Researchers studying the effects of cocaine on the brain have found that men and women with comparable drug use histories do not exhibit comparable damage. One study showed that women suffered less neuronal injury than men; another, that cocaine-dependent women have fewer abnormalities in blood flow to the brain than do cocaine-dependent men. Now, a recent NIDA-funded study has taken an important step toward explaining these differences between the sexes.

Magnetic resonance (MR) image intensity was measured to compare the hemodynamic effects of cocaine during two phases of a woman's menstrual cycle. Following cocaine administration during the follicular phase, image intensity was relatively high, reflecting cerebral blood flow at 97 percent of its pre-cocaine baseline. When the drug was given during the luteal phase, lower image intensity reflected a fall in blood flow to 82 percent of baseline. The MR technique is illustrated on page 6.

Cocaine constricts blood vessels, temporarily narrowing arteries and reducing blood flow to the brain, heart, and other areas of the body. Repeated exposure to cocaine can lead to blood-flow deficits in the brain that persist long after cocaine use has ended, causing permanent damage.

Dr. Marc J. Kaufman and colleagues at McLean Hospital, Harvard Medical School, in Belmont, Massachusetts, found that cerebral blood flow during the follicular phase of women's menstrual cycles (days 1 through 14, prior to ovulation) is not affected by exposure to cocaine. In women during their luteal phase (after ovulation, typically days 15 through 28) and in men, cocaine restricts cerebral blood flow.

"We hypothesized that the differences in blood flow might be caused by sex hormones," says Dr. Kaufman. "We decided to investigate whether women with high levels of estrogen, which improves blood-vessel elasticity, are more resistant to the vasoconstrictive effects of cocaine."

Dr. Kaufman and his colleagues used dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) to study cocaine-induced changes in cerebral blood volume in 13 healthy young women (average age 28) with histories of occasional cocaine use. The women's self-reported lifetime cocaine use averaged 13 exposures (ranging from 1 to 40).

Each woman was given a dose of cocaine and underwent a DSC MRI scan of cerebral blood volume during both phases of her menstrual cycle. During the first part of the menstrual cycle, estrogen levels are high and progesterone levels are low; during the second part, progesterone levels rise. In each imaging session, two brain images were collected: one as a baseline measure of cerebral blood volume and the second 10 minutes after cocaine administration.

The study found no significant changes in cerebral blood volume after cocaine administration during the women's follicular phase. During the luteal phase, when progesterone levels are highest, the women's cerebral blood flow fell approximately 10 percent after cocaine administration. These data compare to Dr. Kaufman's findings in a similar 1998 study, that men experience, on average, a 20-percent reduction in cerebral blood volume after cocaine administration.

A sequence of magnetic resonance images taken at 1-second intervals after a woman received an intravenous blood marker progresses from light to dark to light as her cerebral blood flow carries the marker into her brain and washes it back out again. The total marker present in all the images, measured as their intensity (darkness), reflects total cerebral blood volume. To study the hemodynamic effects of cocaine, investigators compared two such sequences, obtained before and after administration of the drug, during each menstrual period.

"We found what we were expecting," says Dr. Kaufman. "There was a minimal change in follicular cerebral blood volume, attributable, we believe, to the protective effects of estrogen. The greater vasoconstrictive effect of cocaine in luteal-phase women may be attributable to the progesterone, which has been shown to increase cocaine's vascular toxicity."

Dr. Kaufman's next step will be to administer estrogen or progesterone to men and luteal-phase women and measure the effects on cerebral blood volume after cocaine administration. The ultimate goal will be to develop a hormonelike medication to counteract the vascular effects of cocaine.

"Beyond confirming that cocaine does have a damaging effect on the brain and is not safe to use, this research contributes to our understanding of the drug's deleterious effects," says Dr. Steven Grant, of NIDA's Division of Treatment Research and Development. "Additionally, the research points out that we've got to stop thinking of both sexes as the same when it comes to the effects of drugs. Dr. Kaufman has shown that cocaine affects men and women differently."

Sources

• Kaufman, M., et al. Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biological Psychiatry 49(9):774-781, 2001. [Abstract]
• Kaufman, M., et al. Cocaine decreases relative cerebral blood volume in humans: A dynamic susceptibility contrast magnetic resonance imaging study. Psychopharmacology 138:76-81, 1998. [Abstract]
  

Volume 17, Number 2 (May 2002)