Neuropharmacology
1 min de lecture
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