Neuropharmacology
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Dopaminergic Pharmacology
How dopamine pathways regulate movement, reward, and cognition, and how drugs modulate dopaminergic transmission.
Dopamine Synthesis and Metabolism
Dopamine is synthesized from tyrosine via tyrosine hydroxylase (TH, rate-limiting) to L-DOPA, then decarboxylated by AADC. It is metabolized by MAO-B and COMT to DOPAC and HVA. The dopamine transporter (DAT) clears synaptic dopamine, and VMAT2 packages it into vesicles.
Major Dopaminergic Pathways
- Nigrostriatal -- substantia nigra to striatum; controls motor function; degeneration causes Parkinson's disease
- Mesolimbic -- VTA to nucleus accumbens; mediates reward and motivation; implicated in addiction and positive symptoms of schizophrenia
- Mesocortical -- VTA to prefrontal cortex; regulates cognition and executive function; hypofunction linked to negative symptoms of schizophrenia
- Tuberoinfundibular -- hypothalamus to pituitary; inhibits prolactin release
Receptor Subtypes
Dopamine receptors are GPCRs in two families:
| Family | Receptors | Coupling | Effect |
|---|---|---|---|
| D1-like | D1, D5 | Gs | Increase cAMP |
| D2-like | D2, D3, D4 | Gi/Go | Decrease cAMP |
D2 receptors are the primary target of antipsychotics. D1 activation in the prefrontal cortex supports working memory.
Key Drug Classes
- Precursor therapy -- levodopa/carbidopa increases dopamine synthesis (Parkinson's)
- D2 agonists -- pramipexole, ropinirole stimulate postsynaptic D2/D3 receptors
- DAT blockers -- cocaine and methylphenidate increase synaptic dopamine
- Typical antipsychotics -- haloperidol blocks D2 receptors (high EPS risk)
- Atypical antipsychotics -- clozapine, olanzapine have broader receptor profiles with lower D2 occupancy
- MAO-B inhibitors -- selegiline, rasagiline reduce dopamine degradation
Key Takeaways
- Four major dopaminergic pathways serve distinct functions
- D2 receptor antagonism is the basis of antipsychotic efficacy and parkinsonian side effects
- Parkinson's therapy centers on restoring dopaminergic tone in the nigrostriatal pathway
- DAT is a major target for psychostimulants and drugs of abuse