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Article
Brain Dopamine D1 Receptors in Twins Discordant for Schizophrenia Jussi Hirvonen, M.D., Ph.D. Theo G.M. van Erp, M.A. Jukka Huttunen, M.D. Sargo Aalto, M.Sc. Kjell Någren, Ph.D. Matti Huttunen, M.D., Ph.D. Jouko Lönnqvist, M.D., Ph.D. Jaakko Kaprio, M.D., Ph.D. Tyrone D. Cannon, Ph.D. Jarmo Hietala, M.D., Ph.D.
Objective: It has been suggested that deficits in higher-order cognitive functions serve as intermediate phenotypic indicators of genetic vulnerability to schizophrenia. The dopamine hypothesis of schizophrenia postulates that insufficiency of dopamine transmission in the prefrontal cortex contributes to the cognitive deficits observed in patients with the disease, and there is robust empirical evidence for a central role of prefrontal cortex dopamine D 1 receptors in working memory functions.
Results: High D1 receptor density in the medial prefrontal cortex, superior temporal gyrus, and heteromodal association cortex (angular gyrus) was associated with increasing genetic risk for schizophrenia (comparison twins < unaffected dizygotic co-twins < unaffected monozygotic cotwins). Medicated schizophrenia patients demonstrated a widespread reduction in D1 receptor binding when compared with the unaffected co-twin, and higher doses of antipsychotics were associated with lower D1 receptor binding in the frontotemporal regions.
Method: The authors examined the genetic and nongenetic effects on D1 receptor binding in schizophrenia by studying monozygotic and dizygotic twin pairs discordant for schizophrenia as well as healthy comparison twins using positron emission tomography (PET) and the D1 receptor antagonist ligand [11C]SCH 23390. Performance on neuropsychological tests sensitive to frontal lobe functioning was evaluated.
Conclusions: This study demonstrated an association between genetic risk for schizophrenia and alterations in cortical D1 receptor binding, an observation that has implications for future studies of the molecular genetics of schizophrenia. In addition, the data indicate a widespread reduction of D1 receptor binding in medicated schizophrenia patients, supporting a link between antipsychotic drug action and dopamine D 1 receptor downregulation. (Am J Psychiatry 2006; 163:1747–1753)
S
chizophrenia is characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as blunt affect), cognitive impairment, and affective symptoms (1). Cognitive functions involving working memory—the ability to hold and manipulate pieces of information online for subsequent use in planning and acting—are particularly impaired in schizophrenia (2). Working memory is critically dependent on prefrontal cortical functioning (3). Patients suffering from schizophrenia show aberrant activation of the prefrontal cortex during working memory tasks, which suggests a role for the prefrontal cortex in the pathophysiology of cognitive deficits in schizophrenia (4). Animal and human studies have highlighted the significance of dopamine in regulating prefrontal cortical activity related to cognitive processing (5). Accordingly, the dopamine hypothesis of schizophrenia suggests that reduced dopamine function in the prefrontal cortex is responsible for the cognitive deficits encountered in patients with the disorder (6, 7).
At the receptor level, D1 receptor function is essential for working memory function (8). It has been suggested that D1 receptors in the prefrontal cortex, located mostly in apical dendrites and spines of pyramidal neurons (9), modulate the postsynaptic neuron’s response to incoming depolarizing, mostly glutamatergic, signaling (8). This modulation seems to be dependent on the state of the target neurons, and it seems to protect task-associated working memory representations from interfering and distracting stimuli by tuning the functional state of the target neurons (10). Too much or too little stimulation at the D1 receptor can impair working memory, which suggests that the dependence of working memory on D1 receptor stimulation may be described by an inverted U-shaped curve (11). Schizophrenia is highly heritable (12), but the molecular basis of its heritability has remained largely unknown. The search for quantifiable mediators of this genetic vulnerability (intermediate phenotypes, or endophenotypes) could facilitate the exploration of the exact pathophysiological mechanisms behind the genetic vulnerability for
This article is featured in this month’s AJP Audio. Am J Psychiatry 163:10, October 2006
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schizophrenia (13). Recent evidence suggests that neuropsychological deficits (14), reduction of prefrontal cortical gray matter (15), and prefrontal cortical dopaminergic dysfunction (16) are associated with an increased genetic risk of schizophrenia. We recently demonstrated an increased density of dopamine D2 receptors in the caudate nuclei of unaffected identical co-twins of patients with schizophrenia (17) that was similar in magnitude to the overall increase in density observed in a meta-analysis of studies of patients with schizophrenia (7). However, as yet, the role of D1 receptors in the genetic etiology of schizophrenia has remained unaddressed. We used positron emission tomography (PET) and the well-documented D1 receptor tracer [11C]SCH 23390 to examine the genetic and nongenetic contributions to D1 receptor binding in schizophrenia by investigating twin pairs discordant for schizophrenia as well as healthy comparison twins. To explore the effects of genetic proximity to the patient, group comparisons were performed across three levels of genetic loading: comparison twins, dizygotic co-twins, and monozygotic co-twins. Monozygotic co-twins share 100% and dizygotic co-twins on average 50% of their segregating genes with the proband. All subjects also underwent comprehensive neuropsychological testing. Probands were included in the analyses, although they had experienced chronic antipsychotic drug treatment, which has been shown to down-regulate cortical D1 receptors (18, 19). The aim of the study was twofold: to investigate the effects of genetic liability to schizophrenia on D1 receptor binding by comparing unaffected co-twins of patients with schizophrenia with matched healthy comparison twin pairs, and to examine disease- and treatment-specific contributions by comparing medicated patients with their own unaffected co-twins.
Method The study protocol adhered to the principles of the Helsinki Declaration and was reviewed and approved by the institutional review boards or ethical committees of the University of California Los Angeles, the University of Turku, the University of Pennsylvania, and the National Public Health Institute of Finland. All participants provided written informed consent after receiving a complete description of the study.
Sample Ascertainment and Clinical Evaluation Using a procedure described previously, we drew subjects from a twin cohort consisting of virtually all same-sex twin pairs born in Finland from 1940–1957 (14, 17, 20). Nine discordant pairs were studied (four monozygotic and five dizygotic) along with two additional unaffected monozygotic co-twins and 13 twins from seven comparison twin pairs (four monozygotic and three dizygotic). Each co-twin was given a structured diagnostic interview. Clinical patient data have been described previously (14). All patients except one had received chronic antipsychotic treatment with conventional neuroleptics. Use of clozapine or flupenthixol was an exclusion criterion since these drugs have low D2/D1 selectivity (21). The drugs used by these probands were haloperidol (N=4, dose range=1–8 mg/day), levomepromazine (N=1, dose=25
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mg/day), sulpiride (N=1, dose=100 mg/day), thioridazine (N=4, dose range=50–400 mg/day), and chlorprothixene (N=1, dose=50 mg/day). In chlorpromazine equivalents, daily doses ranged from 0 mg to 800 mg. The probands underwent the PET studies despite evidence that antipsychotic drug treatment may down-regulate D1 receptors in the nonhuman primate cortex (18, 19). The duration of illness ranged from 10 years to 36 years. Exclusion criteria for unaffected co-twins and comparison twins have been described previously (14, 17). The study groups were matched for demographic variables. The zygosity of the studied twins was confirmed by genetic markers as described previously (14). All subjects were tested with a comprehensive neuropsychological battery, from which a canonical liability variable was constructed to reflect performance on tests of spatial working memory, divided attention, intrusions during recall of a word list, and choice reaction times to visual targets (14). Deficits on these tests have been shown to be heritable in twins discordant for schizophrenia, increasing in severity with increasing genetic proximity to the proband. Spatial working memory, as measured by the visual span subtest of the Wechsler Memory Scale—Revised, was selected from among these tests to be individually correlated with D1 receptor binding. Findings on the neuropsychological data in the original twin sample have been previously published (14).
PET Studies For the PET studies, a whole-body three-dimensional PET scanner (GE Advance; GE, Milwaukee) was used to acquire 35 slices of 4.25 mm thickness covering the whole brain. The scanning procedure and preparation of [11C]SCH 23390 have been described in detail elsewhere (22). Briefly, an intravenous rapid bolus of 174–268 MBq of [11C]SCH 23390 (mean=233.01 MBq, SD= 24.4) was given to each subject (specific radioactivity, mean=63.5 MBq/nmol [SD=18.3]; amount of radiotracer, mean=1.14 µg [SD= 0.31]). No statistically significant differences were observed between study groups in any of these parameters.
Quantification of [11C]SCH 23390 Binding For the calculation of regional time-activity curves, regions of interest were manually delineated using Imadeus software (version 1.15, Forima, Inc., Turku, Finland) on the putamen, caudate, angular gyrus, anterior cingulate cortex, cerebellum, dorsolateral prefrontal cortex, insular cortex, medial prefrontal cortex, orbitofrontal cortex, posterior cingulate cortex, supramarginal gyrus, subgenual anterior cingulate cortex, and superior, middle, and inferior temporal gyri, as previously described (22). There were no statistically significant differences between groups in region-of-interest size, except in the insular cortex, which was smaller in probands compared with other subjects (–5.0 to –7.1%, p
