central brain structures showing specific DA receptors. Approximately 80% of DA
receptors in the brain are localized in the corpus striatum, which receives major input
from the substantia nigra and participates in coordinating motor movements.
Additional DA receptors are found diffusely throughout the brain cortex. DA has there-
fore been identified as a fully-fledged neurotransmitter. Because of DA’s crucial
involvement in psychosis and its proven role in neurological movement disorders such
as Parkinson’s disease, dopaminergic drugs are the subject of very active research.
Furthermore, in large doses, DA can also act on peripheral vascular α 1 adrenoceptors
and cardiac β 1 receptors, but it has its own receptors in several vascular (arterial) beds,
where its effect is not inhibited by the β-blocker propanolol (4.63).
4.4.1 Dopamine Metabolism and ReceptorsDopamine metabolism was covered in the discussion of general catecholamine bio-
chemistry. Dopamine is stored in synaptic vesicles, and this storage can be manipulated.
Although the reuptake of released DA is the major deactivating mechanism, MAO and
COMT act enzymatically on DA in the same way as on NE. However, following the
degradative pathway of NE, DA will finally be metabolized to homovanillic acid
(3-methoxy-4-hydroxy-phenylacetic acid), since it lacks the β-hydroxyl group.
The dopamine receptors have been studied extensively by classical pharmacological
methods, receptor labeling techniques, and gene cloning experiments. These experi-
ments have revealed that, as with most neurotransmitters, several DA receptor popula-
tions exist. In the brain, DA receptors are located both pre- and postsynaptically. Five
subtypes of DA receptors can be grouped into two main classes: D1-like and D2-like.
There are a number of distinctions between these two classes of receptors. D1-like
receptors activate adenylate cyclase; D2-like receptors inhibit adenylate cyclase. The
D1-like receptors, like the β-adrenergic receptors, are transcribed from intronless
genes. Conversely, the D2-like receptors contain introns, thus providing an opportunity
for alternatively spliced products. In terms of molecular mass, D1-like receptors are
slightly larger than D2-like receptors. D1-like subtypes include the D1 (encoded on
chromosome 5) and D5 (chromosome 4) receptors; D2-like subtypes include the
D2 (chromosome 11), D3 (chromosome 3), and D4 (chromosome 11) receptors. The
primary amino acid sequence for the entire DA receptor class ranges from 387 residues
for D4 to 477 for D5. D2-like receptors have smaller C-terminal intracellular segments
but a larger intracellular loop between the sixth and seventh transmembrane segments.
Two D2 receptor isoforms have been identified: D2 long and D2 short—D2 long has a
29 amino acid insert between the fifth and sixth membrane-spanning segments.
A strong correlation exists between the clinical doses of antipsychotic drugs and their
affinity for brain D2 receptors. This observation led to the hypothesis that psychotic dis-
orders resulted from overactivity of the D2 receptor subpopulation. The relative affini-
ties of D2, D3, and D4 receptors for typical (haloperidol, chlorpromazine) and atypical
(clozapine) antipsychotic molecules, together with the selective expression of D3
receptor mRNA in brain limbic areas, has led to the additional hypothesis that success-
ful agents for psychiatric illness should also have the ability to antagonize stimulation
of D3 or D4 receptors. Finally, long-term administration of antipsychotic agents leads
to an increased density of D2 receptors in the basal ganglia region of the brain, causing
NEUROTRANSMITTERS AND THEIR RECEPTORS 239