dopamine metabolism, circuitry and relevance in psychiatry

1. DOPAMINE

2. What is Dopamine?
 A monoamine neurotransmitter
 Involved in :
Synthesis of Norepinephrine
Reward and pleasure emotions
Locomotion
Regulation of prolactin
Renal- Vasodilation and regulation of GFR
 The “Happy chemical” (an honour it shares with serotonin)

3. DOPAMINE
METABOLISM

4. Synthesis
 Synthesized from- Tyrosine
 Precurser- L-Dopa
 Rate-limiting enzyme- tyrosine hydroxylase
 Final step- decarboxylation from L-dopa
 Co-factor involved- pyridoxal phosphate (Vit. B6)
in the final step

5. Transportation
 VMAT2- storage and release
 DAT- reuptake
 Presynaptic D2 autoreceptor-
regulates release of DA

6. Degradation
 Centrally- MAO A and MAO B-
(mitochondria of presynaptic neuron)
 Peripherally- COMT (extracellular)
 DA that diffuses away from synapses can also
be transported by norepinephrine
transporters (NETs) as a “false” substrate, and
DA action will be terminated in this manner.
 End product- Homovanillic acid

8. Dopaminergic sites
 In the Brain
 Midbrain
 Substantia nigra
 Ventral tegmental area
 Periaqueductal gray
 Hypothalamus
Outside the Brain
Olfactory bulb
Retina
Kidney (adrenal medulla)

9. Dopamine and Acetylcholine
 DA and ACH
have a reciprocal
relationship in
the nigrostriatal
pathway.
 DA suppresses
ACH activity (no
ACH being
released from
the cholinergic
axon on the
right).

10. Dopamine and
Serotonin
 Serotonin (5HT-2A)
 Glutamate
 GABA
 Dopamine

11.  5HT-1A receptors of Serotonin
 Glutamate
 Dopamine

12. Why should we know all this?
 A leading hypothesis in the psychopathology of schizophrenia is the
dopamine hypothesis
 Dopamine also has been implicated in the progress of many other
psychiatric and neurological conditions
 Understanding dopamine metabolism and its pathways, therefore, has
been instrumental in the development of many treatment modalities
and pharmacotherapies.

13. DOPAMINERGIC
PATHWAYS

14. a. Nigrostriatal
b. Mesolimbic
c. Mesocortical
d. Tuberoinfundibular
e. Multiple sites to
Thalamus

15. Mesolimbic pathway
 Midbrain ventral tegmental area to the
nucleus accumbens,
 A part of the limbic system
 Reward
 Pleasurable sensations,
 Euphoria of drugs of abuse
 Delusions and hallucinations of
psychosis.

16. Schizophrenia
 Dopamine hypothesis is posited
on the basis of two observations:
1. The mechanism of action of
antipsychotics which are used in
the treatment regimen
2. That drugs of abuse such as
cocaine and amphetamine
which are associated with
dopaminergic activity are
psychotomimetic
 Mesolimbic and mesocortical
pathways implicated

17. Drug-induced psychosis
 Cocaine
 Amphetamines
 Positive symptoms like those seen in schizophrenia will
develop on repeated use (abuse)

18. Mood Disorders
 DA activity-
Reduced in depression
Increased in mania.
 Drugs and diseases that reduce dopamine concentrations-
associated with depressive symptoms.
 Drugs that increase dopamine concentrations- reduce the
symptoms of depression.
 Two recent theories-
1. Mesolimbic dopamine pathway may be dysfunctional in
depression
2. D1 receptor may be hypoactive in depression.

19. Aggression &
Impulse-Control Disorders
 Found to be facilitated by dopamine
 Especially due to a decrease in the serotonergic inhibition of
dopamine
 Impulse-control disorders (including eating disorders)- linked
to reward circuitry

20. Mesocortical pathway
 Midbrain ventral tegmental
area to areas of the
prefrontal cortex,
 Cognition and executive
functions- DLPFC
 Emotions and affect-
VMPFC

21.  Deficit = Negative
symptoms of
schizophrenia
 Depression
 ADHD treatment
with stimulants
based on the
rationale of
blockade of DA
reuptake due to
feedback inhibition

22. Nigrostriatal pathway
 part of the extrapyramidal nervous system
 controls motor movements.

23. Parkinson’s Disease
 Deficiency of dopamine receptors in the striatal pathway
 Characterized by:
1. Tremor
2. Bradykinesia
3. Rigidity
 Progressive and debilitating course
 Treament- first line- L-dopa (with carbidopa combination)
Dopamine agonists
 Similar picture can be induced by neuroleptics- called drug-induced
parkinsonism

24. Other Movement Disorders
Deficiency Hyperactivity
Parkinsonism Dyskinesias
Akathisia Tic disorders
Dystonia Chorea
Tardive dyskinesia

25. Stereotypic Movement Disorder
 Associated with dopamine dysfunction
 DA agonists have been found to induce stereotypic
movements and DA antagonists to reduce them
 Children with ADHD on medication with stimulants began to
bite their nails and fingers- behaviour which stopped on
stopping the drug.

26. Social Phobia
 Evidence for dopaminergic dysfunction
1. Increased efficacy of MAOIs over TCAs in treatment
2. A study recording decreased levels in Homovanillic acid in
cases
3. A SPECT study showing decreased reuptake of DA in the
striatal pathway in cases.

27. Tuberoinfundibular
pathway
 Hypothalamus to the anterior
pituitary gland
 Associated with dopamine
regulation of prolactin

28. Relationship with Prolactin
 Inhibits prolactin release.
 In the postpartum state, the activity of these dopamine neurons is
decreased. Prolactin levels can therefore rise during breastfeeding so
that lactation will occur.
 If the functioning is disrupted by lesions or drugs, prolactin levels can
also rise.
Galactorrhea (breast secretions),
Amenorrhea (loss of ovulation and menstrual periods),
Sexual dysfunction.
 Such problems can occur after treatment with many antipsychotic drugs
that block D2 receptors

29. DOPAMINE IN
PHARMACOLOGY

30. Typical Antipsychotics
 Pure D2 antagonism
 Action on mesolimbic pathway
 Decreases positive symptoms
 A lot of extra-pyramidal side effects due
to non-specific blockade of D2
receptors across the brain
 Side effects also due to various binding
at M1 (cholinergic), H1
(Sedation/weight gain) and a1 (CVS
side effects)

31. Neurolepsis
1. Blockade of reward and pleasure centres of mesolimbic pathway
2. worsening of already deficit state in mesocortical pathway
 Anhedonia
 Apathy
 Lacking motivation
 Lacking interest in social interactions
 Worsening of negative symptoms

32. Extrapyramidal symptoms
 Due to blocking of
dopamine receptors in
nigrostriatal pathway
 Movement disorders like
rhythmic tremor, rigidity,
akinesia or bradykinesia
 Sometimes called drug-
induced parkinsonism

33. Tardive dyskinesia
 Result of chronic use of antipsychotics
 Hyperkinetic movement disorder
 With facial tics, grimacing, tongue protrusions, constant chewing and
abnormal limb movements (quick, jerky, choreiform)
 Early stages- reversible on stopping of drug- due to “resetting” of
receptors
 Late stages- irreversible- resulting in upregulation of receptors
 1 year risk- 5%; 5-year risk- 25%
 Increased risk- patients with genetic predisposition
elderly
patients with early onset of EPS

34. Neuroleptic Malignant Syndrome
 A rare (~0.02%) but potentially fatal complication
 Extreme muscular rigidity, dystonia, high fever and autonomic
symptoms which can result in coma, and death
 Related in part to D2 receptor blockade in the nigrostriatal
pathway
 High potency FGAs- greater risk
 Treated with dopamine agonists- Bromocriptine and
Amantadine

35. Atypical Antipsychotics
 Clinical profile of equal positive symptom antipsychotic actions, but low
extrapyramidal symptoms and less hyperprolactinemia compared to conventional
antipsychotics.
 D2 antagonism- mesolimbic
 Serotonin 5HT2A receptor antagonism Nigrostriatal pathway
 Partial agonist actions at 5HT1A receptors and
 Partial agonist actions at D2 receptors Tuberoinfundibular pathway

36. Typical antipsychotics Atypical antipsychotics
Chlorpramazine Aripiprazole
Fluphenazine Asenapine
Haloperidol Clozapine
Loxapine Iloperidone
Perphenazine Olanzapine
Thioridazine Lurasidone
Thiothixene Paliperidone
Trifluoperazine Quetiapine
Risperidone
Ziprasidone

37. Dopamine Agonists
 Dopamine agonists activate dopamine receptors in the absence of
endogenous dopamine
Indications:
 Idiopathic Parkinson's disease,
 Hyperprolactinemia, and
 Prolactinoma
 Shock
 Congestive heart failure.
 Adverse effects of antipsychotic drugs as parkinsonism, extrapyramidal
symptoms, akinesia, focal perioral tremors, hyperprolactinemia,
galactorrhea, and neuroleptic malignant syndrome.

38. Dopamine agonists
 Levodopa
 Bromocriptine
 Carbidopa-Levodopa combination
 Amantadine
Primarily for medication-induced movement disorders (neuroleptic-induced
parkinsonism)
Antiviral agent for the prophylaxis and treatment of influenza A infection
Cotard's syndrome (person holds a delusional belief that he or she is dead)
Augmenting antidepressant medications in treatment-resistant depression.

39. New Dopamine Agonists
 Ropinirole
 Pramipexole -
Augmenter to antidepressants;
Possible increased risk of heart failure
 Apomorphine
 Pergolide –
Risk of valvular damage- removed

40. Summary
 Dopamine is a neurotransmitter that plays a role in the
psychopathology of most of the common psychiatric disorders.
 Especially in schizophrenia, mood disorders and movement disorders.
 Research is undergoing for finding out its implications in conditions
such as generalized anxiety disorder, ADHD, aggression and impulse-
control disorders.
 Most of the applications of this knowledge lie in the field of
pharmacotherapy where designing an appropriate drug for an
appropriate set of symptoms without triggering a host of
inappropriate adverse effects is still an ongoing process.

41. References
 Stahl’s Essential Psychopharmacology 4th ed.
 Kaplan & Sadock’s Synopsis of Psychiatry 11th ed.
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