Ebru Bardaş Özkan1, Mehtap Odabaşı2

1Department of Physiology, Erzincan Binali Yıldırım University Faculty of Medicine, Erzincan, Türkiye
2Istanbul Food Control Laboratory Directorate, Republic of Türkiye Ministry of Agriculture and Forestry, Istanbul, Türkiye

Keywords: Autism spectrum disorder, dopaminergic receptors, neurodevelopmental disorder, prefrontal cortex.


Although the etiology of autism is not yet clearly known, it is an executive dysfunction associated with symptoms that reduce the quality of life, such as inadequate social skills, difficulties with speech and non-verbal communication (cognitive impairment), intellectual disabilities, and restricted and repetitive behaviors. Although many factors such as genetic, environmental, and autoimmune factors are included in the etiology of autism, the uncertainty on this issue still continues. However, it is also reported that individuals with autism have dopamine-based abnormalities in their prefrontal systems. Many data have shown that the prefrontal cortex (PFC) is one of the important areas contributing to executive function. Alongside the central claim of the executive dysfunction theory, there is evidence that the root cause of many autistic behaviors may be due to dopaminergic abnormalities in the PFC region of the brain. Although significant progress has been made in autism research in line with this hypothesis, there is no consensus on the basis of the neural disorder. This hypothesis of executive dysfunction suggests that it may underlie the significant cognitive performance impairments seen in autism due to the unregulated development of the PFC. Likewise, detailed analyses show that not all forms of execution are commonly disrupted. Indeed, the part of the executive dysfunction observed in people with autism that raises questions is the impairment of cognitive control while basic cognitive function remains intact. Cognitive control is the ability to perform a given response in a distracting or more automatic situation. Cognitive flexibility is the ability to adjust cognitive control fluently with changing conditions. The pathogenesis of autism has been linked to neurological and environmental factors that alter physiological processes during development. Here, research highlighting the mechanisms of dopaminergic receptors on neurodevelopmental disorders is reviewed. Therefore, this review also suggests that improving dopamine secretion may be an important therapeutic strategy in the management of autism.


A diverse range of neurodevelopmental disorders known as autism spectrum disorder (ASD) are characterized by chronic difficulties in social interaction and communication as well as constrained patterns of behavior, interest, and activity.[1-3] The pathophysiology of ASD is largely unknown, despite the many theories that have been put out. This is due to the high heterogeneity of the spectrum, which ranges from social to non-social behavioral aberrations.[4] According to research, ASD and other neuropsychiatric illnesses with similar behavioral traits, such as schizophrenia, may be related to dopaminergic dysfunctions.[5-7] Indeed, a detailed study by Dichter et al.[8] put forward the idea that dopamine imbalances in specific brain regions may lead to autistic-like behaviors. However, existing research has not been sufficient to clarify the role of dopamine signaling abnormalities in triggering the behavioral features of ASD.[9,10] Therefore, the present study was planned to review the recent research on a dopamine hypothesis for ASD and to determine the current level of knowledge despite the extensive research on this topic.

In this review article, the Medline/PubMed database was searched for systematic reviews and original studies with the keywords “Autismdopamine hypothesis” and “Dopamine antagonists” between 1995 and 2022 that were published in English. Due to its greater breadth and access to more than 25 million pieces of biological literature, the PubMed/Medline database was chosen. In the beginning, the hypotheses proposed in light of the findings of the pertinent studies located in the literature searches were established in various stages. First, how particular dopaminergic dysfunctions could result in behaviors resembling those of autism, Second, an extensive examination of the primary hypothesis' predictions, Third, suggestions for how to put the theory to the test. The limitations of the hypothesis are the final step. We believe it will be feasible to determine if there is a problem in this way.


The key traits of people with autism, according to studies, include social deficiencies and stereotyped behaviors.[11,12] It is believed that disrupted midbrain dopaminergic transmission is the root of these traits.[13] Two divisions of the midbrain dopaminergic neurons, the substantia nigra and ventral tegmental region, are crucial in the control of the functions that are frequently compromised by ASD. These two neuronal clusters function as two ubiquitous modulatory circuits that link diverse regions of the brain via lengthy paths. These neural ensembles can regulate sizable groups of postsynaptic neurons and have a significant behavioral impact. The prefrontal cortex (PFC) and the ventral nucleus accumbens receive projections from neurons in the ventral tegmental region first. Second, the substantia nigra projects neurons to the dorsal striatum, establishing the nigrostriatal (NS) circuit, which regulates the motor components of goal- directed behavior to create the right actions to get a certain result. In light of these, it has been hypothesized that aberrant dopamine signaling in these brain regions is what causes the core characteristics of autism.[14-17] First off, the social difficulties seen in ASD may be a result of a malfunctioning mesocorticolimbic (MCL) circuit. An MCL circuit malfunction may result in altered reward representation and decreased drive to pursue rewarding events due to its role in reward and motivation.[18] Autistic brains may fail to recognize social connections as rewarding if these changes are connected to social behavior, which would further decrease the drive to seek out social interactions and improve social skills. The social motivation theory of ASD, which holds that autistic individuals are an extreme example of low social drive that impacts social cognition and ultimately results in social deficits, expresses this point of view. Numerous studies back up this idea.[19-22] First, MCL dopaminergic circuit signaling alterations in autistic patients include decreased PFC dopamine release and decreased nucleus accumbens neuronal responsiveness.[23] Accordingly, research demonstrates that both social and non-social rewards are affected by the general hypoactivation of the reward system that characterizes ASD.[24-28] Oxytocin may play a facilitative role in MCL dopaminergic signaling as evidenced by the decreased mesolimbic activation was seen in individuals who have the oxytocin receptor gene polymorphism linked to ASD.[29] The alleviation of social deficits brought on by intranasal oxytocin delivery raises the possibility that problems in mesolimbic dopamine signaling are fundamental to the social characteristics of ASD.[30] Last but not least, it has been demonstrated that decreased mesolimbic dopaminergic signaling modifies some reward-related behaviors, including effortbased decision-making for rewards, in autistic people.[31] All of these investigations suggest that autistic individuals exhibit general MCL circuit malfunction, which leads to changes in reward-related behaviors. Thus, they could be the initial steps in a disordered chain of events that eventually results in the social abnormalities seen in ASD. Furthermore, a malfunction in the NS pathway, which has been demonstrated to mediate stereotyped behaviors, may be the cause of the stereotyped behaviors seen in autistic people.[32,33] Due to the NS route's crucial involvement in regulating goal-directed motor behaviors, failure in this pathway may result in autistic-like behaviors by trapping a person in cycles of repetitive, stereotyped behaviors.[33] A D3 dopamine receptor gene polymorphism has been linked to increased striatal volume and stereotypic behavior in autistic people. Additionally, frequent mutations in the genes encoding the dopamine transporter and the dopamine D4 receptor have been linked to repeated behaviors in kids with ASD.[34] All of these studies point to the NS pathway's dopaminergic malfunction as a key factor in the development of stereotypical behavior like that of autistic individuals. According to this dopamine theory, defects in dopamine signaling in the diffuse dopaminergic modulatory networks of the midbrain, which cause social deficits and stereotyped behaviors in ASD, serve as a link between neurobiology and behavior.[5,35]


Models of dopaminergic pathway hyper- or hypoactivity in relation to dopamine imbalances in autistic people have been put up by certain writers.[36] No consensus that is independent of these models has been formed up until this point. Schizophrenia is believed to originate from the interaction of subcortical dopamine excess and cortical dopamine deficiency, and shares behavioral traits with ASD. Given that schizophrenia and ASD have similar behavioral traits, persons with autism may also experience a related pathological mechanism.[37] Unfortunately, there is currently insufficient evidence and further research is needed to develop a reliable dopaminergic model of ASD. It's significant since dopamine antagonists have been seen to improve basic autistic characteristics.[5,11,38] Dopamine modulators may enhance both social and nonsocial behavior if dopaminergic dysfunctions are the cause of autistic-like behaviors.[5,11,39-42] Due to its positive impact on behavior, blocking dopamine neurotransmission could also be a significant therapeutic approach.[43-46] The evidence, however contradictory, points to generalized dopaminergic hypoactivity in autistic people.[47] The contradictory data made it necessary to conduct additional research to identify the dopamine signaling properties in ASD. Therefore, it's crucial to look into other ways to put the dopamine theory of ASD to the test.


Autism spectrum disorder is understood to be a condition with numerous underlying causes that affect certain brain circuits. It is therefore conceivable that distinct molecular abnormalities mix in different proportions and result in abnormal signaling in particular brain circuits.[37] Nevertheless, dopamine signaling anomalies have been linked to a number of ASD comorbidities, including executive function impairments, anxiety, tics, and attention-deficit hyperactivity disorder.[28] It is not viable to claim that ASD is just a dopaminesignaling issue in light of this information. The neurological basis of ASD is also thought to be influenced by further anomalies in neurotransmitter signaling.[44] In fact, a 2020 article made the case that the pathophysiology of ASD is heavily influenced by aberrant glutamate signaling.[39]

In conclusion, despite the fact that ASD has been linked to a number of different dopamine dysfunctions, it would be incorrect to just blame dopamine deficit for the disorder. It has been hypothesized that autistic-like behavior may affect social motivation and goal-directed motor behavior due to dopamine dysfunctions in extensive dopaminergic modulatory networks in the midbrain. Two fundamental truths about autism have emerged from the research: First, dopamine dysfunctions in particular brain regions can create social deficits and stereotyped behaviors in persons who are not autistic. Second, dopamine modulators can enhance behavior when dopamine dysfunctions are the cause of autism- like behaviors. This idea is supported by the effectiveness of dopamine antagonists in helping autistic individuals with their basic behaviors, which creates a pharmacological connection between dopamine and ASD. Additionally, the discovery of dopaminergic dysfunctions in autistic patients may help researchers better understand disorders with behavioral symptoms, the pathogenesis of neuropsychiatric disorders, and the biological underpinnings of human behavior.

Cite this article as: Bardaş Özkan E, Odabaşı M. Dopamine dynamics in autism: Unraveling the neurochemical puzzle. D J Med Sci 2023;9(2):82-87. doi: 10.5606/fng. btd.2023.130.

Author Contributions

All authors contributed equally to the article.

Data Sharing Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/ or publication of this article.

Financial Disclosure

The authors received no financial support for the research and/or authorship of this article.


  1. Baranek G. Sensory and motor features in autism: assessment and intervention. In: Volkmar FR, Paul R, Klin A, Cohen D. Hoboken NJ, editors. Handbook of Autism and Pervasive Developmental Disorders. 3rd ed. New York: John Wiley & Sons Inc; 2005. p. 831-57.
  2. Ozonoff S, Young GS, Goldring S, Greiss-Hess L, Herrera AM, Steele J, et al. Gross motor development, movement abnormalities, and early identification of autism. J Autism Dev Disord 2008;38:644-56. doi: 10.1007/s10803-007-0430-0.
  3. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med 2016;22:345- 61. doi: 10.1038/nm.4071.
  4. King BH, Lord C. Is schizophrenia on the autism spectrum? Brain Res 2011;1380:34-41. doi: 10.1016/j.brainres.2010.11.031.
  5. Pavăl D. A Dopamine Hypothesis of Autism Spectrum Disorder. Dev Neurosci 2017;39:355-360. doi: 10.1159/000478725.
  6. Niculae AŞ, Pavăl D. From molecules to behavior: An integrative theory of autism spectrum disorder. Med Hypotheses 2016;97:74-84. doi: 10.1016/j. mehy.2016.10.016.
  7. Bear M, Connors B, Paradiso M. Chemical control of the brain and the behavior. In: Neuroscience: Exploring the Brain. Philadelphia: Lippincott Williams and Wilkins; 2007.
  8. Dichter GS, Richey JA, Rittenberg AM, Sabatino A, Bodfish JW. Reward circuitry function in autism during face anticipation and outcomes. J Autism Dev Disord 2012;42:147-60. doi: 10.1007/s10803- 011-1221-1.
  9. Kriete T, Noelle DC. Dopamine and the development of executive dysfunction in autism spectrum disorders. PLoS One 2015;10:e0121605. doi: 10.1371/journal. pone.0121605.
  10. Sydor A, Brown R. Widely projecting systems: monoamines, acetylcholine, and orexin. In: Nestler EJ, Hyman SE, Malenka RC, editors. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. 2nd ed. New York: McGraw-Hill Medical; 2001. p. 179.
  11. Pavăl D, Micluția IV. The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects. Dev Neurosci 2021;43:73-83. doi: 10.1159/000515751.
  12. Cai Y, Xing L, Yang T, Chai R, Wang J, Bao J, et al. The neurodevelopmental role of dopaminergic signaling in neurological disorders. Neurosci Lett. 2021 Jan 10;741:135540. doi: 10.1016/j. neulet.2020.135540.
  13. Eissa N, Sadeq A, Sasse A, Sadek B. Role of Neuroinflammation in Autism Spectrum Disorder and the Emergence of Brain Histaminergic System. Lessons Also for BPSD? Front Pharmacol 2020;11:886. doi: 10.3389/fphar.2020.00886.
  14. Damiano CR, Aloi J, Dunlap K, Burrus CJ, Mosner MG, Kozink RV, et al. Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards. Mol Autism 2014;5:7. doi: 10.1186/2040-2392-5-7.
  15. Anagnostou E, Soorya L, Brian J, Dupuis A, Mankad D, Smile S, et al. Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth. Brain Res 2014;1580:188-98. doi: 10.1016/j. brainres.2014.01.049.
  16. Damiano CR, Aloi J, Treadway M, Bodfish JW, Dichter GS. Adults with autism spectrum disorders exhibit decreased sensitivity to reward parameters when making effort-based decisions. J Neurodev Disord 2012;4:13. doi: 10.1186/1866-1955-4-13.
  17. Samsam M, Ahangari R, Naser SA. Pathophysiology of autism spectrum disorders: revisiting gastrointestinal involvement and immune imbalance. World J Gastroenterol 2014;20:9942-51. doi: 10.3748/wjg. v20.i29.9942.
  18. Presti MF, Mikes HM, Lewis MH. Selective blockade of spontaneous motor stereotypy via intrastriatal pharmacological manipulation. Pharmacol Biochem Behav 2003;74:833-9. doi: 10.1016/s0091- 3057(02)01081-x.
  19. Horev G, Ellegood J, Lerch JP, Son YE, Muthuswamy L, Vogel H, et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc Natl Acad Sci U S A 2011;108:17076-81. doi: 10.1073/ pnas.1114042108.
  20. Staal WG. Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge. Eur Neuropsychopharmacol 2015;25:1421-6. doi: 10.1016/j.euroneuro.2014.08.011.
  21. Staal WG, Langen M, van Dijk S, Mensen VT, Durston S. DRD3 gene and striatum in autism spectrum disorder. Br J Psychiatry. 2015;206:431-2. doi: 10.1192/bjp.bp.114.148973.
  22. Gadow KD, Devincent CJ, Olvet DM, Pisarevskaya V, Hatchwell E. Association of DRD4 polymorphism with severity of oppositional defiant disorder, separation anxiety disorder and repetitive behaviors in children with autism spectrum disorder. Eur J Neurosci 2010;32:1058-65. doi: 10.1111/j.1460- 9568.2010.07382.x.
  23. Kosillo P, Bateup HS. Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models. Front Neural Circuits 2021;15:700968. doi: 10.3389/fncir.2021.700968.
  24. Williams KA, Swedo SE. Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond. Brain Res 2015;1617:144-54. doi: 10.1016/j. brainres.2014.09.071.
  25. Orefici G, Cardona F, Cox CJ, Cunningham MW. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). 2016 Feb 10. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016.
  26. Ikeda T, Tokuda T, Monden Y, Hirai M, Mizushima SG, Nagashima M, et al. Hypoactivation of the Right Prefrontal Cortex Underlying MotorRelated Inhibitory Deficits in Children with Autism Spectrum Disorder: A Functional Near-Infrared Spectroscopy Study. Japanese Psychological Research 2018;60:251-264 doi: 10.1111/ jpr.122042018.
  27. Yamauchi T. Neuronal Ca2+/calmodulin-dependent protein kinase II--discovery, progress in a quarter of a century, and perspective: Implication for learning and memory. Biol Pharm Bull 2005;28:1342-54. doi: 10.1248/bpb.28.1342.
  28. Liu XY, Mao LM, Zhang GC, Papasian CJ, Fibuch EE, Lan HX, et al. Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII. Neuron 2009;61:425-38. doi: 10.1016/j. neuron.2008.12.015.
  29. Erbas O, Yılmaz M, Korkmaz HA, Bora S, Evren V, Peker G. Oxytocin inhibits pentylentetrazol-induced seizures in the rat. Peptides 2013;40:141-4. doi: 10.1016/j.peptides.2012.12.003.
  30. de Krom M, Staal WG, Ophoff RA, Hendriks J, Buitelaar J, Franke B, et al. A common variant in DRD3 receptor is associated with autism spectrum disorder. Biol Psychiatry 2009;65:625-30. doi: 10.1016/j.biopsych.2008.09.035.
  31. De Rubeis S, Bagni C. Regulation of molecular pathways in the Fragile X Syndrome: Insights into Autism Spectrum Disorders. J Neurodev Disord 2011;3:257-69. doi: 10.1007/s11689-011-9087-2.
  32. Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry 2001;49:655-64. doi: 10.1016/s0006-3223(00)01008-8.
  33. Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: Making sense of it all. Curr Psychiatry Rep 2007;9:329-36. doi: 10.1007/ s11920-007-0041-7.
  34. McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347:314-21. doi: 10.1056/NEJMoa013171.
  35. Sharmistha S, Mahasweta C, Nilanjana D, Swagata S, Mukhopadhyay K, Ghaeli P, Nikvarz N, Alaghband-Rad J, Alimadadi A, Tehrani-Doost M. Effects of risperidone on core symptoms of autistic disorder based on childhood autism rating scale: An open label study. Indian J Psychol Med 2014;36:66-70. doi: 10.4103/0253- 7176.127254.
  36. Robert TS. Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int J Dev Neurosci 2005;23(2-3):125-141. doi. org/10.1016/j.ijdevneu.2004.12.012.
  37. Kazdoba TM, Leach PT, Yang M, Silverman JL, Solomon M, Crawley JN. Translational mouse models of autism: Advancing toward pharmacological therapeutics. Curr Top Behav Neurosci 2016;28:1- 52. doi: 10.1007/7854_2015_5003.
  38. Lewis MH. Brief report: psychopharmacology of autism spectrum disorders. J Autism Dev Disord 1996;26:231-5. doi: 10.1007/BF02172018.
  39. Zürcher NR, Bhanot A, McDougle CJ, Hooker JM. A systematic review of molecular imaging (PET and SPECT) in autism spectrum disorder: Current state and future research opportunities. Neurosci Biobehav Rev 2015;52:56-73. doi: 10.1016/j. neubiorev.2015.02.002.
  40. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol 2013;27:479-96. doi: 10.1177/0269881113482532.
  41. Kirsten TB, Chaves-Kirsten GP, Chaible LM, Silva AC, Martins DO, Britto LR, et al. Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide. J Neurosci Res 2012;90:1903- 12. doi: 10.1002/jnr.23089.
  42. Masi A, DeMayo MM, Glozier N, Guastella AJ. An overview of Autism Spectrum Disorder, heterogeneity and treatment options. Neurosci Bull 2017;33:183- 93. doi: 10.1007/s12264-017-0100-y.
  43. Gadow KD, Roohi J, DeVincent CJ, Hatchwell E. Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. J Child Psychol Psychiatry 2008;49:1331-8. doi: 10.1111/j.1469-7610.2008.01952.x.
  44. Pasquini S, Contri C, Merighi S, Gessi S, Borea PA, Varani K, et al. Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets. Int J Mol Sci 2022;23:1219. doi: 10.3390/ ijms23031219.
  45. Yang P, Chang CL. Glutamate-mediated signaling and autism spectrum disorders: Emerging treatment targets. Curr Pharm Des 2014;20:5186-93. doi: 10.2 174/1381612819666140110120725.
  46. Yang AC, Tsai SJ. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int J Mol Sci 2017;18:1689. doi: 10.3390/ ijms18081689.
  47. Weinschutz Mendes H, Neelakantan U, Liu Y, Fitzpatrick SE, Chen T, Wu W, et al. High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways. Cell Rep 2023;42:112243. doi: 10.1016/j.celrep.2023.112243.