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The Journal of Neuroscience, March 15, 2003, 23(6):2008
BRIEF COMMUNICATION
Catechol-O-Methyltransferase Genotype and Dopamine
Regulation in the Human Brain
Mayada
Akil,
Bhaskar S.
Kolachana,
Debora A.
Rothmond,
Thomas M.
Hyde,
Daniel R.
Weinberger, and
Joel E.
Kleinman
Clinical Brain Disorders Branch, Intramural Research Program,
National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland 20892
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ABSTRACT |
A functional polymorphism in the gene for
catechol-O-methyltransferase (COMT) has been
shown to affect executive cognition and the physiology of the
prefrontal cortex in humans, probably by affecting prefrontal dopamine
signaling. The COMT valine allele, associated with
relatively poor prefrontal function, is also a gene that may increase
risk for schizophrenia. Although poor performance on executive
cognitive tasks and abnormal prefrontal function are characteristics of
schizophrenia, so is psychosis, which has been related to excessive
presynaptic dopamine activity in the striatum. Studies in animals have
shown that diminished prefrontal dopamine neurotransmission leads to
upregulation of striatal dopamine activity. We measured tyrosine
hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain
and found that the COMT valine allele is also associated with increased
TH gene expression, especially in neuronal populations that project to
the striatum. This indicates that COMT genotype is a heritable aspect
of dopamine regulation and it further explicates the mechanism by which
the COMT valine allele increases susceptibility for psychosis.
Key words:
catechol-O-methyltransferase; dopamine; tyrosine hydroxylase; human; genotype; midbrain; psychosis; schizophrenia
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Introduction |
Dopamine (DA) neurotransmission has
been shown in both human and nonhuman primates to be critical for
cognitive functions subserved by the prefrontal cortex (PFC), such as
executive cognition and working memory (Sawaguchi and Goldman-Rakic,
1994 ; Williams and Goldman-Rakic, 1995). DA levels in the PFC are
determined by DA biosynthesis and release and by the rate of diffusion,
reuptake, and degradation. Breakdown may be particularly relevant to DA inactivation in the PFC in view of recent evidence that the DA transporter (DAT) is rarely expressed within synapses in this region
(Lewis et al., 2001) and exerts minimal influence on DA flux (Mazei et
al., 2002; Moron et al., 2002). Catechol-O-methyltransferase (COMT) is an important enzyme involved in the breakdown of DA and
converts DA to 3-methoxytyramine and the DA metabolite
dihydroxyphenylacetic acid to homovanilic acid (Boulton and Eisenhofer,
1998).
The human COMT gene contains a common functional polymorphism [a
valine (val) substitution for methionine (met)] at the 158/108 locus
in the peptide sequence. The met allele results in a heat-labile protein with a fourfold reduction in enzymatic activity (Mannisto and
Kaakkola, 1999). Studies in peripheral blood and in liver indicate that
this functional polymorphism accounts for most of the human variation
in peripheral COMT activity. Therefore, COMT genotype might also
contribute to differences in prefrontal function between individuals.
Consistent with this prediction, Egan et al. (2001) reported in a large
sample of subjects (n = 465) that COMT genotype is
associated with variations in executive cognition and with PFC
physiological activity during working memory, functions for which DA
levels in the PFC are known to be important. As expected, met/met
individuals had the best performance on executive cognition tasks,
val/val individuals had the worst, and val/met individuals were
intermediate. The effect of COMT genotype on cognitive function related
to prefrontal cortex has been confirmed by other groups (Rosa et al.,
2002; Malhotra et al., 2002; Bilder et al., 2003). The predicted effect
of COMT genotype on prefrontal cortical physiology was demonstrated
using functional magnetic resonance imagining during a working memory
task (Egan et al., 2001). These findings, in conjunction with evidence
of a regionally specific effect of COMT on PFC DA flux and on memory
found in COMT knock-out mice (Gogos et al., 1998; Kneavel et
al., 2000; Huotari et al., 2002), support the notion that COMT genotype
affects DA neurotransmission in the PFC.
In addition to its role in normal cognition, DA neurotransmission in
PFC has been implicated in the pathophysiology of schizophrenia (Weinberger, 1987; Weinberger et al., 1988; Akil et al., 1999). Patients with schizophrenia exhibit deficits in cognitive tasks that
are dependent on the function of the PFC (Weinberger et al., 1986; Park
and Holzman, 1992; Carter et al., 1998) and show abnormalities of
prefrontal physiology during performance of such tasks (Weinberger et
al., 1986, 1988; Carter et al., 1998; Callicott et al., 2000; Barch et
al., 2001). Moreover, these functional abnormalities have been related
to measures of cortical dopamine activity in vivo
(Weinberger et al., 1988; Daniel et al., 1991; Okubo et al., 1997;
Abi-Dargham et al., 2002), and evidence of abnormal dopaminergic innervation of PFC has been found in postmortem brains of patients with
schizophrenia (Akil et al., 1999). Consistent with this evidence, inheritance of the val allele has been found in some family-based association studies to slightly increase risk for schizophrenia (Li et
al., 1996, 2000; Kunugi et al., 1997; Egan et al., 2001), implicating
COMT as a susceptibility gene for schizophrenia.
The mechanism by which inheritance of the COMT val allele increases
risk for schizophrenia may be related to its impact on prefrontal DA
levels and prefrontal function. However, DA neurotransmission in PFC
has also been shown in experimental animals to affect subcortical DA
activity, which is implicated in both the psychotic symptoms of
schizophrenia (Carlsson, 1995; Grace, 2000; Laruelle, 2000) and the
therapeutic response to anti-dopaminergic drugs (Deutch, 1993; Kinon
and Lieberman, 1996). DA flux in PFC modulates the activity of
excitatory cortical neurons that project both directly and indirectly
to mesencephalic DA neurons (Haber and Fudge, 1997; Lu et al., 1997;
Carr and Sesack, 2000). Recent evidence in the rodent indicates that,
whereas prefrontal neurons make direct contacts with DA neurons that
project back to PFC, prefrontal projections do not contact directly DA
neurons projecting to the striatum. This has led to speculation that
prefrontal neurons tonically inhibit striatal DA projections perhaps
via GABA intermediates in the striatum or in the brainstem (Carr and
Sesack, 2000; Carlsson, 2001). Under experimental conditions in
animals, reduced DA signaling in the PFC leads to increased
responsivity of subcortically projecting midbrain DA neurons to stimuli
such as stress (Deutch, 1993, Kolachana et al., 1995; Harden et al.,
1998). The notion that overactive populations of mesencephalic dopamine
neurons might be a "downstream" effect of an abnormality in
prefrontal function has been proposed as an explanation for the
coexistence of both cortical and subcortical dopaminergic abnormalities
in schizophrenia (Weinberger, 1987; Weinberger et al., 1988; Deutch
1993, Grace, 2000). Therefore, to the extent that COMT genotype affects
prefrontal function, it may contribute risk for schizophrenia not only
because of its biological effects at the level of PFC but also because
of indirect downstream effects on DA regulation.
Because of this evidence that DA levels in the PFC and in the striatum
may be inversely related, we hypothesized that inheritance of the val
allele would affect the homeostasis of mesencephalic DA neurons in the
normal human brain in a predictable direction. Thus, compared with the
met allele, the val allele, which is likely associated with relatively
diminished prefrontal DA signaling, would result in relatively
increased disinhibition of mesencephalic DA activity, particularly in
neuronal populations projecting to the striatum. To test this
hypothesis, we compared mRNA levels of TH, the rate-limiting enzyme for
dopamine biosynthesis, in dopamine neurons of postmortem human brain
specimens from normal subjects with the val/val genotype and those with
the val/met genotype.
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Materials and Methods |
Characteristics of subjects. Human brain specimens
were obtained, during the course of routine autopsy, through the Office of the Medical Examiners of the District of Columbia with the informed
consent of the next of kin. Twenty-three normal controls were included
in this study. Ten cases with val/val genotype (seven males and three
females) were compared with 13 cases of val/met genotypes (eight males
and five females). All cases in the val/val group were African American
compared with 10 African Americans and three Caucasians in the val/met
group. Mean postmortem interval (PMI) is comparable between the
two groups (31.0 ± 15.5 for val/val and 33.8 ± 17.5 for
val/met), as is mean age (40.9 ± 14.9 for val/val and 49.9 ± 7.5 for val/met) and mean pH (6.42 ± 0.23 for val/val and
6.39 ± 022 for val/met). Clinical records were reviewed by two
board-certified psychiatrists, and collateral information was obtained,
whenever possible, from telephone interviews with surviving relatives
of the deceased. Blood and/or brain toxicology screens were obtained in
each case. We excluded subjects with known history of neurological
disorders, psychiatric disorders, or substance abuse and all cases with
prolonged agonal state. Each case was examined macroscopically and
microscopically by an experienced neuropathologist. We also excluded
cases with significant neuropathological abnormalities or cases that
met criteria for Alzheimer's disease. Approximately 35% of all cases
initially considered normal controls were eventually excluded from this study for these reasons. The collection of human brain specimens was
approved by the Institutional Review Board of the National Institute of
Mental Health Intramural Research Program.
Tissue specimens. In each case, the midbrain was cut into
1-2 cm blocks in a plane perpendicular to its long axis. Tissue blocks
were frozen immediately in a mixture of dry ice and isopentane, cryostat sectioned at 14 µm, thaw mounted onto gelatin-coated microscope slides, then dried and stored at  80°C. Every 50th section was stained for Nissl substance with thionin. Anatomical levels
corresponding to Figure 57 in the Atlas of the Human
Brainstem by Paxinos and Huang (Paxinos, 1995) were identified in
each case using Nissl-stained sections and TH immunocytochemistry.
Regional boundaries of the DA cell groups within the midbrain were
determined according to McRitchie and Halliday (1995). Five cell groups
were identified: the substantia nigra pars lateralis (SNL), the dorsal and ventral tiers of the pars compacta (SND and SNV respectively), the
paranigral nucleus (PN), and the ventral tegmental area (VTA). These
nuclei were chosen because they could be reliably identified at this
anatomical level. pH measures were conducted in each case using 500 mg
of tissue homogenate from the cerebellum and a 420A Orion
pH meter with a highly-sensitive glass pH SURE-FLOW electrode by Orion.
In situ hybridization. Tissue sections 14-µm-thick were
hybridized with 35S-labeled riboprobes for
TH, for the DAT, and for the house-keeping gene cyclophilin. We used a
545-bp-long riboprobe for human TH (Uhl et al., 1994) and a 350 bp
riboprobe for human DAT (Joh et al., 1998). In situ
hybridization for TH and DAT was performed as described previously
(Little et al., 1998). Two to four tissue sections from each subject at
the chosen anatomical level were included. To control for
between-experiment variations, tissue sections from all subjects were
always processed in the same experiment. Cyclophilin in situ
hybridization was conducted using
35S-labeled riboprobe for human
cyclophilin 103 bp cDNA from exons 1 and 2 of the human gene
(Ambion, Austin, TX) and the Whitfield method (Whitfield
et al., 1990). After overnight hybridization at 60°C in humidified
chambers, slides were placed in x-ray cassettes along with
14C standards (American Radiolabeled
Chemicals St. Louis, MO) and apposed to Kodak
BioMax MR autoradiographic film (Eastman Kodak, Rochester, NY)
for 4-20 d.
Quantitative analysis. Hybridization was quantified by
measuring the optical density of the x-ray film with NIH Image software version 1.61. All quantitative analyses were conducted blind to genotype. We sampled five DA cell groups from each side (SNL, SND, SNV,
PN, and the VTA). An area of 1.76 mm2 in each cell group was sampled
selecting the region of highest density (Fig.
1). Thus, from 20-40 measurements were
taken from each case for TH and for DAT. The results from all
sections and both sides were averaged to produce five mean measures
(one for each cell group) per subject. Mean values from each cell group and a total (sum) of means of all five were used for statistical analyses. The data were analyzed using COMT genotype (two) by cell
group (five) ANOVA on optical density measures of mean mRNA levels. In addition, ANCOVA including age, gender, pH, and PMI as
individual covariates were also conducted. Post hoc analyses were performed when appropriate using the Tukey's honest significant difference test.
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Figure 1.
Illustration of the sampling procedure. Red
circles indicate an area of 1.76 mm2 sampled in each of the five cell groups
selecting the region of highest density.
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Genetic analysis. Frozen tissue samples were collected from
the cerebellum of all cases. DNA was extracted using standard methods.
COMT
val108/158met
genotype was determined as a restriction fragment length polymorphism after PCR amplification and digestion with N1aIII as described previously (Egan et al., 2001). Of twenty-four brains originally genotyped, only one had a met/met genotype, which is not surprising considering the allele frequencies of the study population (Palmatier et al., 1999). This brain was excluded from additional analysis.
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Results |
We found a main effect of COMT genotype on TH mRNA levels
expressed as a summed measure in all five of the mesencephalic DA cell
groups (F = 5.63; df = 1, 22; p = 0.02; effect size = 0.9 d), and, as predicted, val/val cases
had significantly greater expression than val/met cases (41.8%
increase) (Fig. 2).
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Figure 2.
Autoradiograms of midbrain tissue sections after
in situ hybridization with radiolabeled riboprobes for
TH (A, B) or DAT (C,
D) mRNA in two matched cases with val/met (case 1193, A, C) or val/val (case 1111, B,
D) genotypes, respectively. Scale bar, 1 mm
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In an analysis of individual cell groups, significant main effects of
genotype were found in the SNV (71.6% increase; F = 16.6; df = 1, 22; p = 0.0005) (Fig.
3) and the SND (47.6% increase; F = 4.51; df = 1, 22; p = 0.04).
None of the other cell groups showed significant differences, and
covarying for factors such as age, gender, pH, or postmortem interval
did not affect these results (all F values <2.18; all
p values >0.15).
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Figure 3.
Comparisons of mean optical density, reflecting TH
mRNA levels, between subjects with val/met (circles) and
val/val (triangles) genotypes in the SNV. Each
symbol indicates the mean value for one male or female
subject (open and filled symbols,
respectively), and horizontal lines indicate group
means.
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In contrast with the TH data, mRNA expression of the DAT, another
marker of DA neurons, and cyclophilin, a constitutively expressed
protein unrelated to DA metabolism, did not differ between the two COMT
genotypes. Differential modification of DAT and of TH mRNA levels in
human mesencephalon has also been reported in Parkinson's disease and
Alzheimer's disease, which has been interpreted to suggest that TH
expression is a more sensitive measure of the DA metabolic activity
(Joyce et al., 1997).
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Discussion |
We found that COMT val158met genotype
affects TH gene expression in mesencephalic DA neurons and presumably
dopamine biosynthesis in these neurons. COMT is found in low abundance
in DA neurons and may only be expressed in specific subpopulations
(Lundstrom et al., 1995). Kastner et al. (1994) found that DA neurons
in the human VTA and the SNL are weakly immunoreactive for COMT
protein, whereas DA neurons in other cell groups that project to the
striatum show no COMT expression. In contrast, COMT is expressed in
striatal and cortical neurons that receive DA projections. These
findings are consistent with pharmacological evidence that the
degradation of DA by COMT at most DA synapses takes place at the
postsynaptic neuron (Karoum et al., 1993). This means that the effect
of COMT genotype on TH gene expression in the mesencephalon is not
likely to be a local effect but more likely to be a manifestation of feedback from nondopaminergic to DA neurons.
Several lines of evidence suggest that the effects of COMT genotype on
mesencephalic DA function are downstream manifestations of direct
effects of COMT on prefrontal cortical neurons. First, in COMT
knock-out mice, DA levels in the striatum are not altered, but DA
levels in the PFC are increased under certain conditions, and
heterozygote knock-outs are intermediate between homozygote knock-outs
and wild-type animals (Gogos et al., 1998; Huotari et al., 2002).
Importantly, changes in norepinephrine levels are not found in these
animals (Gogos et al., 1998; Huotari et al., 2002). This indicates that
COMT activity has a relatively selective impact on prefrontal cortical
DA signaling and supports speculation that inheritance of the COMT val
allele would lead to a relative increase in DA levels in this region.
The effect of COMT on DA in the PFC is consistent with low abundance of
prefrontal DA transporter (Lewis et al., 2001) and the small effect of
DAT function on prefrontal cortical DA levels (Mazei et al., 2002;
Moron et al., 2002). Second, 6-hydroxy-DA lesions of the PFC, which
destroy DA terminals, have been shown to alter baseline firing of
mesencephalic DA neurons and their response to stress (Deutch 1993;
Harden et al., 1998), and DA blockade in PFC leads to increased release
of DA in striatal terminals (Roberts et al., 1994; Kolachana et al.,
1995). Third, abnormal prefrontal function in humans has been linked to
upregulated presynaptic striatal dopamine activity. For example, levels
of prefrontal cortical N-acetyl aspartate, an intracellular
neurochemical marker of neuronal integrity assayed in vivo
with proton nuclear magnetic resonance spectroscopy, correlate
inversely with amphetamine-stimulated striatal DA release in humans
(Bertolino et al., 2000). In addition, abnormal prefrontal regional
cerebral blood flow during an executive cognition task correlates
inversely with f-18fluorodopa uptake in
the striatum (Meyer-Lindenberg et al., 2002). Although regions other
than the PFC, such as the hippocampus, affect subcortical DA (Floresco
et al., 2001), in clinical studies, only PFC N-acetyl
aspartate levels predicted the responsiveness of subcortical DA
to amphetamine challenge (Bertolino et al., 2000), and only prefrontal
cortical function is affected by COMT genotype (Egan et al., 2002).
These convergent findings implicate PFC projections as mediators of the
downstream effect of COMT genotype on TH gene expression in
mesencephalic DA neurons.
Whereas TH gene expression has been shown to be dependent on the
activity of dopamine neurons (Nagatsu, 1995; Kumer and Vrana, 1996;
Tank et al., 1998), DAT expression is not (Hoffman et al., 1998; Heinz
et al., 1999). Thus, the differential effect of COMT genotype on gene
expression of TH and the DAT in the mesencephalon may reflect
alterations in the activity of DA neurons, although this cannot be
established in postmortem tissue.
We observed the greatest genotype effects on TH mRNA levels in the
ventral tier of the SN and no apparent effects in the VTA, the PN, or
the SNL. Although we cannot rule out the possibility that our study
design is not sensitive enough to detect small effects in these
structures, this intriguing finding may be explained by the pattern of
connectivity between prefrontal cortex and mesencephalic DA neurons.
The ventral tier of the SN compacta in the nonhuman primate projects
primarily to the striatum and amygdala (Haber and Fudge, 1997),
suggesting that the effects of COMT genotype on TH regulation are
greatest in cell groups that do not project back to the PFC. In the
rodent, DA neurons that project to the cortex receive direct prefrontal
cortical inputs, whereas those projecting to the striatum do not (Carr
and Sesack, 2000). It has been suggested that indirect inputs from
prefrontal cortex to DA cell groups that project to the striatum
provide tonic inhibition of these cells via GABA intermediates,
possibly in striatum and elsewhere in the brainstem (Carlsson, 2001).
Thus, relatively decreased DA levels in PFC (presumably related to
greater val allele load, may lead to reduced signal-to-noise ratio in
assemblies of prefrontal pyramidal neurons (Henze et al., 2000; Seamans
et al., 2001). These neurons may then be expected to exert less
coherent corticofugal feedback and, thus, less inhibition of DA neurons projecting to the striatum (for a schematic representation, see Fig.
4). Our data are consistent with these
predicted effects. Of course, the validity of this interpretation
depends on the confirmation of the role of GABAergic neurons in this
hypothesized circuit. It is also interesting to note that the absence
of upregulation in the neuronal populations innervating the cortex
would mean that the COMT val effect on DA signaling in the prefrontal
cortex is not effectively compensated.
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Figure 4.
Diagram illustrating elements of the circuitry and
their putative involvement in the effects of COMT genotype on DA levels
in prefrontal cortex and TH gene expression in the brainstem. Relative
to val/met, the val/val genotype of the COMT enzyme leads to reduced DA
levels in the PFC. It is speculated that indirect PFC projections via
GABA neurons in the striatum or mesencephalon lead to increased gene
expression of TH mRNA in DA cell groups projecting subcortically. The
question mark is to indicate that some of the GABA
projections remain to be confirmed. Sources of anatomical information
include the following: Lewis (1992), Deutch (1993),
Murase et al. (1993), Williams and Goldman-Rakic (1995), Haber
and Fudge (1997), Carr and Sesack (2000),Chiba et al. (2001),
and Seamans et al. (2001).
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Our finding that COMT genotype is a heritable factor in DA modulation
may further clarify the mechanism by which the COMT val allele may
increase risk for schizophrenia and possibly other psychotic states.
Several lines of evidence suggest that a cortical hypo-dopaminergic state is accompanied by a subcortical
hyper-dopaminergic state in schizophrenia, thereby contributing to
cognitive and psychotic symptoms, respectively (Weinberger, 1987;
Weinberger et al., 1988; Grace, 2000). Such reciprocal relationships
between cortical and subcortical DA systems have been demonstrated
repeatedly in animal experiments (Pycock et al., 1980; Finlay and
Zigmond, 1997; Lipska and Weinberger, 1998). Increased responsivity of striatal dopaminergic terminals to amphetamine in schizophrenic patients has also been found (Abi-Dargham et al., 1998; Laruelle, 2000), as has other evidence of presynaptic upregulation of DA metabolism (Hietala et al., 1999; Abi-Dargham et al., 2000;
Meyer-Lindenberg et al., 2002). To the extent that schizophrenia
involves both abnormalities in prefrontal dopamine signaling and in
nigrostriatal dopamine activity, the COMT val allele appears to
contribute risk to each of these elements of the disorder and in the
specific directions associated with the illness. The reciprocal effects of COMT genotype on DA signaling in the prefrontal cortex and on TH
gene expression in the SN implicates a mechanism by which inheritance
of COMT val increases risk for schizophrenia and possibly other
psychotic disorders.
Finally, it should be emphasized that the effects we observed are in
normal human brain. As such, these effects by themselves are compatible
with the range of normal brain function. They appear to represent
genetically determined variations in prefrontal function and DA
neuronal regulation, which, for the val allele, slightly bias humans
toward the expression of two biological phenomena associated with
schizophrenia: abnormal prefrontal function and upregulated striatal DA
activity. It is presumably the interaction of these COMT val effects
with other biological processes (both genetic and environmental) from
which the clinical disorder emerges.
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FOOTNOTES |
Received July 15, 2002; revised Dec. 30, 2002; accepted Jan. 8, 2003.
We thank Dr. Mary Herman for her neuropathology expertise and her
efforts in procuring brain specimen. We also thank Juraj Cervenak, Yeva
Snitkovsky, Shannon O'Connor, and Christopher Keczkemethy for
technical assistance.
Correspondence should be addressed to Dr. Mayada Akil, 10 Center Drive,
4N306, MSC1385, Bethesda, MD 20892. E-mail: akilm{at}intra.nimh.nih.gov.
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TOP
ABSTRACT
Introduction
