Results from a government-funded study at Johns
Hopkins provide what is believed to be the first evidence
in people that amphetamines have a greater effect on men's
brains than women's — a discovery that could lead to
tailored treatments for drug abuse and neurological
diseases.
The study, led by Gary S. Wand, a professor of
endocrinology in the Department of Medicine at the
School of Medicine, found that men's brains showed evidence
of up to three times the amount of chemical dopamine as
women's when exposed to amphetamines.
The study will be published July 1 in The Journal
of Biological Psychiatry.
Dopamine is a neurotransmitter or chemical activator
that also works like a hormone. In the brain, it can
increase heart rate and blood pressure and is critical to
the way the brain controls movement. Commonly linked to the
brain's so-called pleasure system, dopamine is released in
the presence of such high-producing drugs as amphetamines
and cocaine, and shortages are associated with Parkinson's
disease, memory loss, depression and other mental
illnesses.
"These appear to be the first clinical studies whose
results may help explain why we see a greater number of men
abusing amphetamines than women," Wand stated. According to
the Substance Abuse and Mental Health Services
Administration, 6 percent of American males and 3.8 percent
of females, 12 and older, illegally used amphetamines in
2004. Wand said the finding may also explain the higher
incidence of amphetamine-induced neurotoxicity in males
compared to females.
Amphetamines stimulate the central nervous system,
with effects lasting anywhere from four to 24 hours. The
drug has been linked to heart failure, brain damage,
stroke, kidney and lung disorders, liver damage, blood
clots, malnutrition, deficient immune systems, hyperthermia
and convulsions. The drug has also been linked to acute
psychiatric and psychological symptoms that may lead to
suicide or murder.
The Johns Hopkins study focused on dopamine release in
an area in the center of the brain called the striatal
region. Studies have already shown that
amphetamine-stimulated dopamine release in the striatum
differs in male and female mice. This is the first time,
however, that studies in humans have substantiated these
findings, Wand said.
The so-called pleasure experience happens when
dopamine released by one brain cell is taken up by dopamine
receptors in another. To measure the amount of dopamine
stimulated by amphetamine, researchers introduced into the
bloodstream a drug, Raclopride C11, that not only binds
with dopamine receptor sites but also relinquishes these
sites if available dopamine is present.
Raclopride C11 is an antipsychotic drug, Raclopride,
that carries a radioactive tag, C11, that can be read using
a positron emission tomography scan. The doses of
Raclopride C11 administered in this study were well below
therapeutic levels.
For the purpose of the Johns Hopkins study, potential
test subjects had to pass an extensive medical screening to
ensure that they were healthy and normal in regard to
factors such as overall health and fitness, drug and
alcohol use and psychological condition. Once the screening
was completed, 43 individuals, ranging in age from 18 to 29
years, were chosen. Of that group, 28 were men and 15 were
women.
In the first PET scan, Raclopride C11 and saline were
introduced into the bloodstream by injection. In the
absence of amphetamine-stimulated dopamine release,
available receptors bound with Raclopride C11. This gave
researchers a PET scan level that indicated the total
number of available dopamine receptors. Results indicated
an equal number of dopamine receptors for males and females
in the study group.
In the second PET scan, amphetamines were injected
intravenously with Raclopride C11. Since Raclopride C11
bound only to receptors not already filled by dopamine, PET
scan levels gave researchers a clear indication of the
amount of dopamine released between neurons. In this
session, results showed a higher level of dopamine release
for men in the ventral striatum and three out of four of
the other striatal areas scanned.
The study also looked at subjective responses to
amphetamine in the bloodstream. Participants were asked to
verbally rate their experiences, including positive effects
(high, rush, good effect, liking and desire for the drug)
and negative effects (fidgetiness, anxiety, dizziness, dry
mouth and distrust). Subjective responses for males were
significantly higher in all but one category, dizziness. In
that category, women rated higher.
"The fact that the subjective tests supported the
biological ones further supports the hypothesis that men
exhibit a higher response to amphetamines than women," Wand
said.
Since it is known that the drug reward is related to
dopamine release in the ventral striatum, this study
strongly suggests that men undergo more reinforcement from
amphetamines than women. This in turn could help
researchers and clinicians treat people with amphetamine
abuse issues.
Wand said this study might also help researchers learn
more about the sexual differences related to
neuropsychiatric diseases that involve the other areas of
the striatum that were tested. These diseases include
Parkinson's, schizophrenia, Huntington's, obsessive
compulsive disorder and Tourette syndrome.
Other Johns Hopkins researchers who contributed to
this study are Cynthia A. Munro, Mary E. McCaul, Dean F.
Wong and Lynn M. Oswald, all of the Department of
Psychiatry and Behavioral Sciences; and Yun Zhou, James
Brasic, Hiroto Kuwabara, Anil Kumar, Mohad Alexander and
Weiguo Ye, all of the Russell H. Morgan Department of
Radiology and Radiological Services.
This study was supported by a grant from the National
Institutes of Health.
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