Autism and Dopamine

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Autism and Dopamine

• Shannon Vettor

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Symptoms

• Qualitative impairment in social interaction
• Qualitative impairment in communication
• Restricted, stereotyped interest and activities
• Delays or abnormal functioning in one of the
  above major areas before the age of three

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Repetitive Behaviours

• Stereotypy repetitive and apparently
  purposeless body movements (i.e. rocking), body
  part movements (i.e.. hand flapping, head
  rolling), or use of the body to generate object
  movements (i.e.. plate spinning, string twirling)
• Compulsions repetitive, intentional behaviours
  that appear to follow certain rules
• Obsessions repetitive persistent thoughts,
  impulses, or images that are experienced as
  intrusive and inappropriate and that cause marked
  anxiety or distress
• Sameness insistence on sameness involves
  overall repetitive routines and preferences
  rather than discrete repeated acts or thoughts
• Echolalia repetitive use of speech in either an
  immediate manner or delayed manner
• Self-injury repetitive motor movements that
  result in injury to the person or have the
  potential to inflict injury
• Tics brief, rapid, explosive or shock-like
  movements which can be simple or complex
• Dyskinesia repetitive, involuntary movements
  expressed as chorea (i.e. jerky, nonrhythmic),
  athetosis (i.e. slow, writhing), or dystonia
  (i.e. slow, sustained, tensing)
• Akathisia repetitive restless movements and
  hyperkinetic restless states

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Epidemiology

• Prevalence 4-5/10,000
• Males females 3-41
• At least one third have no speech
• Cognitive impairments only 20-25 score within
  normal or near normal ranges on IQ tests
• Comorbidity
• -Seizure Disorders 30
• -Fragile X syndrome 2-5
• -Tuberous Sclerosis 1-3
• -Separation Anxiety approx. 73

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Etiology

• Family
• -risk of autism in the siblings of people with
  the disorder is about 75 times greater
• Twin
• -60-91 concordance for autism between MZ
  compared with DZ at 0-20
• -other studies suggest that autism is linked
  genetically to a broader spectrum of deficits in
  communicative and social areas -higher CSF HVA
  levels in more severely impaired twin

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Neuroanatomy

• Frontal Lobes
• ? Medial PFC memory functions (i.e. visual
  recognition)
• Cerebellum
• ? attention

• Limbic System
• ?amygdala social behaviours
• Brain Stem

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Neurochemistry

• Serotonin
• Dopamine
• Norepinephrine

• Opioids
• Glutamate

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Dopamine

• Primarily found in the limbic system, parts of
  the hypothalamus, the frontal cortex, and the
  forebrain
• Three pathways
• Mesostriatal
• -increases ? stereotypies/repetitive behaviours
• Mesolimbic
• -increases ? increased locomotor activity
• Mesocortical
• Modulates motor activity, attentional skills,
  social behaviour, and perception of the outside
  world, all of which are abnormal in autism

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DA contd

• Hypothesis hyperfunction of dopaminergic
  pathways arising in the brain-stem and projecting
  rostrally to mesolimbic structures in the
  temporal and frontal lobes might be crucial in
  the pathogenesis of certain symptoms of autism
• Early social deprivation ? loss of DA innervation
  of key brain regions with consequent DA receptor
  supersensitivity

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DA contd

• Equivocal Findings Higher levels of CSF HVA vs.
  decreased levels
• Stereotyped behaviours can be induced in animals
  by increasing central DA levels
• Self-injurious behaviour can be induced by a DA
  agonist in monkeys

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PET

• PET FDOPA levels are reduced (39) in the
  anterior medial PFC
• -may contribute to the cognitive impairment given
  the importance of DA in prefrontal function

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Treatment

• Most drug studies are only of a short duration
  and potiental long term impacts are not
  adequately considered.
• 1) Agonists/Stimulants (i.e. bromocriptine,
  LDOPA, amphetamine)
• -release DA from the presynaptic terminal and
  block its reuptake and degradation
• -Amphetamines they exacerbate the symptoms ?
  increased activity, aggression, stereotypes, and
  general disorganization of behaviour
• -Bromocriptine some efficacy in reversing
  repetitive behaviours associated with DA
  depletion
• -(hypothesized) chronic administration should
  reverse the DA receptor supersensitivity ? down
  regulates DA receptors

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Treatment contd

• 2) Antagonists (i.e. Haloperidol,
  trifluoperazine, pimozide)
• -Dopaminergic antagonists are the only drugs with
  consistent clinical efficacy in controlled trials
  in autism
• -effective in improving motor stereotypies,
  anger/uncooperativeness, interpersonal
  withdrawal, speech deviance
• -Haloperidol no adverse effect on IQ or on
  learning in a computerized laboratory
• -older children greater response
• -superior in decreasing levels of stereotypy and
  withdrawal
• -long-term continued reductions in levels of
  maladaptive behaviours
• -drawback development of tardive or withdrawal
  dyskinesias, sedation

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Treatment contd

• 3) Atypical Antipsycotics (i.e. risperidone,
  olanzepine)
• -block D2 receptors and 5-HT2 receptors
• -lower rates of extrapyramidal symptoms
• -animal studies increase in social interaction
• -risperidone repetitive behaviour disorders
• -drawback weight gain

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Future Directions

• Pharmacological studies target specific core or
  comorbid symptoms of autism
• Interaction between behavioural and
  pharmacological treatments
• Further study into the interactions between
  neurotransmitter systems