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