0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Brain Serotonin and Dopamine Transporter Bindings in Adults With High-Functioning Autism FREE

Kazuhiko Nakamura, MD, PhD; Yoshimoto Sekine, MD, PhD; Yasuomi Ouchi, MD, PhD; Masatsugu Tsujii, MA; Etsuji Yoshikawa, BS; Masami Futatsubashi, BS; Kenji J. Tsuchiya, MD, PhD; Genichi Sugihara, MD, PhD; Yasuhide Iwata, MD, PhD; Katsuaki Suzuki, MD, PhD; Hideo Matsuzaki, MD, PhD; Shiro Suda, MD, PhD; Toshiro Sugiyama, MD, PhD; Nori Takei, MD, PhD; Norio Mori, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry and Neurology (Drs Nakamura, Sekine, Iwata, Suzuki, Suda, and Mori), Laboratory of Human Imaging Research, Molecular Imaging Frontier Research Center (Dr Ouchi), and Osaka-Hamamatsu Joint Research Center for Child Mental Development (Mr Tsujii and Drs Tsuchiya, Sugihara, Matsuzaki, Takei, and Mori), Hamamatsu University School of Medicine, Positron Medical Center, Hamamatsu Medical Center (Dr Ouchi), and Central Research Laboratory, Hamamatsu Photonics K.K. (Messrs Yoshikawa and Futatsubashi), Hamamatsu, Japan; Faculty of Sociology, Chukyo University, Toyota, Japan (Mr Tsujii); and Aichi Children's Health and Medical Center, Obu, Japan (Dr Sugiyama).


Arch Gen Psychiatry. 2010;67(1):59-68. doi:10.1001/archgenpsychiatry.2009.137.
Text Size: A A A
Published online

Context  Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown.

Objective  To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems.

Design  Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables.

Setting  Participants recruited from the community.

Participants  Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects.

Results  Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = −0.61; P = .004).

Conclusions  The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

Figures in this Article

Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests.1 There is no established treatment or cure for the disorder. Recent population-based surveys showing that autism is more common than previously believed have aroused serious public concern worldwide.2 In addition, genome-wide linkage scans and copy-number analyses have revealed “hot spots” on several chromosomes.35 To clarify the pathophysiologic mechanism of autism, the neuroimaging approach is a fruitful method. In this study, we used positron emission tomography (PET) to focus on neurotransmitter alterations in the autistic brain.

A wide array of transmitter systems has also been studied with respect to autism. Initial studies on the pathophysiologic mechanism of autism have focused on the serotoninergic system. Prior studies consistently found elevated serotonin levels in the whole blood cells and platelets of patients with autism610 and their relatives.1113 Short-term dietary depletion of tryptophan (ie, the serotonin precursor) has been shown to exacerbate repetitive behavior and to elevate anxiety and feelings of unhappiness in autistic adults.14 Conversely, treatment with selective serotonin reuptake inhibitors—commonly used antidepressants—has been shown to be effective in ameliorating the repetitive and/or obsessive behavior and interests in some but not all autistic individuals.15 Genetic studies have yielded evidence of a critical role for the serotonin transporter gene (SLC6A4; OMIM d182138), which is located on chromosome 17q11.5,16 Several SLC6A4 polymorphisms have been found to be associated with autism.17,18 Furthermore, SLC6A4 promoter polymorphisms may influence the gray matter volume of cerebral cortical structures in young male autistic individuals.19 It has also been shown that SLC6A4 modulates the function of social brain systems when healthy control subjects process facial emotions.20 Neuroimaging studies with PET have provided further evidence that the levels of serotonin synthesis in autistic children aged 2 to 5 years are significantly lower than those in control children.21,22 A recent single-photon emission computed tomography study has shown that autistic children, under light sedation, have a reduction in serotonin transporter binding in the medial frontal cortex, midbrain, and temporal lobe areas.23

Interest in the role of dopamine has been stimulated by the observations that dopamine blockers (ie, antipsychotics) are effective in treating some aspects of autism, such as hyperactivity, aggression, and self-injury.24,25 In addition, some direct evidence suggests that levels of the principal dopamine metabolite homovanillic acid are elevated in the cerebrospinal fluid of autistic individuals,26 although this has not been consistently reported.27 Previous genetic studies have demonstrated that the prevalence of the A1 allele of the dopamine D2 receptor is significantly increased in autism,28 whereas the dopamine D1 receptor gene may be a risk gene for core symptoms of autism in male-only affected sibling-pair families.29 Furthermore, it has been suggested that the 9- and 10-repeat alleles of the dopamine transporter may be associated with hyperactivity, impulsivity, social anxiety, and tic symptoms in autistic children.30 In a PET study of autistic children, low levels of medial prefrontal dopaminergic activity were observed under anesthesia,31 whereas increased dopamine D2 receptor binding in the whole caudate and putamen has also been demonstrated.32 These findings suggest that the alteration of both the serotonin and the dopamine systems is a feature of autism, although these findings remain equivocal and inconclusive.

Taking these results together, we hypothesized that alterations in both the serotoninergic and the dopaminergic systems exist in the brain of autistic individuals, and that the changes are associated with the clinical features of autism. To examine this hypothesis, we used PET to measure the binding of the serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems, in adults with high-functioning autism. We also examined the relationships between some of the clinical symptoms of autism and the binding levels of both transporters.

SUBJECTS

Twenty men with autism (mean [SD] age, 21.2 [2.0] years; age range, 18-26 years) and 20 healthy male controls (mean [SD] age, 21.9 [2.0] years; age range, 18-26 years) participated in this study. All participants were right-handed and had an IQ of greater than 70 (estimated using the Wechsler Adult Intelligence Scale–Revised). The IQ did not differ significantly between the 2 groups (mean [SD], 99.3 [18.1] for the autistic group and 104.6 [15.2] for the control group; P = .30) (Table 1). An autism diagnosis was based on the following: the DSM-IV-TR1; the Autism Diagnostic Interview–Revised33; and the Autism Diagnostic Observation Schedule–Generic.34 All of the autistic individuals and controls underwent screening to exclude comorbid psychiatric illnesses (ie, schizophrenia, affective disorders, mental retardation, and personality or behavioral disorders) by means of the Structured Clinical Interview for the DSM-IV.35 Individuals with a history of neurological disorders (eg, epilepsy or head injury) or genetic disorders (eg, fragile X syndrome or tuberous sclerosis) were also excluded. In addition, controls were excluded if they had a family history of psychiatric illness, measured using the Family History Research Diagnostic Criteria.36 All autistic participants were drug naive. The present study was approved by the local ethics committees. Written informed consent was obtained from each of the participants.

CLINICAL ASSESSMENTS

To assess social cognitive ability, we used the Faux Pas Test.3739 A low score on this test indicates poor social cognition. This test is appropriate for the measurement of theory-of-mind impairment at a higher level. To evaluate the degree of repetitive and/or obsessive behavior and interests, we used the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).40,41 We also assessed anxiety and depressive symptoms using the 17-item Hamilton Anxiety Scale (HAM-A)42 and the 17-item Hamilton Scale for Depression (HAM-D),43 respectively. Aggression was evaluated using the Aggression Questionnaire (AQ).44 These evaluations were performed on the day of the PET examination with radioactive carbon (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652).

IMAGING PROCEDURES AND DATA ANALYSIS

All participants underwent 3-dimensional magnetic resonance imaging (MRI) with a static magnet (MRP7000AD; Hitachi, Tokyo) just before the PET measurement. The MRI and PET examinations were performed under sedation-free conditions. The PET scans were conducted with a high-resolution brain-purpose unit (SHR12000; Hamamatsu Photonics K.K.). The MRI measurements and a mobile PET gantry allowed us to reconstruct PET images parallel to the anterior-posterior intercommissural line without resectioning. Using this approach, we were able to allocate a region of interest (ROI) to the target area of the original PET image. In quantitative PET brain imaging, the partial volume effect is an important degrading factor.45,46 To reduce the partial volume effect, we set ROIs on the MRIs and transferred them onto PET images as described elsewhere.47,48 Participants in both groups underwent 38 serial PET scans during a period of 92 minutes with periodic arterial blood sampling after an intravenous injection of [11C](+)McN-5652 to determine their serotonin transporter binding.49,50 The reproducibility of PET images with [11C](+)McN-5652 was reported in Papio anubis baboons51; when the primates underwent scanning with [11C](+)McN-5652 at 3- to 4-week intervals, good test-retest reliability was obtained. Accordingly, within 4 weeks of the initial PET scan, a second PET measurement with [11C]-labeled 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428) was performed under the same protocol as in the [11C](+)McN-5652 study to measure dopamine transporter binding.5254 As described previously,49 we estimated [11C](+)McN-5652 binding on the basis of a single-tissue–compartment 3-parameter model. Because the distribution volume of [11C](+)McN-5652 estimated by this model correlated with the binding of the serotonin transporter in the brain,49 we constructed parametric images of the [11C](+)McN-5652 distribution volume for all participants with the use of biomedical imaging software (PMOD, version 2.5; PMOD Technologies Ltd, Zurich, Switzerland) (Figure 1A and B). Similarly, applying a 3-compartment 4-parameter model to the [11C]WIN-35,428 data allowed us to estimate the binding potential of the tracer47,53 to evaluate the dopamine transporter binding. This curve-fitting model cannot generate the distribution volume directly. In our voxelwise imaging analyses, we instead calculated the ratio index for subsequent use with statistical parametric mapping (SPM) software (SPM99; Wellcome Department of Cognitive Neurology, Institute of Neurology, London, England). Because this binding potential has been shown to correlate well with the reference tissue-derived ratio index (ie, the ratio of the PET binding value in the target region to the PET binding value in the cerebellum in the late integrated image),53 we constructed parametric images of the [11C]WIN-35,428 ratio index (Figure 1E and F) for subsequent voxelwise analysis. These voxelwise image analyses of the serotonin and dopamine transporter binding were conducted using the SPM software.49,53

Place holder to copy figure label and caption

Figure 1. Positron emission tomography images of radioactive carbon (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428) binding in a healthy control subject and an individual with autism. A and B, Images of the [11C](+)McN-5652 distribution volume with a color scale ranging from 0 to 60 mL/g show a control brain and a global reduction in [11C](+)McN-5652 distribution in an autistic individual. C and D, Radioactivity produced by [11C](+)McN-5652 in the orbitofrontal region and the striatum of a representative control and an autistic subject. E and F, Images of the [11C]WIN-35,428 ratio index reflect the binding potential of [11C]WIN-35,428 with a color scale ranging from 0 to 10 compared with a control and the elevation of its value in the orbitofrontal cortex in an autistic subject. G and H, Radioactivity caused by [11C]WIN-35,428 in the orbitofrontal region and the striatum of a representative control and an autistic subject. To convert radioactivity to curies per milliliter, multiply by 2.7 ×10−8.

Graphic Jump Location
STATISTICAL ANALYSIS

Demographic and clinical variables were compared between the autistic and control groups using the t test, in which a 2-tailed α level of .05 was set as the level of significance (SPSS software, version 11.0J; SPSS Japan Inc, Tokyo). In the SPM analysis, voxelwise between-group comparisons were performed to investigate regional differences in the binding levels of [11C](+)McN-5652 and [11C]WIN-35,428. Correlation analyses were conducted between the 5 clinical behavior scores (Faux Pas Test, Y-BOCS, HAM-A, HAM-D, and AQ) and the total voxel analysis of the whole brain by using SPM analysis within the autistic group. To avert the risk of a type I error, the levels of statistical significance for the voxel and cluster analyses were set at P < .05 after allowing for multiple comparisons. In addition, we performed ROI analysis to examine whether regional serotonin and dopamine binding covaried in autistic individuals. Based on the results of the SPM analysis, we restricted the ROI analysis to the orbitofrontal area, where pronounced disturbances were present in the binding of serotonin and dopamine transporters (Table 2). In this analysis, the Pearson product moment correlation coefficient was computed. P < .05 was considered statistically significant.

Table Graphic Jump LocationTable 2. Results of the Whole-Brain Voxel-Based Statistical Parametric Mapping Analyses of [11C](+)McN-5652 and [11C]WIN-35,428 Binding Parametersa

The demographic and clinical variables of the participants are shown in Table 1. The mean Faux Pas Test score was significantly lower in the autistic participants than in the controls (P < .001).

COMPARISON OF SEROTONIN TRANSPORTER BINDING BETWEEN GROUPS

The SPM results showed significant reductions in the [11C] (+)McN-5652 distribution volume throughout the global brain in the autistic group compared with the control group (P < .05, corrected), with the reductions being most pronounced in the frontal, temporal, parietal, and occipital lobes; in the limbic and subcortical regions; and in the cerebellum (Table 2 and Figure 2A).

Place holder to copy figure label and caption

Figure 2. Statistical parametric mapping results for [11C](+)McN-5652 and [11C]WIN-35,428 binding. A, Glass brain images indicate extensive reduction in the [11C](+)McN-5652 distribution volume in the autistic group (P < .05, corrected). B and C, Statistical parametric maps show brain regions in which the [11C](+)McN-5652 distribution volume correlates positively with the Faux Pas Test score and negatively with the Yale-Brown Obsessive Compulsive Scale score, respectively, in autism (P < .05, corrected). D, A statistical parametric map showing a brain region in which the [11C]WIN-35,428 ratio index is significantly higher in the autistic group than in the control group (P < .05, corrected). Color bars indicate T values. A indicates anterior; L, left; P, posterior; and R, right. See the legend to Figure 1 for expansion of other abbreviations.

Graphic Jump Location
CORRELATES OF SEROTONIN TRANSPORTER WITH CLINICAL CHARACTERISTICS IN AUTISTIC PARTICIPANTS

The [11C](+)McN-5652 distribution volume in the anterior cingulate cortex, the cingulate cortex, and the posterior cingulate cortex extending to the precuneus had a significantly positive correlation with the scores of the Faux Pas Test (P < .05, corrected) (Table 2 and Figure 2B).

We also evaluated the degree of repetitive and/or obsessive behavior and interests, which are additional clinical features of autism, using the Y-BOCS. A higher Y-BOCS score signifies more severe symptoms. There was a significant negative correlation between the Y-BOCS scores and the distribution volume of [11C] (+)McN-5652 in the thalamus extending to the parahippocampal region (P < .05, corrected) (Table 2 and Figure 2C).

No significant correlation was found between the [11C] (+)McN-5652 distribution volume and the symptom profiles of the HAM-A, HAM-D, or AQ.

COMPARISON OF DOPAMINE TRANSPORTER DISTRIBUTION BETWEEN GROUPS

The SPM analysis revealed a significant increase in [11C]WIN-35,428 binding in the medial frontal region covering the orbitofrontal cortex in the autistic group compared with the control group (P < .05, corrected in voxel-level analysis) (Table 2 and Figure 2D).

No significant correlation was found between [11C]WIN-35,428 binding and the symptom profiles of the Faux Pas Test, Y-BOCS, HAM-A, HAM-D, or AQ.

CORRELATION BETWEEN SEROTONIN AND DOPAMINE TRANSPORTER BINDINGS

In the ROI analysis of the orbitofrontal cortex, which showed disturbances in [11C](+)McN-5652 and [11C]WIN-35,428 binding in the autistic group (Figure 1C, D, G, and H), the [11C](+)McN-5652 distribution volumes were significantly negatively correlated with the [11C]WIN-35,428 binding potentials of the autistic group (Figure 3) (r = −0.61; P = .004, according to Pearson product moment correlation coefficient).

Place holder to copy figure label and caption

Figure 3. Correlation between [11C](+)McN-5652 and [11C]WIN-35,428 binding. Pearson product moment correlation analysis shows a significantly negative correlation between the [11C](+)McN-5652 distribution volume and the [11C]WIN-35,428 binding potential in the orbitofrontal cortex in autistic subjects (r = −0.61; P = .004; y = −0.006x + 0.39). The k values represent the binding potential. See the legend to Figure 1 for other abbreviations.

Graphic Jump Location

The autistic participants had a significantly decreased [11C] (+)McN-5652 distribution volume throughout the brain, whereas they had a significantly increased [11C]WIN-35,428 distribution volume in the medial region of the orbitofrontal cortex, compared with those of the controls. These results suggest the impairment of the function of the serotoninergic systems throughout the brain and the overfunctioning of the dopaminergic systems in the orbitofrontal cortex of the autistic adults. However, the autistic participants studied herein are not a representative or a typical sample of the population of autistic individuals. We opted for autistic individuals with an IQ of greater than 70 in this study (ie, high-functioning individuals), although about 65% of autistic individuals are known to have an IQ of less than 70.55 In addition, approximately 20% to 38% of autistic individuals are reported to have epilepsy.56,57 However, in the present study, our autistic participants had no comorbidity, including epilepsy. Furthermore, our autistic participants were all drug naive. Therefore, our findings cannot be generalized to the entire population of autistic adults.

In the anterior and posterior cingulate cortices, where reduced serotonin transporter binding was noted in the autistic group, the magnitude of reduction was correlated with poor performance on the Faux Pas Test, which assesses social cognition ability. Our finding is in line with those of previous PET studies, which showed that reduced metabolism or blood flow in the cingulate cortices is associated with impairment of social cognition in autistic individuals.58,59 Our finding is also supported by a study that used single-photon emission computed tomography and demonstrated that adults with Asperger syndrome, a clinical entity that is part of a spectrum of pervasive developmental disorders, exhibit a reduction in serotonin 2A receptor binding in the cingulate cortices and that this binding reduction is related to impaired social interaction.60

We also found that, in the autistic participants studied, the reduction in the serotonin transporter binding in the thalamus correlated with repetitive and/or obsessive behavior and interests as assessed by the Y-BOCS. This finding is compatible with previous studies that showed that the thalamus is the principal site for the accumulation of selective serotonin reuptake inhibitors,61 which in turn ameliorate repetitive behaviors in some but not all autistic individuals.15 In the present study, there was, however, no correlation in any of the other regions that have been implicated as responsible for repetitive behavior in individuals with obsessive-compulsive disorder (eg, the basal ganglia, frontal regions, and hippocampus). A prior hydrogen 1–labeled magnetic resonance spectroscopy study has shown that, in adults with Asperger syndrome, increased prefrontal N-acetylaspartate levels are positively correlated with obsessional behavior.62 Furthermore, MRI studies of autistic adults have demonstrated enlargement of the caudate and putamen volumes, which is positively correlated with repetitive behaviors.63 Repetitive behaviors have also been shown to be related to the hippocampus volume in obsessive-compulsive disorder.64 In addition, individuals with autistic spectrum disorders were reported to have significantly higher concentrations of glutamate/glutamine and creatine/phosphocreatine in the amygdale-hippocampal region.65 One possible explanation for the lack of correlations found in these regions (the basal ganglia, frontal regions, and hippocampus) is that impairments in the regions other than the thalamus, if any, could be accounted for by altered dysfunctions that are not related to disturbed serotonin transporter bindings per se. Nevertheless, further work is needed to determine whether the localized reduction in serotonin transporter binding in the thalamus is specific to repetitive and/or obsessive behavior and interests seen in adults with high-functioning autism.

Increases in peripheral serotonin levels have been the most consistent finding in autistic children.610 High levels of peripheral serotonin are known to cause a loss of serotonin terminals during development, when serotonin transporters are located,6669 and this may happen in the brain as well. Therefore, we speculate that the reduction of serotonin transporter binding found in the brain of autistic adults in this study may stem from altered serotoninergic systems at the developmental stage. The SLC6A gene polymorphism has been associated with autism,17,18 although other reports have not replicated these findings.70,71 Because the gene polymorphism could modulate the neurodevelopment and function of the brain19,20 and influence SLC6A4 expression,72,73 it may be responsible for the reduction of serotonin transporter binding that we observed in the present study.

Several limitations of our study bear mention. We repeated the SMP analysis separately for each of 5 clinical behaviors within the autistic participants, which may have led to a type I error. However, we found that 2 of the 5 clinical behaviors were correlated with the serotonin transporter bindings in particular brain regions, and, as discussed in the preceding paragraphs, these regions are considered to be critical and biologically plausible areas for involvement in these behaviors. Therefore, our results may not be attributable merely to type I error. Serotoninergic activity of the prefrontal cortical regions has been shown to correlate with aggressive behavior in humans.74 Some autistic individuals were reported to have aggression.75 In this context, we anticipated that our sample of autistic adults would show the relationship between reduced serotonin transporter binding and the degree of aggression. However, SPM analysis did not reveal any brain regions in which the reduced binding correlated with aggression as assessed by the AQ. This negative finding in the present study may have been because we recruited adults with high-functioning autism who were cooperative with the imaging procedures. We showed correlates of alterations in the serotonin transporter binding with clinical features. Causative inference cannot be based merely on such correlations. Therefore, our findings cannot be considered conclusive. To elucidate the direct causal relationship between altered serotonin transporter binding and autism, further studies will be needed. Finally, the present study was limited by its small sample size and lack of female participants.

Dopamine transporter binding was significantly and locally increased in the medial region of the orbitofrontal cortex in our autistic participants. Our finding of overfunctioning in the dopaminergic system is compatible with previous PET studies, which showed increased striatal dopamine D2 receptor binding in autistic children32 and elevated dopamine synthesis and storage in the striatum and frontal cortex of adults with Asperger syndrome.76 The orbitofrontal cortex is a key structure in the network underlying emotional regulation; dysfunction in the orbitofrontal-limbic circuit may be associated with behaviors in autism,77 such as impulsive and aggressive behaviors.75,78 However, the increased dopamine transporter binding was not correlated with aggression as assessed by the AQ in the present study. As mentioned in the preceding paragraphs, this may have been due to a bias arising from the selection of individuals with high-functioning autism in the present study, who are more cooperative with the PET imaging procedures than are autistic individuals as a whole. Thus, more work is needed in this regard.

When the relationship between dopamine and serotonin transporter binding was examined in our autistic participants, the dopamine transporter binding was significantly negatively correlated with that of the serotonin transporter. The mechanism underlying the interaction between the 2 transporters in the orbitofrontal region in autism is still unknown. However, some animal studies have illustrated that the number of dopaminergic neuron fibers increases in response to disruption of the serotoninergic system by a lesion in the nucleus raphe79 and that the uptake of serotonin into dopamine neurons takes place by means of dopamine transporters.80

With respect to our use of [11C]WIN-35,428 to evaluate dopamine transporter binding in the orbitofrontal cortex, a methodological issue should be addressed. The capability of the tracer for measuring low levels of dopamine transporter binding in the extrastriatal region is disputable. In the present study, we conducted 2 types of analytic procedures (ie, ROI method and SPM analysis) to estimate quantitative values of the orbitofrontal binding and to detect brain regions with significant changes. The difference in the shape of the time-activity curve of the orbitofrontal cortex between the groups (Figure 1G and H) and a series of our previous studies that have reported significant changes in the extrastriatal dopamine transporter binding48,8183 indicate the validity for the use of [11C]WIN-35,428 for the purpose of the present study. This contention is also supported by our findings that the level of the orbitofrontal binding potential is higher in autistic individuals (0.27, based on our present data) than in their normal counterparts (0.19)48 and that the magnitude of this increase (58%) is greater than the reported level of within-subject test-retest variability (9.3%).84 Despite these accounts, a PET tracer with a much higher affinity to the extrastriatal dopamine transporter may be desirable.

Correspondence: Norio Mori, MD, PhD, Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan (morin@hama-med.ac.jp).

Submitted for Publication: November 8, 2008; final revision received March 26, 2009; accepted April 27, 2009.

Financial Disclosure: None reported.

Funding/Support: This study was supported by Special Expenses for Educational Research to Osaka-Hamamatsu Joint Research Center for Child Mental Development (Osaka University and Hamamatsu University School of Medicine) and a Grant-in-Aid for Scientific Research (B) (Dr Nakamura) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Research on Brain Science Fund (Dr Mori) from the Ministry of Health, Labor, and Welfare, Japan; by Takeda Science Foundation (Dr Nakamura); and by the Kato Memorial Trust For Nambyo Research (Dr Nakamura).

Additional Contributions: Toshihiko Kanno, BS, Yutaka Naito, MS, Katsuhiko Nishimura, MD, PhD, Kiyokazu Takebayashi, MD, PhD, and Yoshifumi Takai, MA, provided excellent technical support. Masayoshi Kawai, MD, PhD, and Shigeyuki Yamamoto, PhD, recruited the participants. Kaori Matsumoto, MA, conducted clinical assessments, including the Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule.

American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000
Baird  GSimonoff  EPickles  AChandler  SLoucas  TMeldrum  DCharman  T Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006;368 (9531) 210- 215
PubMed Link to Article
Szatmari  PPaterson  ADZwaigenbaum  LRoberts  WBrian  JLiu  XQVincent  JBSkaug  JLThompson  APSenman  LFeuk  LQian  CBryson  SEJones  MBMarshall  CRScherer  SWVieland  VJBartlett  CMangin  LVGoedken  RSegre  APericak-Vance  MACuccaro  MLGilbert  JRWright  HHAbramson  RKBetancur  CBourgeron  TGillberg  CLeboyer  MBuxbaum  JDDavis  KLHollander  ESilverman  JMHallmayer  JLotspeich  LSutcliffe  JSHaines  JLFolstein  SEPiven  JWassink  THSheffield  VGeschwind  DHBucan  MBrown  WTCantor  RMConstantino  JNGilliam  TCHerbert  MLajonchere  CLedbetter  DHLese-Martin  CMiller  JNelson  SSamango-Sprouse  CASpence  SState  MTanzi  RECoon  HDawson  GDevlin  BEstes  AFlodman  PKlei  L McMahon  WMMinshew  NMunson  JKorvatska  ERodier  PMSchellenberg  GDSmith  MSpence  MAStodgell  CTepper  PGWijsman  EMYu  CERogé  BMantoulan  CWittemeyer  KPoustka  AFelder  BKlauck  SMSchuster  CPoustka  FBölte  SFeineis-Matthews  SHerbrecht  ESchmötzer  GTsiantis  JPapanikolaou  KMaestrini  EBacchelli  EBlasi  FCarone  SToma  CVan Engeland  Hde Jonge  MKemner  CKoop  FLangemeijer  MHijimans  CStaal  WGBaird  GBolton  PFRutter  MLWeisblatt  EGreen  JAldred  CWilkinson  JAPickles  ALe Couteur  ABerney  TMcConachie  HBailey  AJFrancis  KHoneyman  GHutchinson  AParr  JRWallace  SMonaco  APBarnby  GKobayashi  KLamb  JASousa  ISykes  NCook  EHGuter  SJLeventhal  BLSalt  JLord  CCorsello  CHus  VWeeks  DEVolkmar  FTauber  MFombonne  EShih  AMeyer  KJAutism Genome Project Consortium Mapping autism risk loci using genetic linkage and chromosomal rearrangements [published correction appears in Nat Genet . 2007;39(10):1285]. Nat Genet2007393319328
PubMed
Sebat  JLakshmi  BMalhotra  DTroge  JLese-Martin  CWalsh  TYamrom  BYoon  SKrasnitz  AKendall  JLeotta  APai  DZhang  RLee  YHHicks  JSpence  SJLee  ATPuura  KLehtimäki  TLedbetter  DGregersen  PKBregman  JSutcliffe  JSJobanputra  VChung  WWarburton  DKing  MCSkuse  DGeschwind  DHGilliam  TCYe  KWigler  M Strong association of de novo copy number mutations with autism. Science 2007;316 (5823) 445- 449
PubMed Link to Article
Weiss  LAShen  YKorn  JMArking  DEMiller  DTFossdal  RSaemundsen  EStefansson  HFerreira  MAGreen  TPlatt  OSRuderfer  DMWalsh  CAAltshuler  DChakravarti  ATanzi  REStefansson  KSantangelo  SLGusella  JFSklar  PWu  BLDaly  MJAutism Consortium, Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358 (7) 667- 675
PubMed Link to Article
Schain  RJFreedman  DX Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961;58315- 320
PubMed Link to Article
Hanley  HGStahl  SMFreedman  DX Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry 1977;34 (5) 521- 531
PubMed Link to Article
Ciaranello  RD Hyperserotonemia and early infantile autism. N Engl J Med 1982;307 (3) 181- 183
PubMed Link to Article
Anderson  GMFreedman  DXCohen  DJVolkmar  FRHoder  ELMcPhedran  PMinderaa  RBHansen  CRYoung  JG Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 1987;28 (6) 885- 900
PubMed Link to Article
Cook  EH  JrLeventhal  BLFreedman  DX Serotonin and measured intelligence. J Autism Dev Disord 1988;18 (4) 553- 559
PubMed Link to Article
Abramson  RKWright  HHCarpenter  RBrennan  WLumpuy  OCole  EYoung  SR Elevated blood serotonin in autistic probands and their first-degree relatives. J Autism Dev Disord 1989;19 (3) 397- 407
PubMed Link to Article
Cook  EH  JrLeventhal  BLHeller  WMetz  JWainwright  MFreedman  DX Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990;2 (3) 268- 274
PubMed
Cross  SKim  SJWeiss  LADelahanty  RJSutcliffe  JSLeventhal  BLCook  EH  JrVeenstra-Vanderweele  J Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychopharmacology 2008;33 (2) 353- 360
PubMed Link to Article
McDougle  CJNaylor  STCohen  DJAghajanian  GKHeninger  GRPrice  LH Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53 (11) 993- 1000
PubMed Link to Article
Kolevzon  AMathewson  KAHollander  E Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 2006;67 (3) 407- 414
PubMed Link to Article
Yonan  ALAlarcón  MCheng  RMagnusson  PKSpence  SJPalmer  AAGrunn  AJuo  SHTerwilliger  JDLiu  JCantor  RMGeschwind  DHGilliam  TC A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003;73 (4) 886- 897
PubMed Link to Article
Cook  EH  JrCourchesne  RLord  CCox  NJYan  SLincoln  AHaas  RCourchesne  ELeventhal  BL Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997;2 (3) 247- 250
PubMed Link to Article
Klauck  SMPoustka  FBenner  ALesch  KPPoustka  A Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997;6 (13) 2233- 2238
PubMed Link to Article
Wassink  THHazlett  HCEpping  EAArndt  SDager  SRSchellenberg  GDDawson  GPiven  J Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry 2007;64 (6) 709- 717
PubMed Link to Article
Surguladze  SAElkin  AEcker  CKalidindi  SCorsico  AGiampietro  VLawrence  NDeeley  QMurphy  DGKucharska-Pietura  KRussell  TAMcGuffin  PMurray  RPhillips  ML Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces. Genes Brain Behav 2008;7 (5) 543- 551
PubMed Link to Article
Chugani  DCMuzik  OBehen  MRothermel  RJanisse  JJLee  JChugani  HT Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999;45 (3) 287- 295
PubMed Link to Article
Chandana  SRBehen  MEJuhász  CMuzik  ORothermel  RDMangner  TJChakraborty  PKChugani  HTChugani  DC Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci 2005;23 (2-3) 171- 182
PubMed Link to Article
Makkonen  IRiikonen  RKokki  HAiraksinen  MMKuikka  JT Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol 2008;50 (8) 593- 597
PubMed Link to Article
Anderson  LTCampbell  MGrega  DMPerry  RSmall  AMGreen  WH Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 1984;141 (10) 1195- 1202
PubMed
Anderson  LTCampbell  MAdams  PSmall  AMPerry  RShell  J The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 1989;19 (2) 227- 239
PubMed Link to Article
Gillberg  CSvennerholm  L CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 1987;15189- 94
PubMed Link to Article
Narayan  MSrinath  SAnderson  GMMeundi  DB Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 1993;33 (8-9) 630- 635
PubMed Link to Article
Comings  DEComings  BGMuhleman  DDietz  GShahbahrami  BTast  DKnell  EKocsis  PBaumgarten  RKovacs  BWLevy  DLSmith  MBorison  RLEvans  DDKlein  DNMacMurray  JTosk  JMSverd  JGysin  RFlanagan  SD The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991;266 (13) 1793- 1800
PubMed Link to Article
Hettinger  JALiu  XSchwartz  CEMichaelis  RCHolden  JJA DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families. Am J Med Genet B Neuropsychiatr Genet 2008;147B (5) 628- 636
PubMed Link to Article
Gadow  KDRoohi  JDeVincent  CJHatchwell  E Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. J Child Psychol Psychiatry 2008;49 (12) 1331- 1338
PubMed Link to Article
Ernst  MZametkin  AJMatochik  JAPascualvaca  DCohen  RM Low medial prefrontal dopaminergic activity in autistic children [letter] [published correction appears in Lancet. 1998;351(9100):454]. Lancet19973509078638
PubMed
Fernell  EWatanabe  YAdolfsson  ITani  YBergström  MHartvig  PLilja  Avon Knorring  ALGillberg  CLångström  B Possible effects of tetrahydrobiopterin treatment in six children with autism-clinical and positron emission tomography data: a pilot study. Dev Med Child Neurol 1997;39 (5) 313- 318
PubMed Link to Article
Lord  CRutter  MLe Couteur  A Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994;24 (5) 659- 685
PubMed Link to Article
Lord  CRisi  SLambrecht  LCook  EH  JrLeventhal  BLDiLavore  PCPickles  ARutter  M The Autism Diagnostic Observation Schedule–Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000;30 (3) 205- 223
PubMed Link to Article
American Psychiatric Association User's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I: Clinician Version.  Washington, DC: American Psychiatric Press; 1997
Andreasen  NCEndicott  JSpitzer  RLWinokur  G The family history method using diagnostic criteria: reliability and validity. Arch Gen Psychiatry 1977;34 (10) 1229- 1235
PubMed Link to Article
Stone  VEBaron-Cohen  SKnight  RT Frontal lobe contributions to theory of mind. J Cogn Neurosci 1998;10 (5) 640- 656
PubMed Link to Article
Baron-Cohen  SO’Riordan  MStone  VJones  RPlaisted  K Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism. J Autism Dev Disord 1999;29 (5) 407- 418
PubMed Link to Article
Stone  VEBaron-Cohen  SCalder  AKeane  JYoung  A Acquired theory of mind impairments in individuals with bilateral amygdala lesions. Neuropsychologia 2003;41 (2) 209- 220
PubMed Link to Article
Goodman  WKPrice  LHRasmussen  SAMazure  CFleischmann  RLHill  CLHeninger  GRCharney  DS The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry 1989;46 (11) 1006- 1011
PubMed Link to Article
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown Obsessive Compulsive Scale, II: validity. Arch Gen Psychiatry 1989;46 (11) 1012- 1016
PubMed Link to Article
Hamilton  M Diagnosis and rating of anxiety. In: Lader  MH, ed. Studies of Anxiety: Papers Read at the World Psychiatric Association Symposium, “Aspects of Anxiety,” London, November, 1967. Ashford, England: Headley Brothers Ltd for Royal Medico-Psychological Association; 1969:76-79. Third special publication of The British Journal of Psychiatry
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Buss  AHPerry  M The Aggression Questionnaire. J Pers Soc Psychol 1992;63 (3) 452- 459
PubMed Link to Article
Rousset  OGMa  YEvans  AC Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998;39 (5) 904- 911
PubMed
Aston  JACunningham  VJAsselin  MCHammers  AEvans  ACGunn  RN Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002;22 (8) 1019- 1034
PubMed Link to Article
Sekine  YIyo  MOuchi  YMatsunaga  TTsukada  HOkada  HYoshikawa  EFutatsubashi  MTakei  NMori  N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001;158 (8) 1206- 1214
PubMed Link to Article
Ouchi  YYoshikawa  EOkada  HFutatsubashi  MSekine  YIyo  MSakamoto  M Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease: compartment analysis for β-CFT binding with positron emission tomography. Ann Neurol 1999;45 (5) 601- 610
PubMed Link to Article
Sekine  YOuchi  YTakei  NYoshikawa  ENakamura  KFutatsubashi  MOkada  HMinabe  YSuzuki  KIwata  YTsuchiya  KJTsukada  HIyo  MMori  N Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. Arch Gen Psychiatry 2006;63 (1) 90- 100
PubMed Link to Article
Meyer  JHHoule  SSagrati  SCarella  AHussey  DFGinovart  NGoulding  VKennedy  JWilson  AA Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 2004;61 (12) 1271- 1279
PubMed Link to Article
Szabo  ZMcCann  UDWilson  AAScheffel  UOwonikoko  TMathews  WBRavert  HTHilton  JDannals  RFRicaurte  GA Comparison of (+)-11C-McN5652 and 11C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 2002;43 (5) 678- 692
PubMed
Wong  DFYung  BDannals  RFShaya  EKRavert  HTChen  CAChan  BFolio  TScheffel  URicaurte  GA  et al.  In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428. Synapse 1993;15 (2) 130- 142
PubMed Link to Article
Ouchi  YKanno  TOkada  HYoshikawa  EFutatsubashi  MNobezawa  STorizuka  TTanaka  K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease. Brain 2001;124 (pt 4) 784- 792
PubMed Link to Article
Meyer  JHMcNeely  HESagrati  SBoovariwala  AMartin  KVerhoeff  NPWilson  AAHoule  S Elevated putamen D2 receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry 2006;163 (9) 1594- 1602
PubMed Link to Article
Ritvo  ERJorde  LBMason-Brothers  AFreeman  BJPingree  CJones  MBMcMahon  WMPetersen  PBJenson  WRMo  A The UCLA–University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling. Am J Psychiatry 1989;146 (8) 1032- 1036
PubMed
Tsakanikos  ECostello  HHolt  GBouras  NSturmey  PNewton  T Psychopathology in adults with autism and intellectual disability. J Autism Dev Disord 2006;36 (8) 1123- 1129
PubMed Link to Article
Danielsson  SGillberg  ICBillstedt  EGillberg  COlsson  I Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 2005;46 (6) 918- 923
PubMed Link to Article
Haznedar  MMBuchsbaum  MSMetzger  MSolimando  ASpiegel-Cohen  JHollander  E Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997;154 (8) 1047- 1050
PubMed
Ohnishi  TMatsuda  HHashimoto  TKunihiro  TNishikawa  MUema  TSasaki  M Abnormal regional cerebral blood flow in childhood autism. Brain 2000;123 (pt 9) 1838- 1844
PubMed Link to Article
Murphy  DGDaly  ESchmitz  NToal  FMurphy  KCurran  SErlandsson  KEersels  JKerwin  REll  PTravis  M Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study. Am J Psychiatry 2006;163 (5) 934- 936
PubMed Link to Article
Smith  DF Neuroimaging of serotonin uptake sites and antidepressant binding sites in the thalamus of humans and “higher” animals. Eur Neuropsychopharmacol 1999;9 (6) 537- 544
PubMed Link to Article
Murphy  DGCritchley  HDSchmitz  NMcAlonan  GVan Amelsvoort  TRobertson  DDaly  ERowe  ARussell  ASimmons  AMurphy  KCHowlin  P Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Arch Gen Psychiatry 2002;59 (10) 885- 891
PubMed Link to Article
Hollander  EAnagnostou  EChaplin  WEsposito  KHaznedar  MMLicalzi  EWasserman  SSoorya  LBuchsbaum  M Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiatry 2005;58 (3) 226- 232
PubMed Link to Article
Atmaca  MYildirim  HOzdemir  HOzler  SKara  BOzler  ZKanmaz  EMermi  OTezcan  E Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32 (5) 1283- 1286
PubMed Link to Article
Page  LADaly  ESchmitz  NSimmons  AToal  FDeeley  QAmbery  FMcAlonan  GMMurphy  KCMurphy  DG In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry 2006;163 (12) 2189- 2192
PubMed Link to Article
Cook  EH  Jr Brief report: pathophysiology of autism: neurochemistry. J Autism Dev Disord 1996;26 (2) 221- 225
PubMed Link to Article
Whitaker-Azmitia  PM Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int J Dev Neurosci 2005;23 (1) 75- 83
PubMed Link to Article
Janusonis  SAnderson  GMShifrovich  IRakic  P Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism. J Neurochem 2006;99 (3) 1019- 1031
PubMed Link to Article
McNamara  IMBorella  AWBialowas  LAWhitaker-Azmitia  PM Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes. Brain Res 2008;1189203- 214
PubMed Link to Article
Maestrini  ELai  CMarlow  AMatthews  NWallace  SBailey  ACook  EHWeeks  DEMonaco  APInternational Molecular Genetic Study of Autism Consortium, Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 1999;88 (5) 492- 496
PubMed Link to Article
Persico  AMMiliterni  RBravaccio  CSchneider  CMelmed  RConciatori  MDamiani  VBaldi  AKeller  F Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000;96 (1) 123- 127
PubMed Link to Article
Lesch  KPBengel  DHeils  ASabol  SZGreenberg  BDPetri  SBenjamin  JMüller  CRHamer  DHMurphy  DL Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274 (5292) 1527- 1531
PubMed Link to Article
Bradley  SLDodelzon  KSandhu  HKPhilibert  RA Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. Am J Med Genet B Neuropsychiatr Genet 2005;136B (1) 58- 61
PubMed Link to Article
Siever  LJ Neurobiology of aggression and violence. Am J Psychiatry 2008;165 (4) 429- 442
PubMed Link to Article
Matson  JLNebel-Schwalm  MS Comorbid psychopathology with autism spectrum disorder in children: an overview. Res Dev Disabil 2007;28 (4) 341- 352
PubMed Link to Article
Nieminen-von Wendt  TSMetsähonkala  LKulomaki  TAAalto  SAutti  THVanhala  REskola  OBergman  JHietala  JAvon Wendt  LO Increased presynaptic dopamine function in Asperger syndrome. Neuroreport 2004;15 (5) 757- 760
PubMed Link to Article
Bachevalier  JLoveland  KA The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev 2006;30 (1) 97- 117
PubMed Link to Article
Davidson  RJPutnam  KMLarson  CL Dysfunction in the neural circuitry of emotion regulation: a possible prelude to violence. Science 2000;289 (5479) 591- 594
PubMed Link to Article
Bolte Taylor  JCunningham  MCBenes  FM Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats. Neuroreport 1998;9 (8) 1811- 1815
PubMed Link to Article
Zhou  FCLesch  KPMurphy  DL Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res 2002;942 (1-2) 109- 119
PubMed Link to Article
Ouchi  YKanno  TOkada  HYoshikawa  EFutatsubashi  MNobezawa  STorizuka  TTanaka  K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease. Brain 2001;124 (pt 4) 784- 792
PubMed Link to Article
Sekine  YIyo  MOuchi  YMatsunaga  TTsukada  HOkada  HYoshikawa  EFutatsubashi  MTakei  NMori  N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001;158 (8) 1206- 1214
PubMed Link to Article
Sekine  YMinabe  YOuchi  YTakei  NIyo  MNakamura  KSuzuki  KTsukada  HOkada  HYoshikawa  EFutatsubashi  MMori  N Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. Am J Psychiatry 2003;160 (9) 1699- 1701
PubMed Link to Article
Villemagne  VYuan  JWong  DFDannals  RFHatzidimitriou  GMathews  WBRavert  HTMusachio  JMcCann  UDRicaurte  GA Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]WIN-35,428 position emission tomography studies and direct in vitro determinations. J Neurosci 1998;18 (1) 419- 427
PubMed

Figures

Place holder to copy figure label and caption

Figure 1. Positron emission tomography images of radioactive carbon (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428) binding in a healthy control subject and an individual with autism. A and B, Images of the [11C](+)McN-5652 distribution volume with a color scale ranging from 0 to 60 mL/g show a control brain and a global reduction in [11C](+)McN-5652 distribution in an autistic individual. C and D, Radioactivity produced by [11C](+)McN-5652 in the orbitofrontal region and the striatum of a representative control and an autistic subject. E and F, Images of the [11C]WIN-35,428 ratio index reflect the binding potential of [11C]WIN-35,428 with a color scale ranging from 0 to 10 compared with a control and the elevation of its value in the orbitofrontal cortex in an autistic subject. G and H, Radioactivity caused by [11C]WIN-35,428 in the orbitofrontal region and the striatum of a representative control and an autistic subject. To convert radioactivity to curies per milliliter, multiply by 2.7 ×10−8.

Graphic Jump Location
Place holder to copy figure label and caption

Figure 2. Statistical parametric mapping results for [11C](+)McN-5652 and [11C]WIN-35,428 binding. A, Glass brain images indicate extensive reduction in the [11C](+)McN-5652 distribution volume in the autistic group (P < .05, corrected). B and C, Statistical parametric maps show brain regions in which the [11C](+)McN-5652 distribution volume correlates positively with the Faux Pas Test score and negatively with the Yale-Brown Obsessive Compulsive Scale score, respectively, in autism (P < .05, corrected). D, A statistical parametric map showing a brain region in which the [11C]WIN-35,428 ratio index is significantly higher in the autistic group than in the control group (P < .05, corrected). Color bars indicate T values. A indicates anterior; L, left; P, posterior; and R, right. See the legend to Figure 1 for expansion of other abbreviations.

Graphic Jump Location
Place holder to copy figure label and caption

Figure 3. Correlation between [11C](+)McN-5652 and [11C]WIN-35,428 binding. Pearson product moment correlation analysis shows a significantly negative correlation between the [11C](+)McN-5652 distribution volume and the [11C]WIN-35,428 binding potential in the orbitofrontal cortex in autistic subjects (r = −0.61; P = .004; y = −0.006x + 0.39). The k values represent the binding potential. See the legend to Figure 1 for other abbreviations.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Results of the Whole-Brain Voxel-Based Statistical Parametric Mapping Analyses of [11C](+)McN-5652 and [11C]WIN-35,428 Binding Parametersa

References

American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000
Baird  GSimonoff  EPickles  AChandler  SLoucas  TMeldrum  DCharman  T Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006;368 (9531) 210- 215
PubMed Link to Article
Szatmari  PPaterson  ADZwaigenbaum  LRoberts  WBrian  JLiu  XQVincent  JBSkaug  JLThompson  APSenman  LFeuk  LQian  CBryson  SEJones  MBMarshall  CRScherer  SWVieland  VJBartlett  CMangin  LVGoedken  RSegre  APericak-Vance  MACuccaro  MLGilbert  JRWright  HHAbramson  RKBetancur  CBourgeron  TGillberg  CLeboyer  MBuxbaum  JDDavis  KLHollander  ESilverman  JMHallmayer  JLotspeich  LSutcliffe  JSHaines  JLFolstein  SEPiven  JWassink  THSheffield  VGeschwind  DHBucan  MBrown  WTCantor  RMConstantino  JNGilliam  TCHerbert  MLajonchere  CLedbetter  DHLese-Martin  CMiller  JNelson  SSamango-Sprouse  CASpence  SState  MTanzi  RECoon  HDawson  GDevlin  BEstes  AFlodman  PKlei  L McMahon  WMMinshew  NMunson  JKorvatska  ERodier  PMSchellenberg  GDSmith  MSpence  MAStodgell  CTepper  PGWijsman  EMYu  CERogé  BMantoulan  CWittemeyer  KPoustka  AFelder  BKlauck  SMSchuster  CPoustka  FBölte  SFeineis-Matthews  SHerbrecht  ESchmötzer  GTsiantis  JPapanikolaou  KMaestrini  EBacchelli  EBlasi  FCarone  SToma  CVan Engeland  Hde Jonge  MKemner  CKoop  FLangemeijer  MHijimans  CStaal  WGBaird  GBolton  PFRutter  MLWeisblatt  EGreen  JAldred  CWilkinson  JAPickles  ALe Couteur  ABerney  TMcConachie  HBailey  AJFrancis  KHoneyman  GHutchinson  AParr  JRWallace  SMonaco  APBarnby  GKobayashi  KLamb  JASousa  ISykes  NCook  EHGuter  SJLeventhal  BLSalt  JLord  CCorsello  CHus  VWeeks  DEVolkmar  FTauber  MFombonne  EShih  AMeyer  KJAutism Genome Project Consortium Mapping autism risk loci using genetic linkage and chromosomal rearrangements [published correction appears in Nat Genet . 2007;39(10):1285]. Nat Genet2007393319328
PubMed
Sebat  JLakshmi  BMalhotra  DTroge  JLese-Martin  CWalsh  TYamrom  BYoon  SKrasnitz  AKendall  JLeotta  APai  DZhang  RLee  YHHicks  JSpence  SJLee  ATPuura  KLehtimäki  TLedbetter  DGregersen  PKBregman  JSutcliffe  JSJobanputra  VChung  WWarburton  DKing  MCSkuse  DGeschwind  DHGilliam  TCYe  KWigler  M Strong association of de novo copy number mutations with autism. Science 2007;316 (5823) 445- 449
PubMed Link to Article
Weiss  LAShen  YKorn  JMArking  DEMiller  DTFossdal  RSaemundsen  EStefansson  HFerreira  MAGreen  TPlatt  OSRuderfer  DMWalsh  CAAltshuler  DChakravarti  ATanzi  REStefansson  KSantangelo  SLGusella  JFSklar  PWu  BLDaly  MJAutism Consortium, Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358 (7) 667- 675
PubMed Link to Article
Schain  RJFreedman  DX Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961;58315- 320
PubMed Link to Article
Hanley  HGStahl  SMFreedman  DX Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry 1977;34 (5) 521- 531
PubMed Link to Article
Ciaranello  RD Hyperserotonemia and early infantile autism. N Engl J Med 1982;307 (3) 181- 183
PubMed Link to Article
Anderson  GMFreedman  DXCohen  DJVolkmar  FRHoder  ELMcPhedran  PMinderaa  RBHansen  CRYoung  JG Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 1987;28 (6) 885- 900
PubMed Link to Article
Cook  EH  JrLeventhal  BLFreedman  DX Serotonin and measured intelligence. J Autism Dev Disord 1988;18 (4) 553- 559
PubMed Link to Article
Abramson  RKWright  HHCarpenter  RBrennan  WLumpuy  OCole  EYoung  SR Elevated blood serotonin in autistic probands and their first-degree relatives. J Autism Dev Disord 1989;19 (3) 397- 407
PubMed Link to Article
Cook  EH  JrLeventhal  BLHeller  WMetz  JWainwright  MFreedman  DX Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990;2 (3) 268- 274
PubMed
Cross  SKim  SJWeiss  LADelahanty  RJSutcliffe  JSLeventhal  BLCook  EH  JrVeenstra-Vanderweele  J Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychopharmacology 2008;33 (2) 353- 360
PubMed Link to Article
McDougle  CJNaylor  STCohen  DJAghajanian  GKHeninger  GRPrice  LH Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53 (11) 993- 1000
PubMed Link to Article
Kolevzon  AMathewson  KAHollander  E Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 2006;67 (3) 407- 414
PubMed Link to Article
Yonan  ALAlarcón  MCheng  RMagnusson  PKSpence  SJPalmer  AAGrunn  AJuo  SHTerwilliger  JDLiu  JCantor  RMGeschwind  DHGilliam  TC A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003;73 (4) 886- 897
PubMed Link to Article
Cook  EH  JrCourchesne  RLord  CCox  NJYan  SLincoln  AHaas  RCourchesne  ELeventhal  BL Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997;2 (3) 247- 250
PubMed Link to Article
Klauck  SMPoustka  FBenner  ALesch  KPPoustka  A Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997;6 (13) 2233- 2238
PubMed Link to Article
Wassink  THHazlett  HCEpping  EAArndt  SDager  SRSchellenberg  GDDawson  GPiven  J Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiatry 2007;64 (6) 709- 717
PubMed Link to Article
Surguladze  SAElkin  AEcker  CKalidindi  SCorsico  AGiampietro  VLawrence  NDeeley  QMurphy  DGKucharska-Pietura  KRussell  TAMcGuffin  PMurray  RPhillips  ML Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces. Genes Brain Behav 2008;7 (5) 543- 551
PubMed Link to Article
Chugani  DCMuzik  OBehen  MRothermel  RJanisse  JJLee  JChugani  HT Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999;45 (3) 287- 295
PubMed Link to Article
Chandana  SRBehen  MEJuhász  CMuzik  ORothermel  RDMangner  TJChakraborty  PKChugani  HTChugani  DC Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci 2005;23 (2-3) 171- 182
PubMed Link to Article
Makkonen  IRiikonen  RKokki  HAiraksinen  MMKuikka  JT Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol 2008;50 (8) 593- 597
PubMed Link to Article
Anderson  LTCampbell  MGrega  DMPerry  RSmall  AMGreen  WH Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 1984;141 (10) 1195- 1202
PubMed
Anderson  LTCampbell  MAdams  PSmall  AMPerry  RShell  J The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 1989;19 (2) 227- 239
PubMed Link to Article
Gillberg  CSvennerholm  L CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 1987;15189- 94
PubMed Link to Article
Narayan  MSrinath  SAnderson  GMMeundi  DB Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 1993;33 (8-9) 630- 635
PubMed Link to Article
Comings  DEComings  BGMuhleman  DDietz  GShahbahrami  BTast  DKnell  EKocsis  PBaumgarten  RKovacs  BWLevy  DLSmith  MBorison  RLEvans  DDKlein  DNMacMurray  JTosk  JMSverd  JGysin  RFlanagan  SD The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 1991;266 (13) 1793- 1800
PubMed Link to Article
Hettinger  JALiu  XSchwartz  CEMichaelis  RCHolden  JJA DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families. Am J Med Genet B Neuropsychiatr Genet 2008;147B (5) 628- 636
PubMed Link to Article
Gadow  KDRoohi  JDeVincent  CJHatchwell  E Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. J Child Psychol Psychiatry 2008;49 (12) 1331- 1338
PubMed Link to Article
Ernst  MZametkin  AJMatochik  JAPascualvaca  DCohen  RM Low medial prefrontal dopaminergic activity in autistic children [letter] [published correction appears in Lancet. 1998;351(9100):454]. Lancet19973509078638
PubMed
Fernell  EWatanabe  YAdolfsson  ITani  YBergström  MHartvig  PLilja  Avon Knorring  ALGillberg  CLångström  B Possible effects of tetrahydrobiopterin treatment in six children with autism-clinical and positron emission tomography data: a pilot study. Dev Med Child Neurol 1997;39 (5) 313- 318
PubMed Link to Article
Lord  CRutter  MLe Couteur  A Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994;24 (5) 659- 685
PubMed Link to Article
Lord  CRisi  SLambrecht  LCook  EH  JrLeventhal  BLDiLavore  PCPickles  ARutter  M The Autism Diagnostic Observation Schedule–Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000;30 (3) 205- 223
PubMed Link to Article
American Psychiatric Association User's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I: Clinician Version.  Washington, DC: American Psychiatric Press; 1997
Andreasen  NCEndicott  JSpitzer  RLWinokur  G The family history method using diagnostic criteria: reliability and validity. Arch Gen Psychiatry 1977;34 (10) 1229- 1235
PubMed Link to Article
Stone  VEBaron-Cohen  SKnight  RT Frontal lobe contributions to theory of mind. J Cogn Neurosci 1998;10 (5) 640- 656
PubMed Link to Article
Baron-Cohen  SO’Riordan  MStone  VJones  RPlaisted  K Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism. J Autism Dev Disord 1999;29 (5) 407- 418
PubMed Link to Article
Stone  VEBaron-Cohen  SCalder  AKeane  JYoung  A Acquired theory of mind impairments in individuals with bilateral amygdala lesions. Neuropsychologia 2003;41 (2) 209- 220
PubMed Link to Article
Goodman  WKPrice  LHRasmussen  SAMazure  CFleischmann  RLHill  CLHeninger  GRCharney  DS The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry 1989;46 (11) 1006- 1011
PubMed Link to Article
Goodman  WKPrice  LHRasmussen  SAMazure  CDelgado  PHeninger  GRCharney  DS The Yale-Brown Obsessive Compulsive Scale, II: validity. Arch Gen Psychiatry 1989;46 (11) 1012- 1016
PubMed Link to Article
Hamilton  M Diagnosis and rating of anxiety. In: Lader  MH, ed. Studies of Anxiety: Papers Read at the World Psychiatric Association Symposium, “Aspects of Anxiety,” London, November, 1967. Ashford, England: Headley Brothers Ltd for Royal Medico-Psychological Association; 1969:76-79. Third special publication of The British Journal of Psychiatry
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Buss  AHPerry  M The Aggression Questionnaire. J Pers Soc Psychol 1992;63 (3) 452- 459
PubMed Link to Article
Rousset  OGMa  YEvans  AC Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998;39 (5) 904- 911
PubMed
Aston  JACunningham  VJAsselin  MCHammers  AEvans  ACGunn  RN Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002;22 (8) 1019- 1034
PubMed Link to Article
Sekine  YIyo  MOuchi  YMatsunaga  TTsukada  HOkada  HYoshikawa  EFutatsubashi  MTakei  NMori  N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001;158 (8) 1206- 1214
PubMed Link to Article
Ouchi  YYoshikawa  EOkada  HFutatsubashi  MSekine  YIyo  MSakamoto  M Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease: compartment analysis for β-CFT binding with positron emission tomography. Ann Neurol 1999;45 (5) 601- 610
PubMed Link to Article
Sekine  YOuchi  YTakei  NYoshikawa  ENakamura  KFutatsubashi  MOkada  HMinabe  YSuzuki  KIwata  YTsuchiya  KJTsukada  HIyo  MMori  N Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. Arch Gen Psychiatry 2006;63 (1) 90- 100
PubMed Link to Article
Meyer  JHHoule  SSagrati  SCarella  AHussey  DFGinovart  NGoulding  VKennedy  JWilson  AA Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 2004;61 (12) 1271- 1279
PubMed Link to Article
Szabo  ZMcCann  UDWilson  AAScheffel  UOwonikoko  TMathews  WBRavert  HTHilton  JDannals  RFRicaurte  GA Comparison of (+)-11C-McN5652 and 11C-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 2002;43 (5) 678- 692
PubMed
Wong  DFYung  BDannals  RFShaya  EKRavert  HTChen  CAChan  BFolio  TScheffel  URicaurte  GA  et al.  In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428. Synapse 1993;15 (2) 130- 142
PubMed Link to Article
Ouchi  YKanno  TOkada  HYoshikawa  EFutatsubashi  MNobezawa  STorizuka  TTanaka  K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease. Brain 2001;124 (pt 4) 784- 792
PubMed Link to Article
Meyer  JHMcNeely  HESagrati  SBoovariwala  AMartin  KVerhoeff  NPWilson  AAHoule  S Elevated putamen D2 receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry 2006;163 (9) 1594- 1602
PubMed Link to Article
Ritvo  ERJorde  LBMason-Brothers  AFreeman  BJPingree  CJones  MBMcMahon  WMPetersen  PBJenson  WRMo  A The UCLA–University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling. Am J Psychiatry 1989;146 (8) 1032- 1036
PubMed
Tsakanikos  ECostello  HHolt  GBouras  NSturmey  PNewton  T Psychopathology in adults with autism and intellectual disability. J Autism Dev Disord 2006;36 (8) 1123- 1129
PubMed Link to Article
Danielsson  SGillberg  ICBillstedt  EGillberg  COlsson  I Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 2005;46 (6) 918- 923
PubMed Link to Article
Haznedar  MMBuchsbaum  MSMetzger  MSolimando  ASpiegel-Cohen  JHollander  E Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997;154 (8) 1047- 1050
PubMed
Ohnishi  TMatsuda  HHashimoto  TKunihiro  TNishikawa  MUema  TSasaki  M Abnormal regional cerebral blood flow in childhood autism. Brain 2000;123 (pt 9) 1838- 1844
PubMed Link to Article
Murphy  DGDaly  ESchmitz  NToal  FMurphy  KCurran  SErlandsson  KEersels  JKerwin  REll  PTravis  M Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study. Am J Psychiatry 2006;163 (5) 934- 936
PubMed Link to Article
Smith  DF Neuroimaging of serotonin uptake sites and antidepressant binding sites in the thalamus of humans and “higher” animals. Eur Neuropsychopharmacol 1999;9 (6) 537- 544
PubMed Link to Article
Murphy  DGCritchley  HDSchmitz  NMcAlonan  GVan Amelsvoort  TRobertson  DDaly  ERowe  ARussell  ASimmons  AMurphy  KCHowlin  P Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Arch Gen Psychiatry 2002;59 (10) 885- 891
PubMed Link to Article
Hollander  EAnagnostou  EChaplin  WEsposito  KHaznedar  MMLicalzi  EWasserman  SSoorya  LBuchsbaum  M Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiatry 2005;58 (3) 226- 232
PubMed Link to Article
Atmaca  MYildirim  HOzdemir  HOzler  SKara  BOzler  ZKanmaz  EMermi  OTezcan  E Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32 (5) 1283- 1286
PubMed Link to Article
Page  LADaly  ESchmitz  NSimmons  AToal  FDeeley  QAmbery  FMcAlonan  GMMurphy  KCMurphy  DG In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry 2006;163 (12) 2189- 2192
PubMed Link to Article
Cook  EH  Jr Brief report: pathophysiology of autism: neurochemistry. J Autism Dev Disord 1996;26 (2) 221- 225
PubMed Link to Article
Whitaker-Azmitia  PM Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int J Dev Neurosci 2005;23 (1) 75- 83
PubMed Link to Article
Janusonis  SAnderson  GMShifrovich  IRakic  P Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism. J Neurochem 2006;99 (3) 1019- 1031
PubMed Link to Article
McNamara  IMBorella  AWBialowas  LAWhitaker-Azmitia  PM Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes. Brain Res 2008;1189203- 214
PubMed Link to Article
Maestrini  ELai  CMarlow  AMatthews  NWallace  SBailey  ACook  EHWeeks  DEMonaco  APInternational Molecular Genetic Study of Autism Consortium, Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 1999;88 (5) 492- 496
PubMed Link to Article
Persico  AMMiliterni  RBravaccio  CSchneider  CMelmed  RConciatori  MDamiani  VBaldi  AKeller  F Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000;96 (1) 123- 127
PubMed Link to Article
Lesch  KPBengel  DHeils  ASabol  SZGreenberg  BDPetri  SBenjamin  JMüller  CRHamer  DHMurphy  DL Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274 (5292) 1527- 1531
PubMed Link to Article
Bradley  SLDodelzon  KSandhu  HKPhilibert  RA Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription. Am J Med Genet B Neuropsychiatr Genet 2005;136B (1) 58- 61
PubMed Link to Article
Siever  LJ Neurobiology of aggression and violence. Am J Psychiatry 2008;165 (4) 429- 442
PubMed Link to Article
Matson  JLNebel-Schwalm  MS Comorbid psychopathology with autism spectrum disorder in children: an overview. Res Dev Disabil 2007;28 (4) 341- 352
PubMed Link to Article
Nieminen-von Wendt  TSMetsähonkala  LKulomaki  TAAalto  SAutti  THVanhala  REskola  OBergman  JHietala  JAvon Wendt  LO Increased presynaptic dopamine function in Asperger syndrome. Neuroreport 2004;15 (5) 757- 760
PubMed Link to Article
Bachevalier  JLoveland  KA The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev 2006;30 (1) 97- 117
PubMed Link to Article
Davidson  RJPutnam  KMLarson  CL Dysfunction in the neural circuitry of emotion regulation: a possible prelude to violence. Science 2000;289 (5479) 591- 594
PubMed Link to Article
Bolte Taylor  JCunningham  MCBenes  FM Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats. Neuroreport 1998;9 (8) 1811- 1815
PubMed Link to Article
Zhou  FCLesch  KPMurphy  DL Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res 2002;942 (1-2) 109- 119
PubMed Link to Article
Ouchi  YKanno  TOkada  HYoshikawa  EFutatsubashi  MNobezawa  STorizuka  TTanaka  K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease. Brain 2001;124 (pt 4) 784- 792
PubMed Link to Article
Sekine  YIyo  MOuchi  YMatsunaga  TTsukada  HOkada  HYoshikawa  EFutatsubashi  MTakei  NMori  N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001;158 (8) 1206- 1214
PubMed Link to Article
Sekine  YMinabe  YOuchi  YTakei  NIyo  MNakamura  KSuzuki  KTsukada  HOkada  HYoshikawa  EFutatsubashi  MMori  N Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. Am J Psychiatry 2003;160 (9) 1699- 1701
PubMed Link to Article
Villemagne  VYuan  JWong  DFDannals  RFHatzidimitriou  GMathews  WBRavert  HTMusachio  JMcCann  UDRicaurte  GA Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]WIN-35,428 position emission tomography studies and direct in vitro determinations. J Neurosci 1998;18 (1) 419- 427
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 80

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles