The Addicted Brain (23 page)

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

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-containing 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.

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 buprenorphine 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 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.

Figure 12-1. The adolescent frontal lobe is not mature compared to the adult frontal lobe. The frontal lobe (shaded) makes up the front part of the brain, and 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.

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 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.

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.

Various drug effects and toxicities can be significantly different in different age groups and in men compared to women. This is useful information to have, not only for the patients but also for the people treating them. Adolescents, because of greater vulnerability and a full life ahead of them, are an especially important target for prevention efforts. The elderly are often more sensitive to alcohol’s effects. There are different elements in various treatment programs that can better address different groups of patients.

¹
Braun, David. “Neanderthal Brain Size at Birth Sheds Light on Human Evolution.
National Geographic
, September 9, 2008.
http://newswatch.nationalgeographic.com/2008/09/09/neanderthal/
.

²
There is extensive literature on sex diffrences in drug abuse: Becker, J.B. and M. Hu. “Sex Differences in Drug Abuse.”
Front Neuroendocrinol
, 29(1): 36–47, 2008; Quinones-Jenab, V. “Why Are Women from Venus and Men from Mars When They Abuse Cocaine?”
Brain Res,
1126(1): 200–203, 2006; Kosten, T.R., et al. Gender Differences in Response to Intranasal Cocaine Administration to Humans.”
Biol Psychiatry
, 39(2): 147–148, 1996; Walker, Q.D., et al. “Sex Differences in Cocaine-Stimulated Motor Behavior: Disparate Effects of Gonadectomy.”
Neuropsychopharmacology
, 25(1): 118–130, 2001; White, T.L., A.J. Justice, and H. de Wit. “Differential Subjective Effects of D-amphetamine by Gender, Hormone Levels, and Menstrual Cycle Phase.”
Pharmacol Biochem Behav
, 73(4): 729–741, 2002; Ignjatova, L. and M. Raleva. “Gender Difference in the Treatment Outcome of Patients Served in the Mixed-Gender Program.”
Bratisl Lek List
, 110(5): 285–289, 2009; Narayanan, S., J.O. Ebbert, and A. Sood. “Gender Differences in Self-Reported Use, Perceived Efficacy, and Interest in Future Use of Nicotine-Dependence Treatments: A Cross-Sectional Survey in Adults at a Tertiary Care Center for Nicotine Dependence.”
Gend Med
, 6(2): 362–368, 2009; Ambrose-Lanci, L.M., R.C. Sterling, and E.J. Van Bockstaele. “Cocaine Withdrawal-Induced Anxiety in Females: Impact of Circulating Estrogen and Potential Use of Delta-Opioid Receptor Agonists for Treatment.”
J Neurosci Res
, 88(4): 816–824, 2010; Jones, H.E., H. Fitzgerald, and R.E. Johnson. “Males and Females Differ in Response to Opioid Agonist Medications.”
Am J Addict
, 14(3): 223–233, 2005; Zhou, W., K.A. Cunningham, and M.L. Thomas. “Estrogen Regulation of Gene Expression in the
Brain: A Possible Mechanism Altering the Response to Psychostimulants in Female Rats.
Brain Res Mol Brain Res
, 100(1-2): 75–83, 2002; Sell, S.L., et al. “Influence of Ovarian Hormones and Estrous Cycle on the Behavioral Response to Cocaine in Female Rats.”
J Pharmacol Exp Ther
, 293(3): 879–886, 2000; Walker, Q.D., R. Ray, and C.M. Kuhn. “Sex Differences in Neurochemical Effects of Dopaminergic Drugs in Rat Striatum.”
Neuropsychopharmacology
, 31(6): 1193–1202, 2006; Parylak, S.L., et al. “Gonadal Steroids Mediate the Opposite Changes in Cocaine-Induced Locomotion Across Adolescence in Male and Female Rats.”
Pharmacol Biochem Behav
, 89(3): 314–323, 2008; Kippin, T.E., et al. “Potentiation of Cocaine-Primed Reinstatement of Drug Seeking in Female Rats During Estrus.”
Psychopharmacology
(Berl)
, 182(2): 245–252, 2005; Fuchs, R.A., et al. “Influence of Sex and Estrous Cyclicity on Conditioned Cue-Induced Reinstatement of Cocaine-Seeking Behavior in Rats.”
Psychopharmacology
(Berl)
, 179(3): 662–672, 2005.