ORIGINAL ARTICLE Brain Serotonin and Dopamine Transporter Bindings in Adults With High-Functioning Autism 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 Context: Autism is a neurodevelopmental disorder that Results: Serotonin transporter binding was signifi- is characterized by repetitive and/or obsessive interests and cantly lower throughout the brain in autistic individu- behavior and by deficits in sociability and communica- als compared with controls (PϽ.05, corrected). Specifi- tion. Although its neurobiological underpinnings are pos- cally, the reduction in the anterior and posterior cingulate tulated to lie in abnormalities of the serotoninergic and cortices was associated with the impairment of social cog- dopaminergic systems, the details remain unknown. nition in the autistic subjects (PϽ.05, corrected). A sig- nificant correlation was also found between repetitive Objective: To determine the occurrence of changes in and/or obsessive behavior and interests and the reduc- the binding of serotonin and dopamine transporters, tion of serotonin transporter binding in the thalamus which are highly selective markers for their respective (PϽ.05, corrected). In contrast, the dopamine trans- neuronal systems. porter binding was significantly higher in the orbitofron- tal cortex of the autistic group (PϽ.05, corrected in vox- Design: Using positron emission tomography, we mea- elwise analysis). In the orbitofrontal cortex, the dopamine sured the binding of brain serotonin and dopamine trans- porters in each individual with the radioligands carbon 11 transporter binding was significantly inversely corre- (11C)–labeled trans-1,2,3,5,6,10-␤-hexahydro-6-[4- lated with serotonin transporter binding (r=−0.61; (methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](ϩ) P=.004). McN-5652) and 2␤-carbomethoxy-3-␤-(4-fluorophenyl) tropane ([11C]WIN-35,428), respectively. Statistical Conclusions: The brains of autistic individuals have parametric mapping was used for between-subject analy- abnormalities in both serotonin transporter and dopa- sis and within-subject correlation analysis with respect to mine transporter binding. The present findings indicate clinical variables. that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism Setting: Participants recruited from the community. of autism. Our sample was not characteristic or repre- sentative of a typical sample of adults with autism in the Participants: Twenty men (age range, 18-26 years; mean community. [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ- matched control subjects. Arch Gen Psychiatry. 2010;67(1):59-68 UTISM IS A PERVASIVE DEVEL- ologic mechanism of autism, the neuroim- opmental disorder that is aging approach is a fruitful method. In this characterized by the behav- study, we used positron emission tomog- ioral traits of impaired so- raphy (PET) to focus on neurotransmitter cial cognition and commu- alterations in the autistic brain. nication, and repetitive and/or obsessive A wide array of transmitter systems has A 1 behavior and interests. There is no estab- also been studied with respect to autism. lished treatment or cure for the disorder. Initial studies on the pathophysiologic Recent population-based surveys show- mechanism of autism have focused on the ing that autism is more common than pre- serotoninergic system. Prior studies con- viously believed have aroused serious public sistently found elevated serotonin levels concern worldwide.2 In addition, genome- in the whole blood cells and platelets of wide linkage scans and copy-number analy- patients with autism6-10 and their rela- Author Affiliations are listed at ses have revealed “hot spots” on several tives.11-13 Short-term dietary depletion of the end of this article. chromosomes.3-5 To clarify the pathophysi- tryptophan (ie, the serotonin precursor) has (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 67 (NO. 1), JAN 2010 WWW.ARCHGENPSYCHIATRY.COM 59 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Clinical Characteristics Controls Autistic Participants (n=20) (n=20) Characteristics Mean (SD) Range Mean (SD) Range Age, y 21.9 (2.0) 18-26 21.2 (2.0) 18-26 WAIS-R score 104.6 (15.2) 80-136 99.3 (18.1) 71-140 Faux Pas Test scorea 35.5 (2.9) 31-40 24.6 (6.6)b 8-34 Y-BOCS scorec NA NA 10.5 (4.3) 2-20 17-Item HAM-A scorec NA NA 3.7 (2.6) 0-8 17-Item HAM-D scorec NA NA 2.1 (2.2) 0-6 AQ scorec NA NA 50.2 (12.5) 34-69 Abbreviations: AQ, Aggression Questionnaire; HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Scale for Depression; NA, not applicable; WAIS-R, Wechsler Adult Intelligence Scale–Revised; Y-BOCS, Yale-Brown Obsessive Compulsive Scale. a Lower scores correspond to a poorer social cognitive ability. b PϽ.001 (unpaired, 2-tailed t test). c Higher scores represent severe symptoms. The range of scores for the Y-BOCS is 0 to 40. been shown to exacerbate repetitive behavior and to el- mine D2 receptor binding in the whole caudate and puta- evate anxiety and feelings of unhappiness in autistic adults.14 men has also been demonstrated.32 These findings sug- Conversely, treatment with selective serotonin reuptake gest that the alteration of both the serotonin and the inhibitors—commonly used antidepressants—has been dopamine systems is a feature of autism, although these shown to be effective in ameliorating the repetitive and/or findings remain equivocal and inconclusive. obsessive behavior and interests in some but not all au- Taking these results together, we hypothesized that tistic individuals.15 Genetic studies have yielded evi- alterations in both the serotoninergic and the dopamin- dence of a critical role for the serotonin transporter gene ergic systems exist in the brain of autistic individuals, (SLC6A4; OMIM 182138), which is located on chromo- and that the changes are associated with the clinical fea- some 17q11.5,16 Several SLC6A4 polymorphisms have tures of autism. To examine this hypothesis, we used been found to be associated with autism.17,18 Further- PET to measure the binding of the serotonin and dopa- more, SLC6A4 promoter polymorphisms may influence mine transporters, which are highly selective markers for the gray matter volume of cerebral cortical structures in their respective neuronal systems, in adults with high- young male autistic individuals.19 It has also been shown functioning autism. We also examined the relationships that SLC6A4 modulates the function of social brain sys- between some of the clinical symptoms of autism and the tems when healthy control subjects process facial emo- binding levels of both transporters. tions.20 Neuroimaging studies with PET have provided further evidence that the levels of serotonin synthesis in METHODS autistic children aged 2 to 5 years are significantly lower 21,22 than those in control children. A recent single- SUBJECTS photon emission computed tomography study has shown that autistic children, under light sedation, have a re- Twenty men with autism (mean [SD] age, 21.2 [2.0] years; duction in serotonin transporter binding in the medial age range, 18-26 years) and 20 healthy male controls (mean frontal cortex, midbrain, and temporal lobe areas.23 [SD] age, 21.9 [2.0] years; age range, 18-26 years) partici- Interest in the role of dopamine has been stimulated pated in this study. All participants were right-handed and by the observations that dopamine blockers (ie, antipsy- had an IQ of greater than 70 (estimated using the Wechsler chotics) are effective in treating some aspects of autism, Adult Intelligence Scale–Revised). The IQ did not differ sig- such as hyperactivity, aggression, and self-injury.24,25 In ad- nificantly between the 2 groups (mean [SD], 99.3 [18.1] for the autistic group and 104.6 [15.2] for the control group; dition, some direct evidence suggests that levels of the prin- P=.30) (Table 1). An autism diagnosis was based on the fol- cipal dopamine metabolite homovanillic acid are el- lowing: the DSM-IV-TR1; the Autism Diagnostic Interview– 26 evated in the cerebrospinal fluid of autistic individuals, Revised33; and the Autism Diagnostic Observation Schedule– although this has not been consistently reported.27 Previ- Generic.34 All of the autistic individuals and controls ous genetic studies have demonstrated that the preva- underwent screening to exclude comorbid psychiatric ill- lence of the A1 allele of the dopamine D2 receptor is sig- nesses (ie, schizophrenia, affective disorders, mental retarda- 28 nificantly increased in autism, whereas the dopamine D1 tion, and personality or behavioral disorders) by means of the receptor gene may be a risk gene for core symptoms of au- Structured Clinical Interview for the DSM-IV.35 Individuals tism in male-only affected sibling-pair families.29 Further- with a history of neurological disorders (eg, epilepsy or head more, it has been suggested that the 9- and 10-repeat alleles injury) or genetic disorders (eg, fragile X syndrome or tuber- ous sclerosis) were also excluded. In addition, controls were of the dopamine transporter may be associated with hy- excluded if they had a family history of psychiatric illness, peractivity, impulsivity, social anxiety, and tic symptoms measured using the Family History Research Diagnostic Cri- 30 in autistic children. In a PET study of autistic children, teria.36 All autistic participants were drug naive. The present low levels of medial prefrontal dopaminergic activity were study was approved by the local ethics committees. Written observed under anesthesia,31 whereas increased dopa- informed consent was obtained from each of the participants.