Nov. 10, 2007 Females seem to be unequally disposed to the harmful effects of stress and to addiction compared with males. Recent studies show that:
- Estrogen can increase the possibility that females will start to take, and continue taking, cocaine.
- Females appear to have a genetic predisposition toward reproducing the physiological reward produced by cocaine, suggesting sex chromosomes may influence habit formation.
- Mothers with post-traumatic stress disorder (PTSD) may uniquely pass on biological risk factors to their offspring, according to work with the descendents of Holocaust survivors.
- Stress can damage an area of the brain with a controlling effect on mood.
- Females without a growth-factor gene can become more depressed than males.
"The comparisons between male and female responses to pain, depression, injury, and addiction are manifold," says Bruce McEwen, PhD, at Rockefeller University in New York City. "Neuroscientific proof of these differences can have profound impacts on everything from over-the-counter pharmaceuticals to government reimbursements for health care."
In three experiments with rats, Jill Becker, PhD, of the University of Michigan, found in each case that females showed an increased vulnerability to cocaine addiction.
In the study, a pool of 150 male and female rats of various predetermined hormone levels (some males were castrated, some females had their ovaries removed) were exposed to various combinations of estrogen, progesterone, or a peanut oil control. The rats were allowed to self-administer cocaine for a three-week period, during which time doses increased every seven days.
Becker found that female rats were more likely to use cocaine when circulating estrogen was high, but also that progesterone could counter the effects of estrogen. Further, she found that the administration of estrogen had no effects on self-administration in male rats.
"The factors that cause some people to try drugs despite all of society's warnings about their dangers are complex, but we know that among the factors are gender, personality type, and prior stress experiences," Becker says. "Women tend to try cocaine earlier in life, susceptible individuals become addicted faster, and, once addicted, they suffer worse damage to their brains, hearts, and livers as a result of their cocaine use, compared with men."
The study attributed this tendency to activity in the nucleus accumbens and the striatum -- two areas in the brain where neurons producing the brain chemical dopamine transmit signals related to reward and motivation. Estrogen's activation of this brain region appears to be critical in determining the brain's response to narcotics and why it might be different for men and women.
"Females acquire self-administration at lower doses of cocaine and escalate drug taking more rapidly than males, so they take more cocaine in relation to their body weight," Becker says. "They will also work harder for cocaine than males will."
Becker also found that stress in early life or even during the prenatal period can increase vulnerability to drug use and abuse. Preliminary findings indicate that the tendency to begin using cocaine is enhanced following prenatal stress, and that males and females are uniquely affected by stress in the womb. Further research will focus on the interaction of gender, stress response, hormonal fluctuations, and novelty-seeking. Such studies may help researchers understand women's susceptibility to cocaine use, abuse, and addiction.
In related work with rats, scientists found that females appear to have a genetic predisposition to reproduce the physiological reward produced by cocaine.
Jane Taylor, PhD, of Yale University, studied cocaine's effects on the signaling pathway for protein kinase A (PKA), the enzyme that helps transfer dopamine-transmitting signals inside cells.
In the experiment, rats were given access over a 24-hour period to either cocaine or a saline solution. Their degree of dependence was rated by counting the number of times rats would return to the dispenser when either the cocaine or saline had been removed. Taylor examined one group immediately after the 24-hour exposure period; she studied a second group after a 10-day delay. Taylor examined the rats' brains and measured levels of protein kinase A (PKA), which is a sign of the activation of pleasure circuits.
Compared to males, females had higher levels of markers for PKA in the striatum, indicating increased dopamine and therefore greater reinforcement of reward signals in the female rats' brains. Increased levels of markers for PKA were seen also in the pleasure-indicative nucleus accumbens of females more than males, particularly among controls and rats tested after the 10-day abstinence period. Cocaine also increased PKA marker levels when male rats, but not females, were tested immediately after exposure.
"Our data appear to be a unique demonstration of a role of gender in a complex behavior: habit formation. These habits do not appear to be hormone-dependent," says Taylor. "This has allowed us to make significant progress in understanding some of the distinct contributions of genetic and hormonal factors to behaviors that are argued to be associated with an increased vulnerability to addiction."
Further studies may follow the mice through different phases of the cycle of addiction, which could aid in the development of gender-specific treatments to prevent relapses in cocaine-dependent women.
Recent examination of risk factors associated with PTSD show that mothers may contribute uniquely to the possibility that their offspring will develop the disorder.
Working with the children of Holocaust survivors, Rachel Yehuda, PhD, at Mount Sinai Medical Center in New York City, studied biological risk factors by examining levels of the stress hormone cortisol.
The study assembled 49 subjects, none of whom had been diagnosed with PTSD. Twenty-three subjects had parents who were Holocaust survivors with PTSD. The parents of the remaining 26 subjects did not have PTSD, but in 10 cases, a parent had survived the Holocaust. The three groups were monitored for basal cortisol secretion over a 24-hour period, to account for any fluctuations in hormone release over the circadian cycle.
On average, the study team found lower cortisol levels in offspring who had at least one parent with PTSD. In previous research, low cortisol levels have been associated with an increased risk for developing PTSD; some researchers think it could serve as a marker for vulnerability to developing the disorder.
It also complements work showing that mothers with PTSD confer different risk on their offspring than fathers with PTSD.
In earlier research, Yehuda studied about 38 children whose mothers were pregnant and in New York's World Trade Center on the morning of Sept. 11, 2001. Half of these mothers developed PTSD and showed low levels of cortisol. Examining results from healthy-baby checks when the infants were a year old, she found a trimester effect: Babies of PTSD mothers born closest to the traumatic event had the lowest levels of cortisol, if mothers were in their third trimester on 9/11.
"The risk factor has something to do with effects that are uniquely maternally transmitted," says Yehuda. "Paternal PTSD contributes to other outcomes, but maybe not low cortisol." The maternal contribution to increased risk, she suggests, is "a real gender difference."
Other findings indicate that stress may damage a region of the brain that regulates mood, adding to previous findings that had indicated damage in the hippocampus, which can regulate levels of cortisol. By identifying the biological changes that result from stress, researchers hope to pin down the ways stress can trigger depression in some people, and, in particular, how this may affect women, who show increased sensitivity to stress.
Tracy Bale, PhD, of the University of Pennsylvania, studied the effects of stress on male mice that were 3 months old, the equivalent of human adults. In particular, she focused on the role of corticotrophin-releasing factor (CRF), an important element in the brain's stress-response pathway. In one group of mice, a gene aiding the transmission of CRF was knocked out.
Half of the mice in each group were then exposed to several different types of mild stress, in a random order, each day for three weeks. They were put in a cage with damp bedding overnight, for example, moved to several different cages in a short period of time, or restrained for 15 minutes.
When the responses of the mice were later tested when they were placed in a cage or on an elevated cross-shaped maze with no protective siding, Bale found that normal mice responded by becoming more active and alert, showing they had adapted to the chronic stress. They started exploring the new environment and were curious to look over the edge of the maze. In contrast, the genetically altered, stress-sensitive mice showed no change in behavior in the new setting, "as though they had shut down or their brains hadn't dealt with the stress they had experienced," she says.
Detailed examination of the brains of the mice showed that the stress-sensitive mice exposed to stress, but not normal mice exposed to the same conditions, lost cells in the raphe nucleus, which releases serotonin, an important brain chemical that is associated with depression.
Biologically identifiable changes, such as cell loss in the raphe nucleus, ultimately could provide ways to look for susceptibility to depression in people before disorders develop and help researchers pinpoint different reactions to stress in males and females.
"Finding a significant loss of cells following a period of mild stress in a brain region that is critical for regulating serotonin and mood is essential to our understanding of how stress is related to the onset of affective disorders, such as depression," Bale says.
"We've shown that changes in gene expression in this area are probably vital to coping with stress, and the absence of such changes in the stress-sensitive mice may suggest potential sex differences linking heightened stress responsivity to disease."
The next step, Bale says, will be to repeat this study, examining differences between male and female mice.
Bale is a shareholder in Neurocrine Biosciences, which is developing drugs for treating insomnia, anxiety, depression, irritable bowel syndrome, pain, and CNS-related disorders.
Previous work has shown that anxiety and depression are more often diagnosed in females and that stress is a predisposing factor in the development of these mood disorders. Tara Perrot-Sinal, PhD, at Dalhousie University, in Halifax, Canada, studied differences in stress responding between male and female rats using a number of models, including reactions to the natural stress of predator odor.
In one experiment, Perrot-Sinal restrained rodents, resulting in the release of stress hormones. The process demonstrated that levels of a protein that is important for normal brain cell function, brain-derived neurotrophic factor (BDNF), was reduced after stress in both males and females.
However, she also found that BDNF levels in nonstressed males were different than in females in two areas of the hippocampus, a brain region important for responses to stress. This indicates that males and females start out with differing levels of BDNF and therefore could be at differential risk of developing pathologies involving this brain region following exposure to stress. Previous work suggests that alterations in BDNF may contribute to depression-related behaviors, but also that they may be involved in the therapeutic effect of antidepressants.
"Most stress experienced by humans today is psychological in nature, and therefore we need to mimic that in our animal models," Perrot-Sinal said.
Psychological stress can be triggered in rats by exposing them to the smell of a cat. Perrot-Sinal's team used this scenario to highlight several gender differences in response to stress. Her findings included the tendency for females to show more caution than males when exposed to acute cat odor-whether the animals had been stressed previously or not. Female rats also failed to show stress hormone responses upon exposure to the smell of cats, unlike males.
Her most recent work shows differences between males and females in the serotonin system following cat odor stress. The serotonin system is targeted by many antidepressants. Further research will include assessing how these gender differences in stress responding are related to the development of depression-like behavior and related diseases in female subjects.
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