. For example, in rats, while the locomotor responses to amphetamine and ► methamphetamine show sex differences with females being more sensitive than males, no sex differences are reported for conditioned place preference. Alternatively, sex differences are observed in responses to nicotine both in locomotor activity and in ► conditioned place preference, albeit in different directions: The effect of nicotine on locomotion is more pronounced in females, but unlike males, females do not show nicotine induced place preference. Similar to nicotine, ► LSD induces place preference in male but not in female rats. On the other hand, female rats are reported to be more sensitive to the conditioning effect of cocaine.

► Sensitization of behaviors such as rotation, stereotyped grooming, head bobs, and forelimb movements observed following chronic exposure to ► psychostimulants is greater in female rats than in males.

Methamphetamine, another abused drug like cocaine, increases dopamine levels in some brain regions but through different mechanisms: while cocaine blocks re-uptake, methamphetamine induces release from nerve terminals. The sex differences observed in the effects of methamphetamine are similar to cocaine: Females are more sensitive to the locomotor activating effects, but the effect gradually declines with repeated treatment in rats.

Drug Abuse

Until recently, preclinical (► Addictive disorder: animal models) and clinical research on drug abuse has been conducted mainly on male subjects. Drug abuse was generally accepted as a male problem and males were thought to be more vulnerable to drug abuse (► abuse liability evaluation). However, this view did not take into consideration the opportunity for use. There is growing evidence that points to sex differences the effects of abused drugs. Biological and environmental predictors of drug use such as ► depression, conduct disorder, physical and sexual abuse, prenatal drug exposure, and family dysfunction affect males and females differently. Therefore, treatment strategies that are effective in one sex may not be equally successful in the other. Sex differences in sensitivity to abused drugs and in drug self-administration is also observed in laboratory animals, and during different stages of the addiction process (i.e., acquisition, maintenance, and relapse). Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, ► opiates, and nicotine as revealed by their behavioral, neurological, and pharmacological responses to these drugs. Women take less time to progress to dependence (tobacco, ► caffeine, alcohol, ► cannabinoids, opiates, ► sedatives, cocaine, inhalants, amphetamine, ► hallucinogens, and ► phencyclidine) than men. Furthermore, in many cases, women appear to be more sensitive to the adverse health effects of drugs than men, pointing to the importance of developing gender-specific prevention and treatment programs in drug-related health problems. Methamphetamine (► amphetamine derivative) abuse may be an exception. It is reported that women begin to use methamphetamine at their earlier ages, and appear to be more dependent, but also they also respond better to treatment than men do. In women, use of methamphet-amine is associated with depression, suggesting a type of self-medication.

Epidemiological studies indicate that during adulthood, men outnumber women in using illicit substances (except prescription medications), alcohol and tobacco, and that men are more likely to have a ► drug abuse/dependence disorder or an alcohol use disorder than women. However, this gender difference in prevalence is not observed among adolescents; in fact, some studies point to a slightly higher prevalence of smoking among girls than boys. Nonetheless, ► alcohol abuse and dependence is higher in males than females at all age groups.

Women are more sensitive to the physiological effects of alcohol than men, have higher blood levels following similar doses of alcohol and report feeling more intoxicated. However, negative mood-induced craving for alcohol is greater in women than men.

Following different routes of cocaine intake, women detect the subjective effects of cocaine later than men and report less euphoria and dysphoria, but feel more "nervous'' compared to men. Women show greater reactivity than men to cocaine-related cues and the ► craving during abstinence is significantly higher in women.

Women have greater vulnerability for smoking-related diseases (specifically myocardial infarction and lung cancer) than men, but are less successful in quitting smoking. Men benefit from nicotine replacement therapy more than women. Studies on rodents point to similar sex differences, suggesting the involvement of underlying sexual dimorphisms in biology. Females may take a shorter time to become dependent than males, they make fewer quit attempts and can stay abstinent for shorter periods than males; the rate of relapse is higher in females than males. Sexually dimorphic pharmacokinetics that causes variance in blood/brain levels of nicotine or the effects of gonadal hormones may underlie some of the sex differences observed in nicotine/tobacco addiction.

There are established sex-dependent differences in ► opiate reward. Female rats are more sensitive to the rewarding effects of ► morphine, and work more than males to self-administer morphine, and acquire conditioned place preference at lower doses than males. Additionally, there are also sex-related differences in the effect of morphine on locomotor activity, cardiovascular system, temperature, stimulus discrimination, ► physical dependence, and analgesia.

The cyto-architecture of male and female brains is not the same; for example, the dendritic arborization in the anterior cingulate cortex, implicated in craving, is greater in male rats than in females. ► Psychoactive drugs modify the action of various neurotransmitter systems at the cellular and molecular levels and impact synaptic structure and function. There are clearly established sex differences in the action of neurotransmitters, with specific characteristic. The organizational and ► activational effects of ► gonadal hormones underlie some of the sex differences in brain and behavior. Since sex steroids, and especially estrogens, modify the binding of ligands to their receptor sites, sex differences in the action of pharmaceuticals deserve attention.

Antipsychotics

The response and end-organ sensitivity to antipsycho-tic treatment, similar to other drugs, are influenced by genetics, age, height, weight, lean-fat ratio, diet, exercise, concurrent disease, smoking and alcohol, and the

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