12. Autism as a dopaminergic Disorder

Autism is a spectrum disorder, so it manifests itself in different forms and with different dimensional intensity.
The prevalence of ASD in the overall population is 1.85% of boys and 0.40% of girls. Among people with ADHD, the prevalence of ASD is between 3.6% and 21%. People with ADHD show diagnosable differences in social behavior and in repetitive and sensory-oriented behaviors from the age of 9 months.¹²³⁴

In addition to dopamine, ASA has other neurophysiological causes, such as noradrenaline⁵⁶ , GABA, glutamate, serotonin, N-acetylaspartate, oxytocin, arginine vasopressin, melatonin, vitamin D, orexin, endogenous opioids and acetylcholine.⁷ Against the background of the points of contact with ADHD, we have summarized the dopaminergic aspects in this article.

• 1. Symptoms of ASA
• 2. Dopamine and ASA
  • 2.1. Reduced dopamine reuptake, increased dopamine efflux
  • 2.2. Other dopaminergic ASA phenotypes
• 3. Medication and ASA

1. Symptoms of ASA¶

The main symptoms of autism are⁵

• Impairments in social communication and interaction
  • persistent impairments
    • social reciprocity
    • non-verbal communication
    • building, maintaining and understanding relationships
  • Examples:
    • Avoid eye contact
    • flat or inappropriate facial expressions
    • Inability to understand the boundaries of personal space
    • Deficits in reciprocal back-and-forth communication
    • Difficulty using and understanding gestures, tone of voice or body language
• Patterns of restricted and repetitive behaviors, interests or activities
  • repetitive motor movements
  • inflexible adherence to routines
  • severely restricted interests that are abnormal in their intensity
  • Hyper- or hyporeactivity to sensory stimuli
• Learning problems
• Attention problems
• Deficits in sensory processing
• Emotion regulation problems
• Sleep problems
• Language and language acquisition problems
• Communication problems
• Prompt dependency

These symptoms are a common adaptive behavior in young, normally developing children and should be distinguished from ASD.⁸

Autism comprises a group of manifestations that were previously recognized as independent forms, including⁹

• early childhood autism
• Autism in childhood
• Kanner autism
• high-functioning autism
• atypical autism
• profound developmental disorder not otherwise specified
• disintegrative Disorder of Childhood
• Asperger syndrome

The most common comorbidities of ASD in children are:

• ADHD: 28.2% to 81.2%
• oppositional defiant disorder (ODD): 28.1 % to 45.5 %
• Anxiety disorders: 45.5 %
  • social anxiety disorder: 29.2 %
  • generalized anxiety disorder: 13.4 %

2. Dopamine and ASA¶

Disorders of dopamine signaling are not only associated with ADHD, but also with ASD (or an ASD subtype)⁹. To understand ADHD, it is exciting to grasp the ways in which dopaminergic signaling is disrupted in ASD and how this disorder differs from that in ADHD. Since ADHD and ASD can occur comorbidly, it is unlikely that they are purely opposing dopaminergic disorders.
Precise regulation of synaptic (phasic) dopamine signaling by the dopamine transporter (DAT) supports the ability of dopamine to encode reward prediction errors and thereby control motivation, attention and behavioral learning.

The mesocorticolimbic dopamine system (in relation to social deficits) and the nigrostriatal dopamine system (in relation to stereotyped behavior) appear to play a major role in the core deficits of ASD.¹⁰¹¹
The mesocorticolimbic dopamine system, which is important for reward processing, is hypoactivated in ASD¹², which greatly reduces the value of social rewards and thus causes a lack of social motivation.¹³
In addition, dysfunction of the social brain network (consisting of the inferior frontal gyrus, amygdala and fusiform gyrus) can reduce social motivation.¹⁴
The nigrostriatal dopamine system¹⁵, which is important for motor aspects of goal-directed behavior, appears to be able to trigger repetitive and stereotypical behavior through increased dopamine in the dorsal striatum via the D1 receptor. D1 antagonists stopped this behavior. Mice without D2 receptors in the dorsal striatum also showed repetitive and stereotyped behavior.¹⁶

2.1. Reduced dopamine reuptake, increased dopamine efflux¶

A de novo mutation in the SLC6A3 gene encoding the DAT leads to a threonine-methionine substitution at site 356 (DAT T356M) and causes sustained dopamine efflux and has been associated with ASD. In Drosophila melanogaster, the DAT mutation causes hyperlocomotion.
Mice homozygous for this mutation show impaired striatal DA neurotransmission and altered DA-dependent behaviors consistent with some of the behavioral phenotypes observed in ASD.
This DAT mutation was shown in vitro:

• reduced dopamine reuptake¹⁷
  • DAT expression in the striatum unchanged
  • Vmax of the resumption reduced
  • consequences of reduced resumption are
    • D2R desensitization
    • reduced dopamine synthesis due to increased synaptic dopamine levels
    • reduced total content of dopamine in the tissue
    • reduced tyrosine hydroxylase phosphorylation at Ser31
    • synaptic hyperdopaminergia
    • increased striatal dopamine metabolism
• permanent DA efflux¹⁸
• reduced DAT affinity for cocaine and MPH (suggesting an important role of T356 in inhibitor binding)¹⁷
  • DA peak release on cocaine as with wild type
  • Decay time of amperometric current in DAT T356M+/+ mice significantly longer than in wild type, corresponding to reduced reuptake
• reduced body weight
• only T356M+/+, not T356M+/- mice show behavioral peculiarities compared to wild type
  • spontaneous hyperactivity persistent
    • reduced by DAT antagonists
      • ACT-01: within 20 minutes
      • GBR12909: within 10 minutes
  • repetitive behaviors
  • social deficits
    • Loss of preference for new social encounters
    • Loss of social dominance
  • Loss of motivated behavior or altered choice of action (reduced burying of marbles)
• unchanged:
  • Power
  • Coordination
  • motor learning
  • Anxiety
  • Stress behavior

The DAT gene variant Ala559Val, which was found in two people with ASD (12), also shows increased diopamine efflux without increased dopamine reuptake¹⁹
- very rare gene variant
- tripled dopamine efflux, with depolarized cell potentials
- at the level triggered by AMP in normal DAT
- MPH and AMP both blocked Ala559Val-mediated dopamine efflux
- in wild-type HDAT, MPH and AMP increase this
- increased sensitivity to intracellular Na+, but not to intracellular dopamine
- possibly increased basal hDAT A559V phosphorylation, which is attenuated by AMP
- normal DAT protein and cell surface expression
- normal dopamine (re)uptake¹⁷ at both low and high dopamine levels
- normal effect of AMP, MPH, cocaine on dopamine reuptake inhibition
- an older A559V carrier showed
- high hyperactivity/restlessness
- high impulsivity/emotional susceptibility
- high hyperactive-impulsive symptom scores according to DSM-IV (over 90)
- increased efflux is CaMK-dependent and is mediated by DRD2²⁰
- indicates the involvement of endogenous signaling and phosphorylation mechanisms
- Increased PKCβ activity²⁰

However, homozygous Ala559Val mice do not show any:²¹

• spontaneous locomotor hyperactivity

• Stereotypes

• DAT1 gene variant Asn336 (ΔN336)²²

  • hDAT mutation
  • associated with ASD in humans
  • reduced dopamine uptake
    • almost non-existent
    • with L-dopa administration 1/3 of wild-type DAT
  • Dopamine efflux reduced to approx. 1/3
  • in Drosophila:
    • impaired social behavior during the flight
    • Hyperactivity
    • prolonged freezing and a reduced willingness to flee in response to predatory signals
    • increased anxiety
    • repetitive behavior

Asn336 therefore shows that increased DAT dopamine efflux is not a mandatory prerequisite for ASD. However, the non-existent dopamine reuptake is likely to result in a massively excessive extracellular dopamine level.

This is consistent with the fact that high D-amphetamine administration (5 to 10 mg/kg in the rat), which leads to increased extracellular dopamine levels in the caudate nucleus and putamen, is associated with focused-repetitive (stereotypic) behavior.²³

Parkinson’s patients who received strong dopamine replacement therapy and chronic amphetamine drug users (both cases of marked dopamine excess) exhibit stereotypic behaviors such as intense fascination with repetitive manipulation of mechanical objects, touching and examining common objects, excessive grooming, and delivering long monologues ⁹

Decreased dopamine reuptake and increased dopamine efflux with ASA would be consistent with dopamine reuptake inhibitors not improving ASA main symptoms, as they enhance exactly these two dopaminergic effects.
However, the very frequent comorbidity between ASD and ADHD raises the question of how some contradictions can be reconciled:

• reduced dopamine (re)uptake in ASD and increased dopamine reuptake in ADHD (which is typically treated with dopamine reuptake inhibitors)
• increased dopamine efflux in ASA and increased dopamine efflux in ADHD due to stimulants (the ADHD medication of choice)

2.2. Other dopaminergic ASA phenotypes¶

Several studies have consistently found an enlargement of the caudate nucleus in ASA, which also points to dopaminergic connections ⁹

Referring to the D1/D2 balance, one study reports that increased D1 signaling correlates with stereotypic behaviors and is reduced by D1 antagonists²⁴ and that increased postsynaptic D2 receptor density was observed in ASA model mice (which could be an adaptive response to decreased postsynaptic D2 signaling)²⁵

Prenatal exposure to valproate is a known risk factor for ASD. Valproate appears to alter the expression of over 1300 genes ⁹
Prenatal valproate exposure in zebrafish causes

• ASS symptoms (in young animals)
  • Loss of social preference
  • Hyperactivity
  • anxiety-like behavior
• Dopaminergic changes
  • reduced th1 mRNA gene expression (encodes tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis)
  • reduced dbh mRNA gene expression (encodes dopamine β-hydroxylase, which converts dopamine into noradrenaline)
  • a reduced number of TH1-immunoreactive cells
• Other changes
  • inhibited histone deacetylase (which is involved in the epigenetic regulation of gene expression)
  • altered subunits of the GABA receptor

Prenatal exposure to valproate in rodents ⁹

• ASS symptoms (in young animals)
  • repetitive behaviors
  • Deficits in social interactions
  • reduced isolation-induced vocalization
• Dopaminergic changes
  • increased basal dopamine
  • an increasingly increased dopamine concentration in response to swimming stress
  • Hyperexcitability of the striatal MSN
  • Changes in dopamine receptor expression
  • increased D2R expression in the nucleus accumbens
  • increased D1R expression in the nucleus accumbens and hippocampus

ASA does not necessarily appear to be associated with increased extracellular dopamine levels and decreased dopamine reuptake.
A dopaminergic ASA phenotype appears to be associated with reduced DAT expression in the striatum.
Fmr1-KO (Fragile X Mental Retardation 1 Knockout) mice exhibit ASD-associated behaviors, including⁹

• ASS symptoms
  • Impairment of social behavior
    • intranasal dopamine administration increased social novelty seeking
  • anxiety-like behavior
  • Hyperlocomotion
• dopaminergic changes:²⁶²⁷²⁸
  • less striatal DAT
  • reduced D1R expression
    • Absence of D1R-mediated amplification of evoked inhibitory postsynaptic currents (IPSCs)
    • D1R signal transmission in synapses of the PFC disrupted
      • can be partially restored by D1 receptor agonists
      • can be remedied by pharmacological inhibition of GRK2
  • Dopaminergic signaling pathway: cerebellum -> dopamine neurons in the VTA -> mPFC relatively weakened
    • reduced cerebellar-evoked dopamine release in the mPFC
    • VTA inactivation reduced dopamine release in Fmr1-KO mice less than in wild type
  • abnormal morphology of the striatal TH-positive axons with higher “complexity” and lower “texture”
  • increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1) and TH signals
  • unaltered GABAergic neurons
  • reduced number of SNc cells

BTBR mice (Black and Tan BRachyury T+Itpr3tf/J) show²⁶

• ASS symptoms
  • Impairment of sociability
  • altered ultrasound vocalization
  • increased self-care behavior
• ADHD symptoms
  • cognitive
  • emotional
• intranasal administration of dopamine corrected the deficits
  • non-selective attention
  • object-related attention
  • the social approach
• dopaminergic changes
  • less striatal DAT
  • reduced D2R-mediated neurotransmission
  • unaltered D1 receptor-mediated neurotransmission
  • reduced tyrosine hydroxylase expression in
    • Substantia nigra
    • VTA
    • dorsal striatum
  • increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1) and TH signals
  • unaltered GABAergic neurons

3. Medication and ASA¶

The FDA has approved risperidone and aripiprazole for the treatment of ASD.

METASTUDY found that the D2 antagonist and serotonin 5-HT2A antagonist risperidone improved major symptoms in children with autism:²⁹³⁰

• Lethargy/social withdrawal
• Irritability
• disruptive behavior
• restricted, repetitive and stereotypical behaviors, interests and activities
• Self-harm
• social and linguistic communication (slight improvements)

A meta-analysis found improvements with short-term treatment with aripiprazole (albeit with significant side effects such as weight gain, sedation, drooling and tremors) regarding:³¹

• Irritability
• Stereotypes (repetitive, purposeless actions)
• Hyperactivity

Methylphenidate improved in ASD, albeit with a slightly lower responder rate than in ADHD³²

• Hyperactivity
• Inattention

In an animal study, the H3R, D2R and D3R antagonist ST-713 improved autistic behavior in male BTBR T+tf/J mice:³³

• social deficits
• repetitive/compulsive behaviors
• disturbed states of anxiety
• but not the hyperactivity of the mice tested
• 5 mg i.p. attenuated the elevated protein levels in the hippocampus and cerebellum of
  • NF-κB p65
  • COX-2
  • iNOS
• Simultaneous administration of an HR agonist or an anticholinergic drug abolished the improvement in social parameters