Supportive Laboratory Findings

Because of the importance of this topic, there have been many interesting laboratory studies that support the idea of sex differences. For example, female rats show greater behavioral responses than males after cocaine administration. They require lower doses than males to produce the same kind of responses, and the responses last longer than those in males. In cocaine self-administration studies, female rats take cocaine faster and more often than males. There are also sex differences in responses to opiates. Dr. Ann Z. Murphy, her colleagues, and others have noted that morphine is more effective in men than women for treating pain. Interestingly, there are corresponding sex differences in the anatomy of pain pathways in the lower brain and spinal cord.

There doesn't seem to be any doubt that females are different from males when it comes to drug taking. The question is "Why?" The thing that comes to mind most readily is that females have different hormones than men. Estrogen is known as the female hormone, and testosterone is the male hormone. Are the sex differences in drug use based on the hormonal differences? It is now clear that estrogen is a key factor in the sensitivity of females to cocaine and other drugs. This has been shown in basic experiments with animals that manipulate hormone levels in females and males. An effective way of removing or lowering estrogen in females is to surgically remove the ovaries; likewise, the way to remove or lower testosterone in males is to remove the testicles. If there is an effect of removing the ovaries, then the way to see if it is due to estrogen is to give estrogen back to the animals. Table 12-1 shows data from one of the many experiments on this topic. It shows the amount of cocaine taken by animals with and without estrogen and testosterone.

TABLE 12-1 The Female Hormone Estrogen Influences the Intake of Cocaine

Animal Type Cocaine Intake

TABLE 12-1 The Female Hormone Estrogen Influences the Intake of Cocaine

OVX + E

14.4 **

OVX

11.0 *

CAST

8.0

SHAM (males)

7.5

By using surgically manipulated males and females, it is possible to test for the influence of sex hormones on various processes. Removing the ovaries (OVX) removes circulating estrogen in females, and removing the testicles (CAST) removes circulating testosterone in males. In cases where OVX changes the animal's behavior, we can test if the change is due to estrogen (E) by adding it back to the animal (OVX + E). Another good comparison is a SHAM male animal where the rats have been subjected to some surgery but nothing has been removed. The data shows that CAST and SHAM males are not statistically different, indicating that testosterone has no influence on cocaine intake. The OVX animals took more cocaine than males, which shows a known sex difference. But there is an effect of E; cocaine intake (0.4 mg/kg) is increased further when E is given (OVX + E). Statistical differences are shown by asterisks. One asterisk indicates OVX females took more cocaine than CAST or SHAM males, and two asterisks indicate that OVX + E females took more cocaine than all of the other groups. (Summarized from Hu, H., H.S. Crombag, T.E. Robinson and J.B. Becker. "Biological Basis of Sex Differences in the Propensity to Self-Administer Cocaine." Neuropsychopharmacology 29:81-85, 2004. Data summarized from Figure 12-2.)

SHAM males, males who have had surgery but did not have any organs removed, took about the same amount of cocaine as castrated (CAST) males (see Table 12-1). So, testosterone does not seem to be a factor in drug taking. But there is a marked effect of manipulating estrogen (E) levels. Females who had their ovaries removed (OVX) took more cocaine than males, repeating the known result that females take more cocaine than males under many conditions. Females took even more when estrogen was given as a supplement (OVX + E). This clearly shows that estrogen influences cocaine intake, and this type of experiment has been performed many times in many laboratories with a similar result. Thus, a hormonal mechanism affects the cocaine intake in women, at least to some degree.

Because cocaine and estrogen can have many effects in many different places in the brain, the new questions are: where and how is estrogen working? Based on the knowledge that cocaine's effects are due to increased dopamine levels in the brain synapses, an initial question is, "Does estrogen work through dopamine?" It turns out that OVX lowers dopamine release, but CAST has no effect. From this, it appears that estrogen can affect dopamine release in brain. Now the question is, how does estrogen affect dopamine? Is it a direct effect of estrogen at estrogen receptors on dopamine-contain-ing neurons? Or is it an indirect effect? Answers to these questions are being developed. It has also been noted by Dr. Jill Becker and colleagues that dopamine cannot be the full story behind sex differences and cocaine, and there must be additional factors that contribute to the differences in the brain as well.3 Someday, with additional research, we will have a better idea of why female brains differ from male brains in their vulnerability to drugs.

Should Treatment Also Be Different?

In a comparison of men and women in a methadone maintenance program, women sometimes relapsed more than men; perhaps there should be more focus and study of relapse factors in women. There also appeared to be sex differences in the responses to buprenor-phine or methadone, medications to treat heroin dependence. The exact nature of these differences could influence the way the medications are used when treating women. In a treatment program for smokers (a nicotine replacement program), more women than men thought that the nicotine inhaler was effective. Recall that morphine is more effective in treating pain in men than in women.

Overall, it seems likely that sex has an influence on the response to treatment,4 and this suggests that there should be an emphasis on understanding the importance of sex differences in treatment. Further studies and improvements in treatment will benefit both men and women in that treatment will be sex-specific and more efficacious. In any case, if you are a woman and your treatment does not seem to be going as well as perhaps it is for some men, don't give up. Keep trying and searching for solutions.

Adolescents

Adolescents do not have mature brains (see Figure 12-1) because they continue to develop throughout adolescence. This development continues particularly in the frontal regions that are so critical for judgment and making appropriate decisions.5 Not only are frontal brain regions poorly developed in adolescents, continued drug use disrupts normal frontal cortex function, and both of these significantly contributes to being an addict. In the chapter on vulnerability, it was stated that the earlier in life that drug use begins, the greater the chance of becoming an addict in later life (see Chapter 8, "Could I Become An Addict?," Figure 8-3). Some children and adolescents appear to be at greater risk for drug abuse because of various factors that include genetics, family history of drug use, personality factors, birth defects, and co-existing emotional problems such as conduct disorder. Adolescents abuse a number of drugs, and marijuana is the most often used illicit drug in this age group. Inhalants, a toxic group of substances, are also often used by adolescents and children. Alcohol abuse by adolescents is considered a major problem. It is associated with premature adolescent death, crime, unplanned pregnancies, and sexually transmitted diseases. Just as the use of therapeutic medications (for example, antidepressants) in children and adolescents is of great concern, because of possible long lasting side effects, drug use with its uncertainties and toxicities is also a significant worry for parents. Thus, the period of adolescence has received much attention from drug abuse researchers, and appropriately so. Damage done in adolescence can result in a lifelong disadvantage.

many studies have shown that adolescent frontal lobes (ages 12-16 years) are not fully developed compared to adult frontal lobes (23-30 years). Because the frontal cortex serves judgment and executive functions, these functions develop more slowly in teens than most other functions. In a study done in monkeys, the innervation of the frontal cortex with dopaminergic neurons continued through adolescence and into early adulthood.6 (From http://www.drzukiwski.com/brain-function, accessed on June 15, 2011.)

many studies have shown that adolescent frontal lobes (ages 12-16 years) are not fully developed compared to adult frontal lobes (23-30 years). Because the frontal cortex serves judgment and executive functions, these functions develop more slowly in teens than most other functions. In a study done in monkeys, the innervation of the frontal cortex with dopaminergic neurons continued through adolescence and into early adulthood.6 (From http://www.drzukiwski.com/brain-function, accessed on June 15, 2011.)

We know that puberty (adolescence) is a time of great vulnerability to drug abuse in humans. This is likely due to many factors including the immature brain and peer pressure. An interesting finding is that the adolescent brain seems more sensitive to rewards, and a teenager is likely to want more of a rewarding substance. This has been studied in rats that have, for example, access to sweetened condensed milk, a highly rewarding substance to animals. The experiments included breakpoints, which, as discussed earlier are a measure of reward. Overall, the data in this particular study (see Figure 12-2) showed that pubertal rats took much more of the milk than adults. Was milk more desirable in adolescence compared to adulthood? Probably so. It is something in the brain itself that causes the difference, but we do not yet fully understand it. It is relevant that foods are natural rewards and are thought to use many of the same neuronal circuits in the brain as drugs. Because of this, food data is often interesting to drug researchers.

The data in Figure 8-4 from Chapter 8 comes to mind. Young dopamine neurons respond more than adult neurons to the same stimulus, and it has been shown in many ways that adolescents are different from adults in response to rewards. Having demonstrated higher intake in younger animals suggests that further experimentation will reveal the underlying causes of this enhanced intake. Moreover, having an animal model of this adolescent vulnerability might allow us to test for medications that might be especially efficacious in teen agers. The combination approach of first observing human problems and then modeling and testing the problems in animals is powerful.

pubertal adult

Figure 12-2 Adolescents seek more rewards than adults. This study in rats examined the intake of sweetened condensed milk (SCM) during both puberty and adulthood. The pubertal rat (ages postnatal days 40-60) had a marked increase in milk intake compared to the adult rat (age postnatal day 90). This may help explain why human adolescents are more vulnerable to drug use than those of other ages. The asterisks over the bar indicate that the differences between pubertal and adult are significant. SCM is a substance found to be highly rewarding in animals. (Adapted from Friemel, C.M. et al. "Reward Sensitivity for a Palatable Food Reward Peaks During Pubertal Development in Rats." Frontiers in Behavioral Neuroscience, 4: 1-10, Figure 1c, 2010.)

The Elderly

The preceding discussion shows that certain groups of patients, women, and adolescents present special problems for the drug abuse treatment system. The elderly also have some unique issues. The abuse of alcohol and drugs by older adults has been called the invisible epidemic because we know much less about drug use in this population. There are also additional factors that make drug use in the elderly noteworthy. For one, metabolism of alcohol (and other drugs) is slower, meaning that lower doses have stronger effects compared to effects in younger adults. The total amount of water in the body is lower in older adults, and because alcohol occupies this space, its brain concentration is higher in the elderly, resulting in greater effects on the brain with fewer drinks. Older adults often have more chronic health problems that can be made worse by chronic alcohol use. For example, the loss of mental sharpness that occurs with age can be made worse by intoxication, which occurs at lower alcohol doses in the elderly. Also, depression found in the elderly can be made worse by alcohol.

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