ABI-DARGHAM,

STRIATAL
Am J Psychiatry
DOPAMINE
GIL,
155:6,
KRYSTAL,
TRANSMISSION
June 1998
ET AL.

Increased Striatal Dopamine Transmission in Schizophrenia:

Confirmation in a Second Cohort

Anissa Abi-Dargham, M.D., Roberto Gil, M.D., John Krystal, M.D., Ronald M. Baldwin, Ph.D.,
John P. Seibyl, M.D., Malcom Bowers, M.D., Christopher H. van Dyck,
Dennis S. Charney, M.D., Robert B. Innis, M.D., Ph.D., and Marc Laruelle, M.D.

Objective: The authors previously observed an increase in striatal dopamine transmission

following amphetamine challenge in 15 untreated patients with schizophrenia compared to
15 matched healthy subjects. The purpose of this study was to replicate this finding in a new
cohort of schizophrenic patients and healthy subjects. Method: Fifteen patients with schizo-
phrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeco-
nomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia,
had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a
minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction
in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg,
intravenous bolus). Reduction in D2 receptor availability was measured with single photon
emission computed tomography and the D2 receptor radiotracer [123I]IBZM. Results: No
differences were observed between patients with schizophrenia and the comparison group in
D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger
reduction in D2 receptor availability following acute amphetamine challenge than the com-
parison group. In this study, the effect size was smaller than in the first study. Excess dopamine
release following amphetamine was associated with transient emergence or worsening of posi-
tive symptoms. Conclusions: In this new cohort of subjects the authors replicated their initial
observation of a dysregulation of striatal dopamine release in schizophrenia.
(Am J Psychiatry 1998; 155:761767)

C onventional in vivo neuroreceptor imaging with

positron emission tomography (PET) or single
photon emission computed tomography (SPECT) pro-
vides noninvasive measurement of the density and af-
finity of a variety of neuroreceptors in the living brain.
In addition, these techniques can be used to measure
fluctuations in the concentration of endogenous trans-
Presented in part at the annual meeting of the Society for Neuro-
science, Washington D.C., Nov. 1621, 1996, and at the American
College of Neuropsychopharmacology, Puerto Rico, Dec. 913,
1996. Received July 30, 1997; revision received Dec. 4, 1997; ac-
cepted Dec. 16, 1997. From the Departments of Psychiatry and Diag-
nostic Radiology, Yale University, New Haven; and the VA Medical
Center, West Haven, Conn. Address reprint requests to Dr. Abi-Dar-
gham, New York State Psychiatric Institute, Unit 28, 177 West 168th
St., New York, NY, 10032; aadar@neuron.cpmc.columbia.edu (e-
mail).
Supported by National Alliance for Research in Schizophrenia and
Depression Young Investigator Award (Dr. Laruelle), NIMH grants
MH-54192 (Dr. Laruelle) and MH-30929 (Dr. Bowers), and the Vet-
erans Administration.
The authors thank Christine Fingado, Donna M. Damon, Melyssa
K. Madrak, Louis A. Amici, Richard Weiss, Lynn Pantages-Torok,
and the staff of the NeuroSPECT Laboratory at Yale-New Haven
Hospital for technical assistance and the staff of the Neuropsychiatric
Studies Unit at the West Haven VA Medical Center for the clinical
care of the patients.
mitters in the vicinity of these receptors (1, 2). Compe-
tition between radiotracers and transmitters for bind-
ing to neuroreceptors is the principle underlying this
application. This recent development of neuroreceptor
imaging allows direct measurement of regional synaptic
transmission in specific neurotransmitter systems, cor-
relation of these measurements with behaviors and
symptoms, and an exploration of the role of neuro-
chemical imbalances in the pathogenesis of neuropsy-
chiatric disorders.
Specifically, we developed a method to measure am-
phetamine-induced dopamine release with SPECT and the
radiotracer [123I](S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-
[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM),
an antagonist at the D2 and D5 receptors (3). We initially
observed that amphetamine challenge reduced the [123I]-
IBZM binding potential in baboons. In vivo binding po-
tential is the product of the density and affinity of avail-
able receptors, i.e., receptors not occupied by dopamine.
Since amphetamine is devoid of significant affinity for D2
receptors, we postulated that this effect was mediated by
increased dopamine release and displacement of [123I]-
IBZM specific binding by dopamine. This mechanism was
supported by the observation that pretreatment with the

Am J Psychiatry 155:6, June 1998 761

STRIATAL DOPAMINE TRANSMISSION
dopamine depleter alpha-methyl-para-tyrosine prevented
the effect of amphetamine on [123I]IBZM binding poten-
tial (4). In addition, we established the existence of a good
correlation between amphetamine-induced dopamine re-
lease measured with microdialysis and the amphetamine-
induced decrease in [123I]IBZM binding potential mea-
sured with SPECT (4). Therefore, measuring the reduc-
tion in [123I]IBZM binding potential following ampheta-
mine administration provides a noninvasive method to
estimate the magnitude of amphetamine-induced dopa-
mine release. Extending this method to healthy volun-
teers demonstrated its feasibility in humans (5).
We used this technique to study amphetamine-induced
dopamine release in patients with schizophrenia. In a first
cohort of 15 patients and 15 matched healthy subjects,
we observed a significantly greater amphetamine-in-
duced decrease in the [123I]IBZM binding potential in the
schizophrenic group (mean=19.5%, SD=15.7%) than
in the healthy group (mean=7.6%, SD=8.0%) (two-
tailed t test, F=6.87, df=1, 28, p<0.05) (6). These data
provided the first in vivo evidence for a dysregulation of
striatal dopamine release in schizophrenia. This result
was independently replicated by Breier et al. (7) using
PET, the radiotracer [11C]raclopride, and a smaller dose
of amphetamine (0.2 mg/kg).
In the present investigation, we attempted to replicate
these findings in a new cohort of 15 drug-free schizo-
phrenic subjects and 15 matched healthy subjects. We
kept the experimental conditions similar to those of the
first study in order to allow subsequent meta-analysis
of the pooled data.
METHOD
Subjects
Inclusion criteria for patients were as follows: 1) diagnosis of schizo-
phrenia according to DSM-IV; 2) no other DSM-IV axis I diagnosis;
3) no history of alcohol or substance abuse or dependence; 4) absence
of any psychotropic medication for at least 21 days before the study
(with the exception of lorazepam, which was allowed at a maximal
dose of 3 mg/day up to 24 hours before the study); 5) no concomitant
or past severe medical conditions; 6) no pregnancy; 7) no current
suicidal or homicidal ideation; and 8) ability to provide informed con-
sent. After explanation of the nature and risks of the study, the ability
of the patient to provide informed consent was formally evaluated by
asking the patient to complete a multiple-choice questionnaire (avail-
able from Dr. Abi-Dargham on request). According to the recommen-
dations of the National Alliance for the Mentally Ill (Arlington, Va.),
assent from involved family members was also obtained. All patients
were admitted to a research ward for the duration of the study, in-
cluding the washout period.
Inclusion criteria for the comparison group were as follows: 1) ab-
sence of past or present neurological or psychiatric illnesses; 2) no
concomitant or past severe medical conditions; 3) no pregnancy; and
4) ability to provide informed consent. Groups were matched for age,
gender, race, and parental socioeconomic level, assessed by the
Hollingshead scale (8).
Scan Protocol
SPECT experiments were carried out as previously described (5).
Briefly, [123I]IBZM with specific activity >5,000 Ci/mmol and radio-
762
chemical purity >95% was prepared by direct electrophilic radioiodi-
nation of the desiodoprecursor BZM. A total mean [123I]IBZM dose
of 10.7 mCi (SD=2.5) was given as a bolus (mean=4.0 mCi, SD=0.9)
followed by a continuous infusion at a mean rate of 1.0 mCi/hour
(SD=0.2) for the duration of the experiment (372 minutes). This pro-
tocol of administration (bolus plus constant infusion with bolus to
hourly infusion rate ratio of 3.92 hours) has been shown to induce a
state of sustained binding equilibrium. In the absence of ampheta-
mine injection, both the specific and nonspecific activity remained at
a constant level (within plus or minus 5%) from 150 minutes to the
end of the experiment (5).
SPECT data were acquired on the PRISM 3000 (Picker, Cleveland,
Ohio) with high-resolution fan beam collimators (resolution full
width at half maximum, 11 mm; 123I point source sensitivity, 16.5
counts/seconds/Ci). Two scanning sessions were obtained for each
subject during the course of the [123I]IBZM infusion (before and after
amphetamine injection). Each scanning session consisted of nine con-
secutive acquisitions of 8 minutes each. The first scanning session was
obtained from 180 to 252 minutes. After completion of the first scan-
ning session, dextroamphetamine sulfate was injected intravenously
at a dose of 0.3 mg/kg over 30 seconds. During the 45 minutes fol-
lowing the amphetamine injection, subjects were outside the scanner
in order to evaluate the psychiatric response to amphetamine. The
second scanning session (i.e., after amphetamine injection) was ob-
tained from 300 to 372 minutes.
The clinical response to the amphetamine challenge was evaluated
with the Positive and Negative Syndrome Scale (9). Baseline ratings
were obtained 60 minutes before the first scanning session. Postam-
phetamine ratings were obtained 30 minutes after the injection of
amphetamine (i.e., during the interval between the first and second
scanning sessions). For positive and negative subscales, a change of at
least 4 points from baseline was considered clinically significant.
Plasma metabolite-corrected [123I]IBZM steady-state concentration
was measured by extraction followed by high pressure liquid chroma-
tography on four venous samples collected at 20-minute intervals from
180 to 260 minutes (5). Determination of the plasma [123I]IBZM free
fraction was performed by ultrafiltration (10). Plasma [123I]IBZM clear-
ance was calculated as the ratio of steady-state concentration to infusion
rate. Amphetamine plasma concentration was measured by gas chroma-
tography on three venous samples obtained at 10, 20, and 40 minutes
after amphetamine injection. To measure peripheral effects of ampheta-
mine on dopamine metabolism, plasma levels of the dopamine metabo-
lite homovanillic acid (HVA) were measured on six samples: three pre-
amphetamine samples were collected at 20-minute intervals during the
first scanning session (180, 200, and 220 minutes), and three postam-
phetamine samples were collected during the second scanning session
(300, 320, and 340 minutes). Plasma HVA levels were assayed as pre-
viously described by gas chromatography and mass spectrometry; deu-
terated internal standards were used (11).
Data Analysis
SPECT images were analyzed as previously described (6). Unless
otherwise specified, between-group comparisons were performed
with two-tailed unpaired t tests. Relationships between continuous
variables were analyzed with the Pearson product-moment correla-
tion coefficient. A probability value of 0.05 was selected as the sig-
nificance level. Effect size was calculated as the mean for schizo-
phrenic patients minus the mean for healthy subjects divided by the
standard deviation for healthy subjects. Because of lack of a second
intravenous line, plasma [123I]IBZM and amphetamine were not col-
lected for three patients and two healthy subjects.
RESULTS
Subjects
The groups did not significantly differ in age, gender,
ethnicity, or parental socioeconomic status (table 1).
Patients had significantly lower socioeconomic status
Am J Psychiatry 155:6, June 1998
 ABI-DARGHAM, GIL, KRYSTAL, ET AL.

TABLE 1. Demographic Characteristics of Healthy Comparison FIGURE 1. Baseline (Preamphetamine) [123I]IBZM Binding Poten-
Subjects and Schizophrenic Patients tial to Striatal D2 Receptors in Healthy Subjects (N=13) and Patients
With Schizophrenia (N=12)a
Comparison Schizophrenic
Subjects Patients
Characteristic (N=15) (N=15)
N N
Sex
Male 12 12
Female 3 3
Race
Caucasian 9 9
African American 4 4
Hispanic 2 2

Mean SD Mean SD

Age (years) 40 11 41 9
Socioeconomic statusa
Parental 37 10 34 18
Subjectb 42 9 29 9
aAssessed by Hollingshead scale (8).
bPatients had significantly lower
socioeconomic status than compari-
son subjects (t=3.72, df=28, p<0.001; unpaired two-tailed t test).

aNo significant between group difference was observed. The variance

than subjects in the comparison group (F=13.8, df=1,
28, p<0.001). Two patients were experiencing a first
psychotic episode and were considered neuroleptic
naive (one had never received a neuroleptic; the other
had less than 1 week of lifetime exposure). The other
13 patients had a mean duration of illness of 17 years
(SD=7). Antipsychotics were discontinued in three pa-
tients for the purpose of participation in this study
(for 2238 days). Ten patients were noncompliant
with antipsychotic treatment at the time of recruit-
ment. For these patients, the average neuroleptic-free
interval was 169 days (SD=145) (an index of 365 days
was used for patients drug free for more than 1 year
[N=3]). After completion of the study, all patients
were offered antipsychotic medication and clinical fol-
low-up.
Five patients received lorazepam at doses lower than
3 mg/day up to 24 hours before the scan. At the time of
the scan, baseline scores were 44 (SD=11) on the Brief
Psychiatric Rating Scale (BPRS) (12) and 18.5 (SD=5.1)
and 19.6 (SD=7.0), respectively, on the positive and
negative symptom subscales of the Positive and Nega-
tive Syndrome Scale.
Scan Parameters
As previously reported, the bolus plus constant infu-
sion paradigm used in this study, with a bolus to hourly
infusion ratio of 3.92 hours, induced steady-state
[123I]IBZM plasma levels by the time of the scan. The
steady-state quality of the plasma input function was
evaluated by the slope of the metabolite-corrected
plasma [123I]IBZM concentration from 180 to 260 min-
utes. This slope was small and not different between
groups (schizophrenic patients: mean=1.7%/hour,
SD=7.3%; healthy subjects: mean=2.3%/hour,
SD=3.5%). Similarly, the slope of the occipital activity
in the schizophrenic group was larger than in the comparison group.
The horizontal line is the group average.
was negligible and did not differ between the groups
(schizophrenic patients: mean=0.5%/hour, SD=3.6%;
healthy subjects: mean=0.6%/hour, SD=2.9%). None
of these slope distributions had a mean value signifi-
cantly different from zero (one-sample t test), indicating
that an adequate steady-state input function was
achieved in both groups. Plasma [123I]IBZM clearance
or free fraction did not differ between the groups
(plasma [123I]IBZM clearance: schizophrenic patients,
mean=63 liters/hour, SD=21; healthy subjects, mean=
71 liters/hour, SD=10; plasma [123I]IBZM free fraction:
schizophrenic patients, mean=3.2%, SD=0.7%; healthy
subjects, mean=3.6%, SD=0.9%).
Baseline [123I]IBZM Binding Potential
No differences were observed in baseline [123I]IBZM
binding potential between patients (mean=239 ml g1,
SD=115) and healthy subjects (235 ml g1, SD=46) (fig-
ure 1). The variability of [123I]IBZM binding potential
was significantly larger in patients (F=6.10, df=11, 12,
p<0.005). Baseline [123I]IBZM binding potential was
significantly correlated with age (r2=0.18, F=5.2, df=1,
23, p<0.05), showing a mean decline of 14% (SD=6%)
per decade. The interaction between age and diagnosis
was not significant, showing no differences in the rate
of [123I]IBZM binding potential decrease with age be-
tween schizophrenic and healthy subjects. In the schizo-
phrenic group, baseline [123I]IBZM binding potential
was not correlated with baseline clinical symptoms (to-
tal BPRS and positive and negative subscales of the
Positive and Negative Syndrome Scale), the neuroleptic-
free interval, or lifetime neuroleptic exposure.

Am J Psychiatry 155:6, June 1998 763

STRIATAL DOPAMINE TRANSMISSION
FIGURE 2. Transaxial Slice at the Level of the Caudate Nucleus
Showing the Distribution of Activity During Constant Infusion of the
Selective D2 Receptor Radiotracer [123I]IBZM, Before (A) and After
(B) Amphetamine Injection (0.3 mg/kg bolus) in a 38-Year-Old
Healthy Subjecta
aBoth images represent the sum of nine consecutive acquisitions of 8
minutes and were decay corrected to the beginning of the experiment.
The amphetamine injection induced a decrease in the specific to non-
specific activity ratio. This effect is due to the synaptic release of
dopamine following amphetamine. Increased dopamine concentra-
tion leads to increased D2 receptor occupancy by dopamine, and
fewer available receptors for [123I]IBZM binding.
Amphetamine Peripheral Effects
Amphetamine plasma levels were similar between
groups (schizophrenic patients: mean=23 ng/ml, SD=7;
healthy subjects: mean=23 ng/ml, SD=10). Ampheta-
mine induced a marked but transient increase in systolic
and diastolic blood pressure. No between-group differ-
ences were observed in the blood pressure response to
amphetamine (peak increase in systolic blood pressure:
schizophrenic patients, mean=36 mm Hg, SD=12;
healthy subjects, mean=41 mm Hg, SD=14; peak in-
crease in diastolic blood pressure: schizophrenic pa-
tients, mean=20 mm Hg, SD=24; healthy subjects,
mean=18 mm Hg, SD=6). Plasma HVA levels at base-
line were not different between groups (schizophrenic
patients: mean=9.7 ng/ml, SD=2.7; healthy subjects:
mean=9.7 ng/ml, SD=3.9). Mean postamphetamine
plasma HVA levels were 3.6 ng/ml (SD=1.1) and 3.2
ng/ml (SD=0.6) in healthy subjects and schizophrenic
patients, respectively. No differences between groups
were observed in the reduction of plasma HVA induced
by amphetamine (schizophrenic patients: mean=60%,
SD=10%; healthy subjects: mean=63%, SD=13%).
Amphetamine Effect on [123I]IBZM Binding Potential
Amphetamine-induced reduction in [123I]IBZM bind-
ing potential was larger in schizophrenic patients
(mean=13.8%, SD=10.3%) than in healthy subjects
(mean=7.1%, SD=6.2%) (F=4.64, df=1, 28, p<0.05)
(figures 2 and 3). A nonsignificant higher variability in
the response was observed in the schizophrenic group
(F=2.71, df=14, 14, p=0.07). No relationship between
764
FIGURE 3. Amphetamine-Induced Reduction in [123I]IBZM Binding
Potential in Healthy Subjects (N=15) and Schizophrenic Patients
(N=15)a
aThe amphetamine effect was significantly larger in schizophrenic pa-
tients (mean reduction of 13.8%, SD=10%, relative to baseline) than
in healthy subjects (mean=7.1%, SD=6.2%) (F=4.64, df=1, 28,
p<0.05). The horizontal line is the group average.
age and amphetamine-induced [123I]IBZM displace-
ment was observed in the two groups (patients and
healthy subjects) combined (r2<0.01, N=30, p=0.71) or
analyzed separately (schizophrenic patients: r2<0.01,
N= 15, p=0.91; healthy subjects: r2=0.02, N=15,
p=0.58). No relationship was observed between am-
phetamine plasma levels and [123I]IBZM displacement,
either in the entire study group (r2<0.01, N=30, p=0.98)
or in each group considered separately (schizophrenic
patients: r2<0.01, N=15, p=0.68; healthy subjects: r2=
0.03, N=15, p=0.58). No correlations were observed
between amphetamine-induced [123I]IBZM displace-
ment and other indices of peripheral amphetamine ac-
tivity, such as changes in systolic blood pressure (r2=
0.03, N=30, p=0.33) or changes in plasma HVA (r2=0.05,
N=30, p=0.28).
In the schizophrenic group, amphetamine-induced
[123I]IBZM displacement was not associated with dura-
tion of the neuroleptic-free interval (r2=0.03, N=13, p=
0.50), lifetime neuroleptic exposure (r2<0.01, N=13, p=
0.88), duration of illness (r2=0.03, N=15, p=0.54), or
the use of lorazepam in the week preceding the study
(patients taking lorazepam [N=5]: mean=20%, SD=
12%; patients without lorazepam [N=10]: mean=11%,
SD=1%) (F=3.10, df=1, 13, p=0.10). The two neuro-
leptic-naive patients had an amphetamine-induced
[123I]IBZM binding potential decrease of 7% and 35%,
respectively. The baseline [123I]IBZM binding potential
was not associated with the amphetamine-induced
[123I]IBZM reduction, either in the groups analyzed to-
gether (r2=0.04, N=30, p=0.31) or separately (schizo-
phrenic patients: r2=0.06, N=15, p=0.40; healthy sub-
jects: r2<0.01, N=15, p=0.85).
Am J Psychiatry 155:6, June 1998

FIGURE 4. Significant Relationship Between Changes in Positive
Psychotic Symptoms, Measured With the Positive and Negative Syn-
drome Scale, and the Increase in Striatal Dopamine Transmission
Following Amphetamine, Measured as the Amphetamine-Induced
Reduction in [123I]IBZM Binding Potentiala
ar2=0.42,
F=9.6, df=1, 13, p<0.001. Solid bars indicate the threshold
of clinically significant changes (plus or minus 4 points).
Relationship Between Clinical and Biochemical Response
No psychotic reaction was observed in the comparison
group (healthy subjects). In the schizophrenic group, six
patients experienced a psychotic reaction to the ampheta-
mine injection (i.e., increase of 4 or more points on the
positive subscale of the Positive and Negative Syndrome
Scale), eight patients showed no significant change in
positive symptoms, and one patient significantly im-
proved (i.e., decrease of 4 or more points on the positive
subscale of the Positive and Negative Syndrome Scale).
Amphetamine-induced dopamine release was signifi-
cantly larger in the patients who had a psychotic reaction
(mean=23%, SD=9%, N=6) than in the patients who
did not have a psychotic reaction (mean=8%, SD=5%,
N=9) (F=16.6, df=1, 13, p<0.005). The increase in positive
symptoms was significantly correlated with the reduction
in [123I]IBZM binding potential (r2=0.42, F=9.6, df=1,
13, p<0.001) (figure 4). Baseline [123I]IBZM binding po-
tential was not different between schizophrenic patients
who had a psychotic reaction (mean=216 ml g1, SD=95,
N=6) and those who did not (mean=255 ml g1, SD=132,
N=9). The severity of positive symptoms at baseline was
not associated with the magnitude of the amphetamine
effect on positive symptoms (r2=0.03, N=15, p=0.91) or
[123I]IBZM displacement (r2=0.07, N=15, p=0.32).
Eleven patients showed no significant changes in
negative symptoms following the amphetamine chal-
lenge, and four patients showed a clinically significant
improvement (i.e., decrease of 4 or more points on the
negative subscale of the Positive and Negative Syndrome
Am J Psychiatry 155:6, June 1998
ABI-DARGHAM, GIL, KRYSTAL, ET AL.
Scale). No significant relationship was observed between
improvement in negative symptoms and [123I]IBZM
displacement (r2=0.07, N=15, p=0.31). Amphetamine-
induced changes in positive and negative symptoms
were not correlated (r2<0.01, N=15, p=0.76).
Comparison With First Study
Results in this second cohort of subjects are compa-
rable to the results obtained in the first cohort (6) (table
2). Both cohorts were relatively similar in terms of clini-
cal and demographic composition. In each study, no
between-group differences were observed in baseline
[123I]IBZM binding potential. In comparison subjects,
the amphetamine effects on [123I]IBZM binding poten-
tial were identical in studies 1 and 2. In both studies,
the amphetamine effect on [123I]IBZM binding poten-
tial was larger in schizophrenic patients than in healthy
subjects. However, in this study, the effect size was
lower (1.06) than in the first study (1.49), and the sig-
nificance level of the group difference was lower
(p=0.04 for this study and p=0.01 for the first study).
Since the study protocols were identical, results of both
studies can be combined. When the results were com-
bined, the effect size was 1.32 and the p value was
0.001 (F=11.4, df=1, 58, p=0.001).
DISCUSSION
In a new cohort of 15 schizophrenic subjects and 15
matched healthy subjects, we replicated the observation
of a larger decrease in [123I]IBZM binding potential fol-
lowing amphetamine challenge in schizophrenic pa-
tients than in healthy subjects. Findings from these two
studies, together with the independent replication by
Breier et al. (7) and the preliminary results recently pre-
sented by a third group (13), clearly indicate abnormal
reactivity of dopaminergic transmission to ampheta-
mine exposure in the brain of schizophrenic subjects.
We also replicated the observation that this excessive
reaction is associated with behavioral consequences,
i.e., worsening or emergence of psychotic symptoms.
As in the first study, the increased stimulation of do-
pamine transmission observed in the striata of schizo-
phrenic patients could not be attributed to differences
in plasma amphetamine levels. The measurement of
plasma HVA before and after amphetamine was a new
feature of this study. Since HVA is formed mainly inside
the cell, the decrease in plasma HVA following am-
phetamine is generally attributed to depletion of the do-
pamine cytoplasmic pool (1416). Thus, the decrease in
plasma HVA is an indirect measure of the intracellular
effect of amphetamine in the peripheral nervous system.
The similarity in plasma HVA response to ampheta-
mine indicates that the intracellular bioavailability of
amphetamine was comparable between the groups.
Thus, the observed group differences in striatal dopa-
mine response to amphetamine exposure are related to
central nervous system factors.
765
STRIATAL DOPAMINE TRANSMISSION
TABLE 2. Results of Two Studies of Amphetamine-Induced Decrease in [123I]IBZM Binding Potential in Healthy Comparison Subjects and
Schizophrenic Patients
Comparison Subjects Schizophrenic Patients
Decrease in
Binding
Potential (%)
Study N Mean SD N Mean
Previous (4) 15 7.6 8.0 15
Present 15 7.1 6.3 15
Combined data 30 7.3 7.1 30
As in the first study, we could not attribute the in-
creased dopamine response in schizophrenic patients to
prior neuroleptic exposure, because of the lack of asso-
ciation between the amphetamine effect and previous
neuroleptic exposure or duration of neuroleptic inter-
val. These results indicate that the effect is unlikely to
represent a long-term effect of previous neuroleptic
medication. Similarly, we were unable to link the effect
with lorazepam exposure during the week preceding
the study. In conclusion, the effect seems to be associ-
ated with the illness process per se.
Abnormal dopaminergic transmission has been sus-
pected in schizophrenia for a long time. These studies
represent the first direct demonstration of abnormal
regulation of striatal dopaminergic transmission in
schizophrenia. The increase in dopaminergic transmis-
sion following amphetamine might be due to an in-
creased affinity of D2 receptors for dopamine (for ex-
ample, due to a higher proportion of high versus low
affinity sites), a larger or more prolonged dopamine re-
lease (i.e., presynaptic factors), or a combination of
both. Additional studies are needed to better character-
ize the exact mechanisms responsible for this increased
transmission (4, 6).
Several limitations of this study should be discussed.
This method has a relatively low sensitivity. We pre-
viously examined in primates the relationship between
increase in extrastriatal dopamine, measured with mi-
crodialysis, and decrease in [123I]IBZM binding poten-
tial, measured with SPECT. An increase of 45% above
baseline of striatal dopamine is needed to decrease
[123I]IBZM binding potential by 1% (4). A similar ratio
(44:1) has been reported by Breier et al. (7) for [11C]-
raclopride. In a previous study, we showed that in the
absence of amphetamine, the reproducibility of [ 123I]-
IBZM binding potential measurement had an average
variability (test minus retest divided by the average) of
plus or minus 3.3% (SD=1.7%, range=5% to 5%).
The low signal to noise ratio of the method explains
why two comparison subjects had an apparent increase
in [123I]IBZM binding potential following ampheta-
mine. On the other hand, the low sensitivity of the
method implies that a very large difference in synaptic
dopamine increase between patients and comparison
subjects corresponded to the measured differences in
[123I]IBZM binding potential decrease.
Another important limitation of the method is that it
766
Decrease in
Binding
Potential (%) Analysis
Effect
SD Size F df p
19.5 15.7 1.49 6.87 1, 28 0.01
13.8 10.3 1.06 4.64 1, 28 0.04
16.7 13.4 1.32 11.45 1, 58 0.001
does not provide any information about the baseline
dopamine concentration, i.e., concentration in the ab-
sence of amphetamine. In this study we measured only
the relative increase in dopamine concentration result-
ing from the amphetamine challenge. The observation
of a normal D2 receptor availability at baseline does not
imply that baseline dopamine levels are unaltered in
schizophrenia (17). A study based on rapid induction of
dopamine depletion with alpha-methyl-para-tyrosine is
currently being conducted in our group to address this
issue (18).
Finally, the low number of patients not previously ex-
posed to antipsychotics makes it difficult to rule out the
possibility that the observed effect might represent a
long-term consequence of prolonged neuroleptic expo-
sure. More neuroleptic-naive patients should be studied
to address this important question.
The effect size in the second cohort (1.06) was lower
than that in the first cohort (1.49). The reasons for the
lower effect size are unclear. The scan protocol was
identical, comparison subjects had similar effects (table
2), and the clinical characteristics of the patients were
similar (tables 1 in this article and in reference 6).
Therefore, it is likely that the difference in effect size is
due to a sampling effect, possibly related to the large
variance of the amphetamine effect in the schizophrenic
group.
The mechanism, specificity, significance, and etiology
of this increased dopaminergic response in schizophre-
nia remains to be elucidated. However, recent preclini-
cal studies do offer interesting hypotheses. Neonatal
hippocampal lesions in rodents and primates provide a
potential neurodevelopmental animal model for some
clinical and biochemical features of schizophrenia (19).
Regulations of striatal dopamine release were com-
pared with microdialysis between adult rhesus mon-
keys who underwent ablation of the amygdala-hippo-
campal formation within 3 weeks of birth, comparison
monkeys, and monkeys who underwent the same lesion
ablation during adulthood (20). Local perfusion of am-
phetamine in the prefrontal cortex induced a decrease
in striatal dopamine release in comparison monkeys
and in monkeys with adult lesions. This observation is
consistent with the inhibition of subcortical dopamine
by prefrontal dopamine (21). In contrast, in monkeys
with neonatal lesions, prefrontal amphetamine perfu-
sion induced an increase in striatal dopamine release,
Am J Psychiatry 155:6, June 1998

i.e., a reversal of the normal effect (inhibition). Thus, a
neonatal hippocampal lesion does affect prefrontal in-
hibition of striatal dopamine release. The relevance of
this model to schizophrenia remains to be established.
Brain imaging techniques now provide the tools to di-
rectly test these preclinical models in patients.
In conclusion, we replicated in this second cohort our
previous observation that schizophrenia is associated
with an increased dopamine transmission following
acute amphetamine challenge (6). The results of both
studies were very similar, with the exception that the
effect size in the second study was less pronounced than
that in the first study. These studies, as well as similar
results provided by other groups (7, 13), are consistent
in documenting this excessive neurochemical response
and provide direct evidence to support the hypothesis
of a dysregulation of central dopamine transmission in
schizophrenia.
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