Sex Differences in Striatal Dopamine Release in Healthy Adults

Article (PDF Available)inBiological Psychiatry 59(10):966-74 · June 2006with63 Reads
DOI: 10.1016/j.biopsych.2006.01.008 · Source: PubMed
Abstract
Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses. We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

Figures

Sex Differences in Striatal Dopamine Release
in Healthy Adults
Cynthia A. Munro, Mary E. McCaul, Dean F. Wong, Lynn M. Oswald, Yun Zhou, James Brasic,
Hiroto Kuwabara, Anil Kumar, Mohab Alexander, Weiguo Ye, and Gary S. Wand
Background: Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine
system in these differences, but human studies have yet to substantiate these findings.
Methods: Using positron emission tomography (PET) scans with high-specific-activity [
11
C] raclopride and a reference tissue approach,
we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine
and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined.
Results: Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral
striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions.
Paralleling the PET findings, men’s ratings of the positive effects of amphetamine were greater than women’s. We found no sex
difference in neuroendocrine hormone responses.
Conclusions: We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could
account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future
studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the
striatum.
Key Words: Addiction, amphetamine, binding potential, dopa-
mine release, gender, sex differences, striatum
M
en and women differ in their vulnerability to addictive
disorders (Brady and Randall 1999; Brecht et al 2004).
Sex differences in the prevalence of psychostimulant
drug dependence in general, and in methamphetamine use in
particular, have been identified (Brady & Randall, 1999; Brecht et
al 2004; Substance Abuse and Mental Health Services Adminis-
tration 2005). Moreover, men compared with women are more
susceptible to methamphetamine toxicity (Dluzen et al 2003;
Miller et al 1998). Except for N-methyl-D-aspartate antagonists,
the amphetamines are the only class of addictive drugs known to
be associated with depletion of striatal dopamine (McCann and
Ricaurte 2004).
Because the ventral striatum is well recognized as an impor-
tant site for reward in addictive behaviors, attempts to elucidate
the neurobiology of sex differences underlying addiction have
focused on gender differences in this region. These investiga-
tions have revealed the nucleus accumbens, an area within the
ventral striatum, as principally important in the rewarding effects
of drugs of addiction (for a review, see Di Chiara et al 2004). In
preclinical studies, sex differences in the striatal dopamine
system have been observed (Dluzen 2004; Pohjalainen et al
1998). Rodent studies have documented sex differences in the
depletion, turnover, and extracellular accumulation of dopamine
following methamphetamine administration (Dluzen and
Ramirez 1985; Hruska and Silbergeld 1980; Shimizu and Bray
1993; Xiao and Becker 1994; Yu and Wagner 1994).
In addition to addictive disorders, sex differences in the
clinical presentation and age of onset of or vulnerability to other
neuropsychiatric illnesses that involve the striatum, such as
Parkinson’s disease (Scott et al 2000), schizophrenia (Aleman
et al 2003), Huntington’s disease (Tamir et al 1969), obsessive–
compulsive disorder (Bogetto et al 1999), and Tourette’s syn-
drome (Kidd et al 1980), have been described. Whether these
differences might also be related to striatal dopamine is not
known, however.
The purpose of this study was to test the hypothesis that the
magnitude of dopamine, subjective, and neuroendocrine re-
sponses to amphetamine is greater in men than in women. The
hypothesis was studied by measuring striatal binding potential
using the D
2
/D
3
dopamine (DA) receptor radioligand [
11
C]raclo-
pride with positron emission tomography (PET). The ventral
striatum was the primary volume of interest.
Methods and Materials
Forty-three healthy individuals (28 men, 15 women), aged 18
to 29 years, were recruited for participation by newspaper
advertisements and fliers posted in the Baltimore metropolitan
area. Under the auspices of the Johns Hopkins School of
Medicine Institutional Review Board, all participants provided
written informed consent after receiving oral and written descrip-
tions of study procedures and aims. Subject assessment included
a medical history and physical examination performed by a
physician, blood chemistry profile, complete blood count, liver
and renal function tests, electrocardiogram, urinalysis, alcohol
breathalyzer test, and urine toxicology screen. The Semi-Struc-
tured Assessment for the Genetics of Alcoholism (SSAGA; Bu-
cholz et al 1994) was administered by a master’s-level interviewer
to identify Diagnosis and Statistical Manual (4th edition; DSM-
IV) Axis I psychiatric diagnoses. Exclusionary criteria included
1) presence of DSM-IV Axis I disorder; 2) treatment in the last 6
months with antidepressants, neuroleptics, sedative hypnotics,
glucocorticoids, appetite suppressants, sex hormones, or opiate
or dopamine medications; 3) use of any prescription medications
From the Department of Psychiatry and Behavioral Sciences (CAM, MEM,
DFW, LMO, GSW), Russell H. Morgan Department of Radiology and Ra-
diological Sciences (DFW, YZ, JB, HK, NK, MA, WY), and Department of
Medicine (GSW), The Johns Hopkins University School of Medicine, Bal-
timore, Maryland.
Address reprint requests to Gary Wand, M.D., Department of Medicine, The
Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 863,
Baltimore, MD 21205; E-mail: gwand@jhmi.edu.
Received November 30, 2005; revised January 10, 2006; accepted January
13, 2006.
BIOL PSYCHIATRY 2006;59:966 –9740006-3223/06/$32.00
doi:10.1016/j.biopsych.2006.01.008 © 2006 Society of Biological Psychiatry
within the past 30 days; 4) women currently using a hormonal
method of birth control, hormone replacement therapy, currently
pregnant or lactating women, women with oligo- or amenorrhea;
5) medical conditions, including history of seizure disorder or
closed head trauma; 6) unable to provide clean urine drug
screens at intake or during study participation; 7) report of
drinking more than 30 alcoholic drinks per month or illicit drug
use within the 30 days before participation; and 8) current
smoking. Following screening procedures, eligible subjects were
scheduled for admission to the Johns Hopkins General Clinical
Research Center (GCRC) to complete the study.
Behavioral Measures
Measures of psychiatric symptoms and perceived stress were
administered during the initial assessment interview. These as-
sessments included the following: State–Trait Anxiety Inventory
(STAI; Spielberger 1983), Beck Depression Inventory (2nd edi-
tion; BDI-II; Beck et al 1996), Brief Symptom Inventory (BSI;
Deragotis and Melisaratos 1993), Perceived Stress Scale (PSS;
Cohen et al 1983), Life Experiences Survey (LES; Sarason et al
1978), and the Combined Hassles and Uplifts Scale (Lazarus and
Folkman 1989).
Analog Rating Scales (Bigelow and Walsh, 1998)
At 5 min before each scan and 3, 6, 10, 15, 25, 55, and 85 min
during scans, subjects were asked to rate verbally, on a 5-point
scale (0 least, 4 most), the degree to which they were
experiencing each of 10 possible drug effects. Positive effects
included “high,” “rush,” “good effects,” “liking,” and “desire for
drug.” Negative effects included “fidgety,” “anxious,” “dizziness,”
“dry mouth,” and “distrust.”
Magnetic Resonance Imaging Assessment and Mask Fitting
Use of magnetic resonance imaging (MRI) allowed coregis-
tration of the emission images so that anatomically accurate
volumes of interest (VOIs) could be drawn (see VOI Definition).
To minimize head motion during MRI acquisition, each subject
was fitted for a thermoplastic mask modeled to his or her face
before admission to the General Clinical Research Center
(GCRC). The MRIs were acquired with an SPGR (spoiled gradi-
ent) sequence (TE 5, TR 25, flip angle 40°, slice
thickness 1.5 mm, image matrix 256 192, field of view
24 cm) for anatomic identification of brain structures, and a
double echo (proton density and T2-weighted, 5-mm-thick
slices) sequence, used as a diagnostic scan and to segment
extracerebral cerebrospinal fluid.
PET Procedures and Data Acquisition
Subjects were admitted to the GCRC in-patient unit the day
before the PET procedures. They were instructed not to ingest
any alcohol, drugs, or over-the-counter medications for 48 hour
before admission. Laboratory studies at admission included a
urine toxicology screen, alcohol breathalyzer test, hematocrit,
electrolyte panel, and urine pregnancy screen for women. A
calorie-controlled, caffeine-free breakfast was provided to sub-
jects before the PET procedures. Beginning at 8:30
AM, subjects
underwent two consecutive 90-min PET scans with [
11
C] raclo
-
pride. This radioligand is a benzamide antagonist at D2 and D3
receptors, previously shown to be sensitive to stimulant-induced
changes in brain dopamine concentration (Endres et al 1997;
Volkow et al 1994). At the beginning of each scan, a high-
specific-activity intravenous bolus injection of approximately 18
mCi [
11
C] raclopride was administered. The first scan was pre
-
ceded at 5 min by an intravenous injection of saline; the second
scan was preceded at 5 min by .3 mg/kg amphetamine, each
delivered over 3 min. The amphetamine free base used in this
study was 73.4% of the amphetamine sulfate. The .3 mg/kg of
amphetamine sulfate given to each subject is .22 mg/kg amphet-
amine free base as a bolus over 3 min, starting 5 min before
radiotracer injection of bolus [
11
C] raclopride. The scanning
image protocol consisted of up to 30 scan acquisitions in
three-dimensional (3D) mode, starting from a 15-sec duration
and increasing to 6 min in length over a 90-min period. All
images were acquired on the 3D GE Advance whole body PET
scanner and were preceded by a 10-min attenuation scan em-
ploying a rotating germanium-68 source. Subjects were under
continuous cardiovascular monitoring during the scans. They
were permitted to arise briefly after the first scan and were
repositioned on the scanner table for the second. Subjects were
escorted back to the GCRC following the scans. Before discharge,
they were evaluated by a physician.
Volumes of Interest Definition
Volumes of interest (VOIs) were defined using interactive
segmentation software on spoiled gradient (SPGR) MRI volumes
for the caudate nucleus and the putamen bilaterally to obtain
regional BP values. The software program allowed for the
selection of upper and lower MRI intensity thresholds to delin-
eate striatal structures from surrounding structures and required
minimal hand drawing. The ventral striatum (VS) was automati-
cally defined on the SPGR MRI volume, reoriented so the plane
containing the midline separating the left and right halves of the
brain is orthogonal to the horizontal plane containing the points
representing the anterior commissure and the posterior commis-
sure (anterior commissure–posterior commissure plane). On
each coronal slice, the portion of the striatal volumes of interest
ventral to the line crossing the ventral corner of the lateral
ventricle and perpendicular to the bisector of the internal capsule
defined the VS (Baumann et al 1999). The MRI volumes were
spatially aligned to the PET volumes (averaged volumes across
frames taken between 30 and 90 min after tracer-injection) using
information theory (Collignon et al 1995) and implemented in
SPM2b software (Friston 2002; see http://www.fil.ion.ucl.ac.uk/
spm/). The same transformation parameters were applied to
transfer VOIs from MRI space to PET space. The cut-off level of
VOIs in PET spaces was set at .5; the value of VOI voxels in the MRI
spaces was set to 1, and that of remaining voxels was set to 0.
Modeling of PET Outcome Measures
The binding potential (BP) Bmax/Kd was used to measure
[
11
C]raclopride D2-like receptor-specific binding (Wong 2002).
The BP used in this work is based on a simplified reference tissue
model (SRTM), which is based on the BP defined as k3/k4 or
(DV_total DV_ f n.(BP f2B’max/Kd, where f2 is the free
fraction of tracer in brain tissue, B’max is the available receptor
density for tracer binding in nM, and Kd is the equilibrium
dissociation constant in NM; see Gunn et al 2001). The cerebel-
lum was the reference tissue used to estimate BP (Lammertsma
and Hume 1996). Because the cerebellum is nearly devoid of D2
and D3 receptors, specific binding of [
11
C]raclopride is thought to
be negligible in the cerebellum. A linear regression with spatial
constraint algorithm was used to fit SRTM model to measured
voxel kinetics, and parametric BP images were generated (Zhou
et al 2003). The VOIs defined on MRI images were transferred to
BP images to obtain VOI BP values. The percent change in BP
from baseline was used to estimate dopamine release as ((BPpla-
cebo-BPamphetamine)/BPplacebo) 100, with lower BP values
C.A. Munro et al
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during the amphetamine scan indicating greater levels of endog-
enous dopamine.
Hormone Assays
Cortisol, estradiol, progesterone, total testosterone, and free
testosterone were measured by radioimmunoassay (Diagnostic
Products Corporation, Los Angeles, California). Plasma concen-
trations of growth hormone (GH) were assayed by a two-site
IRMA (Nichols immunoradiometric assay). Blood for estradiol,
progesterone, and testosterone measurement were collected on
the day of the scan. Women with progesterone levels 2 ng/mL
were identified as being in the luteal phase of the menstrual
cycle. Blood was collected for amphetamine measurement at 10,
20, 45, 55, and 85 min following injection of amphetamine.
Plasma amphetamine levels were assessed by gas chromatogra-
phy mass spectroscopy (Quest Diagnostics). Inter- and intraassay
coefficient of variation was less than 10% for all assays.
Statistical Analysis
All statistical analyses were conducted using SPSS 12.0 for
Windows. Demographic characteristics of men and women were
compared using t tests or Chi-Square tests, as appropriate. Men’s
and women’s scores on psychological symptom measures ad-
ministered at baseline were compared with a series of t tests, and
differences between men and women on these measures were
entered as covariates in subsequent analyses. In the ventral
striatum, BP and dopamine release were examined separately
using t tests, with sex as the independent variable and then with
analyses of covariance (ANCOVA) with baseline differences
between men and women entered as covariates. In the anterior
and posterior regions of the putamen and caudate nuclei, BP and
dopamine release were examined using multivariate analyses of
variance (MANOVA), with sex as the independent variable and
BP or dopamine release in the four volumes of interest as the
dependent variables. BP and dopamine release were also exam-
ined with multivariate analyses of covariance (MANCOVA) to
control for baseline differences between men and women.
Subjective analog scales of drug effect were examined by
identifying each subject’s highest (peak) rating for each scale first
under the placebo condition and then under the amphetamine
condition. To adjust for nonnormal distribution, all peak values
were square-root transformed. Each square-root-transformed
peak value under the placebo condition was subtracted from the
square-root transformed peak value under the amphetamine
condition to obtain a “response.” The five positive scales were
highly correlated. Therefore, a single “positive” score was de-
rived by computing the mean of the five square-root-transformed
positive “response” scores. This measure was used in the analysis
comparing men and women. The five negative scales were also
highly correlated; a “negative” scale was thus derived in the same
manner as the “positive” scale for use in analyses. A MANOVA
was used to compare men’s and women’s responses on the
“positive” and “negative” scales. An ANOVA was then used to
explore any sex differences for each of the five scales comprising
the “positive” and “negative” response scores. Cortisol and GH
for men and women were compared by subtracting the hormone
level under the placebo condition at each time point from the
hormone level in the amphetamine condition at each time point.
The resulting “response” values were then compared in a
MANOVA for repeated measures. For exploratory analyses inves-
tigating the association between women’s menstrual phase (fol-
licular vs luteal) and dopamine release, BP, subjective responses,
and cortisol and GH, univariate analyses of variance were
performed.
Results
Demographics
Table 1 summarizes the demographic characteristics of the
sample. Men and women did not differ in age, race, body mass,
education, or the frequency or amount of alcohol consumed
weekly.
Psychological Measures
Scores on mood assessments and measures of distress are
shown in Table 2. Women had higher trait anxiety (STAI),
endorsed a greater severity of subjective distress (BSI), and
perceived more events as negative (LES) than did men.
Dopamine Binding and Release
Figure 1 illustrates D2 receptor availability during the placebo
and amphetamine challenge and the volumes under investiga-
tion. There was no sex difference in baseline BP in the ventral
striatum (Table 3). In contrast, dopamine release in the ventral
striatum was higher in men than in women (p .010; Figure 2).
Secondary analyses revealed that baseline BP in the other striatal
regions did not differ between men and women but that men had
greater dopamine release in three of four striatal regions exam-
ined [F (4,38) 2.628, p .049]. Differences were revealed in the
anterior putamen (p .017), as well as the anterior and posterior
Table 1. Subject Demographics
Men Women p Value
Sample size (n)2815
Age 22.0 (3.0) 21.7 (3.1) .731
Race, n (%) .297
Caucasian 19 (67.9) 8 (53.3)
African American 4 (14.3) 5 (33.3)
Asian 4 (14.3) 1 (6.7)
Hispanic 0 (0.0) 1 (6.7)
Other 1 (3.6) 0 (0.0)
BMI (kg/m
2
)
24.9 (3.1) 23.2 (2.4) .074
Education, years 14.7 (1.7) 14.5 (2.1) .762
Drinking episodes per week 0.7 (0.7) 0.6 (0.4) .418
Drinks per drinking episode 3.3 (2.7) 2.7 (1.7) .544
Except for sample size and race, all variables are presented as mean (SD).
Table 2. Psychological Symptom Measures
Men Women p Value
Sample Size 28 15
Trait Anxiety (STAI) 27.8 (6.6) 34.1 (9.4) .017
State Anxiety (STAI) 26.8 (7.3) 30.1 (6.8) .156
Depression (BDI) 2.2 (3.2) 3.6 (4.0) .257
Global Severity Index (BSI) 0.2 (0.2) 0.3 (0.3) .020
Perceived Stress Scale (PSS) 11.0 (6.5) 13.6 (7.0) .295
Hassles Frequency/Severity (H-U)
No. items 16.7 (8.9) 17.8 (4.8) .683
Mean item score 1.2 (0.3) 1.4 (0.3) .062
Life Experiences Survey (Negative Items)
No. items 2.0 (2.2) 4.1 (2.3) .015
Mean item score 1.5 (0.7) 1.4 (0.3) .638
Except for sample size,all variables are presented as mean (SD). BDI, Beck
Depression Inventory; BSI, Brief Symptom Inventory; H-U, Combined Hassles
and Uplift Scale; PSS, Perceived Stress Scale; STAI, State–Trait Anxiety
Inventory.
968 BIOL PSYCHIATRY 2006;59:966 –974 C.A. Munro et al
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caudate nuclei (ps .010 and .012, respectively) but not in the
posterior putamen (p .128; see Table 3). After controlling for
differences between men and women on a measure of trait
anxiety (STAI), severity of distress related to psychiatric symp-
toms (BSI), and number of life events judged as having a
negative impact (LES), results for all analyses were unchanged.
Plasma amphetamine concentrations obtained at 10, 20, 45, 55,
and 85 minutes following the injection of amphetamine did not
differ by sex.
Estradiol and progesterone levels are provided in Table 4.
Women in the luteal phase of the menstrual cycle (n 6) had
lower baseline BP in both the anterior putamen (p .045) and
posterior putamen (p .034) but not in the caudate (ps .123
anterior, .351 posterior) or ventral striatum (p .199), when
compared with women in the follicular phase (n 9). Dopamine
release, however, did not differ by phase of the menstrual cycle
in any brain region explored (all p values .206). Neither
estradiol nor progesterone level was correlated with baseline BP
or dopamine release.
In men, neither total nor free testosterone levels correlated
with baseline BP or dopamine release in the ventral striatum.
Subjective Drug Effects
Subjective responses to amphetamine were greater in men
than in women [F (2,40) 3.902, p .028] above the effects of
the placebo. In particular, men had greater positive (p .008)
but not negative (p .262) responses than women to amphet-
amine. Examination of each scale comprising the “positive” and
“negative” subjective responses indicated that men’s ratings on
four of the five positive scales were higher than women’s (all
significant p values .026), whereas none of the negative scales
differed by sex. Results for each subscale comprising the “posi-
tive” and “negative” scales are shown in Figure 3. As previously
shown (Oswald et al 2005), dopamine release in all regions
examined correlated with positive subjective responses to am-
phetamine in the whole sample (R values ranged from .309 to
.365, p values ranged from .019 to .049).
Women in the follicular and luteal phases of the menstrual
cycle did not differ in either positive or negative subjective
responses (data not shown). In men, neither total nor free
Table 3. Raclopride Binding Potentials During Placebo and Amphetamine
PET Scans
a
Region Placebo Amphetamine
Dopamine
Release
b
aPU
Men 3.06 0.33 2.67 0.31 12.59 6.30
Women 3.09 0.25 2.84 0.27 8.19 3.56
p value .777 .091 .017
pPU
Men 3.04 0.40 2.43 0.33 19.94 6.59
Women 3.19 0.27 2.65 0.20 16.97 4.56
p value .185 .021 .128
aCN
Men 2.63 0.30 2.45 0.28 6.58 5.62
Women 2.70 0.25 2.64 0.26 2.20 3.72
p value .409 .032 .010
pCN
Men 1.86 0.40 1.68 0.34 9.59 7.09
Women 1.95 0.30 1.86 0.29 4.16 5.00
p value .463 .079 .012
VS
Men 2.12 0.32 1.88 0.31 11.64 5.52
Women 2.08 0.21 1.94 0.22 7.13 4.54
p Value .686 .512 .010
aCN anterior caudate nucleus; aPU anterior putamen; pCN pos-
terior caudate nucleus; PET positron emission tomography; pPU pos-
terior putamen; VS ventral striatum.
a
Values represent mean SD.
b
Dopamine release ((placebo BP amph BP)/placebo BP) * 100.
Figure 1. Representative transaxial (top row) and coronal images (bottom row) of parametric binding potential (BP) volumes, baseline saline (left panel), and
post-amphetamine (right panel) scans take from one subject (20-year-old man). Outlines of volumes of interest for the caudate nucleus, putamen, and ventral
striatum are shown. Color scale bar indicates voxel BP values that can assume negative in cerebrospinal fluid space and outside the brain.
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testosterone levels correlated with subjective responses to am-
phetamine.
Cortisol and Growth Hormone
Measurements of plasma cortisol and GH were obtained at
baseline (25 and 5 min) and at scheduled intervals (15, 35, 55,
and 75 min) during the scans. Although both cortisol and GH
increased following administration of amphetamine, these in-
creases did not differ between men and women. Comparison of
women in the follicular phase to those in the luteal phase also
revealed no differences (data not shown).
Discussion
The aim of this study was to determine whether striatal
dopamine response following administration of amphetamine
was similar in men and women. Our primary finding was a
robust sex difference; men exhibited greater dopamine release
than women in the ventral striatum, anterior putamen, and
anterior and posterior caudate nuclei. These findings were
maintained whether or not the analyses was adjusted for sex
differences on psychological symptom measures, for phase of
the menstrual cycle in women, or for testosterone levels in men.
Supporting this neurochemical observation was the finding that
men also rated the positive effects of amphetamine higher than
did women. Plasma amphetamine levels did not differ by sex and
therefore cannot explain differences in dopamine release or
subjective responses to the drug.
To our knowledge, this is the first report in humans of a sex
difference in dopamine release. Prior studies have compared
men and women on other aspects of the striatal dopaminergic
system. Consistent with our finding of equivalent baseline bind-
ing potential in men and women, two previous studies found no
sex difference in dopamine receptor density (Farde et al 1995;
Pohjalainen et al 1998). Dopamine receptor affinity, in contrast,
was found to be lower in women than men in one study
(Pohjalainen et al 1998). This is not, however, a consistent
finding (see Farde et al 1995). In an investigation of dopamine
synthesis capacity, women had higher [
18
F] fluorodopa uptake
than men in striatum (Laakso et al 2002), suggesting that female
sex hormones enhance presynaptic dopamine turnover. Results
of preclinical studies support this claim (Dluzen and Ramirez
1985; Shimizu and Bray 1993; Xiao and Becker 1994).
In women, surges of estrogen are associated with increased
dopamine activity (DiPaolo et al 1988; Levesque et al 1989). For
example, striatal dopamine turnover is high (Shimizu and Bray
1993) and extracellular dopamine concentrations in the striatum
and nucleus accumbens are elevated in rats during high estrogen
states associated with estrus (Dluzen and Ramirez 1985; Xiao and
Becker 1994). Furthermore, estradiol administration has been
shown to increase receptor density in the striatum (Hruska and
Silbergeld 1980) as well as increase dopamine turnover in the
nucleus accumbens (Shimizu and Bray 1993). In contrast, pro-
gesterone has an overall blunting effect on the striatal dopamine
system, opposing the actions of estradiol (Fernandez-Ruiz et al
1990; Shimizu and Bray 1993; White et al 2002). In fact, proges-
terone administration to men dampens subjective and physiolog-
ical responses to cocaine (Sofluoglu et al 2004). It has been
posited that the ratio of estrogen to progesterone, which changes
throughout the menstrual cycle, helps determine responsiveness
to amphetamine (White et al 2002). We observed lower baseline
BP measurements in the putamen during the luteal phase
compared with the follicular phase of the menstrual cycle.
Dopamine release did not differ as a function of menstrual phase
in any striatal region, however. Sample size and the between-
subject design may have precluded capturing intercycle varia-
Table 4. Hormone Levels by Menstrual Phase
Follicular Luteal
Sample Size 9 6
Estradiol, pg/mL (SD) 59.63 (45.03) 118.41 (69.62)
Progesterone, ng/mL (SD) 0.83 (0.48) 10.18 (7.12)
Figure 2. Dopamine release in the ventral striatum
by sex. Bars represent mean and standard error.
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tions in dopamine release or subjective responses. Regardless of
menstrual phase differences, however, men had greater dopa-
mine release than women.
The second finding from this investigation was that men rated
the positive effects of amphetamine higher than did the women.
Previous research (Laruelle et al 1995; Oswald et al 2005; Volkow
et al 1999) as well as this study demonstrate a correlation
between dopamine release and subjective responses to stimulant
drugs; greater subjective responses to amphetamine, cocaine,
and methylphenidate are associated with greater dopamine
release. Our findings of greater dopamine release and subjective
responses in men compared to women are thus compatible with
this observation. In contrast to our finding regarding the subjec-
tive responses to amphetamine, preclinical studies have shown
that female subjects exhibit greater behavioral response and
sensitization to stimulants than do male subjects (Becker et al
2001). Perhaps the fact that our findings were seen in the
associative, but not in the sensorimotor, areas of the striatum
(Martinez et al 2005) accounts for the apparent discrepancy
between behavioral observations made from preclinical studies
and sex differences in subjective responses seen in our study.
Our findings are in agreement with clinical observations
regarding drug dependence. The ventral striatum is well recog-
nized as an important site for reward in response to various drugs
of abuse (Bonci et al 2003; Koob 1992; Robinson et al 1988;
Volkow et al 1997). Pharmacological studies have shown that
men have greater subjective responses to amphetamine and
cocaine compared with women, especially when women are in
the luteal phase of the menstrual cycle (Sofuoglu et al 2004;
White et al 2002). Sex studies have also shown a higher
prevalence of stimulant and alcohol use disorders in men than
women (Substance Abuse and Mental Health Services Adminis-
tration 2005). Men are also more vulnerable to methamphet-
amine toxicity (Dluzen et al 2003; Miller et al 1998), and male
stimulant abusers show greater electroencephalogram abnormal-
ities than female stimulant users (King et al 2000). Our findings
suggest that differences between men and women in dopamine
release may serve as a possible mechanism underlying the
observed sex differences in the clinical presentation and neuro-
logical consequences of stimulant use. That is, given that the
ventral striatum is a reward center for drugs of abuse, men’s
higher level of dopamine release in this vulnerable substrate may
predispose them to greater use and abuse of stimulant drugs.
The third finding in our study was that there was no signifi-
cant sex difference in the degree to which cortisol and growth
hormone responded to amphetamine. Although amphetamine is
a robust activator of the hypothalamic-pituitary-adrenal axis, the
gender effect on dopamine release does not appear to affect the
more distal event, namely, the release of cortisol or growth
hormone.
It remains unclear how male sex accounts for greater dopa-
mine responses to amphetamine throughout the striatum, but it
most likely relates to the influence of sex hormones on the
dopaminergic system. Preclinical studies have shown that men
have greater amphetamine-induced striatal dopamine release as
well as dopamine depletion than women (Yu and Wagner 1994).
Findings from our study concur with preclinical studies. Al-
though estradiol may enhance presynaptic dopaminergic func-
tion, preclinical studies have shown opposite effects in regard to
dopamine release. For example, using striatal tissue fragments
from gonadectomized and intact male and female mice, the
amount of dopamine evoked by methamphetamine was signifi-
cantly reduced when estrogen was coinfused (Myers et al 2003).
In contrast, testosterone failed to produce an overall change in
methamphetamine-evoked dopamine output. It appears that
estrogen but not testosterone exerts modulatory effects on
methamphetamine-evoked dopamine output (Bisagno et al 2003;
Gao and Dluzen 2001). In agreement with these observations,
our study found no relationship between testosterone and
dopamine measures in men. Combining the various findings
outlined earlier, we posit that in women, estrogen dampens
dopamine release but also enhances presynaptic dopamine
turnover and thus limits the kind of severe dopamine depletion
observed in men following chronic amphetamine exposure. This
difference between estrogen and testosterone may explain why
estrogen plays a neuroprotective role in modulating the effects of
stimulants on the central nervous system (Bisagno et al 2003).
The relevance of our findings may extend beyond addiction
Figure 3. Subjective analog scale responses by sex.
C.A. Munro et al BIOL PSYCHIATRY 2006;59:966 –974 971
www.sobp.org/journal
to include other disorders involving the striatum. Obsessive–
compulsive disorder, for example, is associated with reduced
availability of striatal dopamine transporter (Hesse et al 2005). In
this disorder, men have an earlier age of onset, more tics, and
worse outcomes than women (Bogetto et al 1999). Tourette’s
syndrome, associated with altered dopamine release in response
to amphetamine (Singer et al 2002), is more prevalent in boys
than in girls (Kidd et al 1980). Reduced transporter binding in the
striatum has also been found in patients with Parkinson’s disease
(Schwarz et al 2000). Sex differences in the symptom profiles of
patients with Parkinson’s disease, as well as greater prevalence of
this disease in men compared with women, have also been
reported (Fall et al 1996; Scott et al 2000). B y far, the most
widely researched neuropsychiatric disorder in terms of its
relation to abnormalities in the striatial dopaminergic system is
schizophrenia. Sex differences, such as earlier onset and more
negative symptoms in men, are consistently reported (Aleman
et al 2003). Although the mechanisms for sex differences in
disorders involving the striatal dopamine system are poorly
understood, the consistency with which men appear to be
more vulnerable than women is striking. To the extent that our
findings suggest an increased reactivity of the striatal dopa-
mine system in men compared with women, we speculate that
the sex differences in these various neuropsychiatric disorders
is at least partially related to this difference in striatal dopa-
minergic reactivity. Our findings bear relevance to these
differences and indicate that future studies of dopamine release
should control for sex.
This study has several strengths. First, the sample size is larger
than that of most PET studies examining changes in [
11
C]raclo
-
pride binding potential. Second, inclusion of this larger number
of participants allowed us to perform a meaningful, comprehen-
sive assessment of mood, stress, and sex hormones and then
control for these important measures in assessing dopamine
response to amphetamine. Third, the PET procedure employed
has been well validated (Hietala et al 1999; Singer et al 2002).
Fourth, adjusting the analysis for comparing dopamine release in
multiple striatal regions (MANOVA) provides a conservative
assessment, thus minimizing type I error.
Several weaknesses of this investigation should be noted.
First, because of the potential for prolonged sensitization to
amphetamine, the order of the scans was not counterbalanced.
The placebo scan always preceded the amphetamine scan.
Second, the rationale for this investigation was based in part on
findings from preclinical data. Because the species differences in
pharmacokinetics and neurotoxicity are far from understood,
caution should be taken when extrapolating to humans. Third,
we based this study on literature concerning methamphetamines
and extrapolated it to amphetamine. Because methamphetamine
is converted to amphetamine in the body and it would seem logical
to assume that the findings from methamphetamine would apply to
amphetamine. This assumption remains to be proven, however,
because amphetamine may not have the same neurotoxicity as
methamphetamine. A number of studies have reported negligible
displacement of the radioactivity in the cerebellum after amphet-
amine challenge using bolus-plus-infusion scheme in which the
radioactivity in the cerebellum remained constant (e.g., Breier et
al 1997). Nevertheless, we cannot determine to what extent this
approach might have affected our results. Fourth, although the
term “dopamine release” has been used conventionally in the
PET literature to describe amphetamine-induced changes in [
11
C]
raclopride BP, the increases in dopamine concentrations that
occur following amphetamine administration probably result
from several mechanisms, including dopamine reuptake block-
ade, reverse transport of dopamine through the dopamine
transporter (Schmitz et al 2001) as well as possible actions on
endogenous opioid systems (Schad et al 2002). Other mecha-
nisms such as internalization of dopamine receptors (Ginovart et
al 2004; Laruelle 2000) and change in the affinity status (Naren-
dran et al 2004) a r e also under investigation to explain the
sustained [
11
C] raclopride displacement after amphetamine
administration. Our use of the term “dopamine release,”
therefore, does not convey a full description of the mecha-
nisms by which amphetamine alters dopamine concentration.
Fifth, although the study was adequately powered for a
meaningful comparison between men and women, the rela-
tively small number of women in the luteal phase of the cycle
precludes definitive statements about dopamine release as a
function of menstrual cycle phase.
Conclusion
We report for the first time in humans a sex difference in
dopamine release in vivo. This finding has implications for
observed sex differences in a wide variety of neuropsychiatric
illnesses involving the striatum and indicates that future
studies of these disorders need to control for sex.
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    • "women were more likely than men to be unemployed) (Back et al. 2011). On the other hand, men showed larger striatal dopamine release accompanied by higher ratings of positive effects after a challenge of amphetamine, which could account for their increased vulnerability to stimulant use disorders (Munro et al. 2006). Accordingly, non-alcoholic men showed greater striatal dopamine release than nonalcoholic women following oral alcohol challenge (Urban et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Sex differences in inhibition and self-regulation at a behavioral level have been widely described. From an evolutionary point of view, the different selection pressures placed on male and female hominids led them to differ in their behavioral strategies that allowed our species to survive during natural selection processes. These differences reflect changes in neural and structural plasticity that might be the core of sex differences, and of the susceptibility towards one psychiatric condition rather than another. The goal of the present review is to summarize current evidence for such a dichotomy in impulsive and compulsive behavior with a focus on drug addiction. Sex-dependent differences in drug abuse and dependence will be examined in the context of pathophysiological regulation of impulse and motivation by neuromodulators (i.e. gonadal hormones) and neurotransmitters (i.e. dopamine). Advances in the understanding of the sex differences in the capability to control impulses and motivational states is key for the determination of efficacious biologically based intervention and prevention strategies for several neuropsychiatric disorders where loss of impulse control and compulsivity are the core symptoms.
    Full-text · Article · Mar 2016
    • " ovariectomized females compared with males with or without estradiol treatment (Cummings et al., 2014). A similar sex difference was reported for the dopamine response to amphetamine in the nucleus accumbens core (Gillies et al., 2014; Virdee et al., 2014) and dopamine response to nicotine in the ventral striatum in humans (Cosgrove et al., 2014). Munro et al. (2006) reported that men had greater dopamine release in the nucleus accumbens and presented greater subjective effects in response to amphetamine compared with women."
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    • "This change in brain neurotransmitters could help to reduce the induced fever due to infection (1994). Nishizawa et al. (1997) and Munro et al. (2006) reported that the neurotransmitter level in mice infected with P. berghei was increased in males than females. At the molecular level, our results revealed that malaria increased brain Adam23, Glrb, Vdac3, Cacnb4, and Cabp1 gene expression. "
    [Show abstract] [Hide abstract] ABSTRACT: Malaria is considered to be one of the most prevalent diseases in the world. Severity of the disease between males and females is very important in clinical research areas. In this study, we investigated the impact of sex differences in brain response to infection with Plasmodium berghei. Male and female C57Bl/6 mice were infected with P. berghei-infected erythrocytes. The infection induced a significant change in weight loss in males (-7.2 % ± 0.5) than females (-4.9 % ± 0.6). The maximum parasitemia reached about 15 % at day 9 postinfection. Also, P. berghei infection caused histopathological changes in the brain of mice. These changes were in the form of inflammation, hemorrhage, and structural changes in Purkinje cells. In addition, P. berghei was able to induce a marked oxidative damage in mice brain. The infection induced a significant increase in male brain glutathione than females while the brain catalase level was significantly increased in infected females than infected males. Moreover, the change in brain neurotransmitters, dopamine, epinephrine, norepinephrine, and serotonin, was more in infected males than infected females. At the molecular level, P. berghei was able to induce upregulations of Adam23, Cabp1, Cacnb4, Glrb, and Vdac3-mRNA in the brain of mice. These genes were significantly upregulated in infected males than in infected females. In general, P. berghei could induce structural, biochemical, and molecular alterations in mice brain. Severity of these alterations was different according to sex of mice.
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