Dopamine

PD is characterized by a progressive loss of dopaminergic function. In addition to controlling movement, dopamine plays roles in behavior and cognition, motivation and reward, sleep, mood, attention, and learning, all of which can be affected in PD. Dopamine receptors are classified based on functional and pharmacological criteria. The D1 receptors show widespread expression in the brain, while the D2 receptors are mainly found in the striatum and nucleus accumbens. The excitatory D1 receptors activate adenylyl cyclase increasing cAMP, while the inhibitory D2 receptors decrease cAMP levels.

Dopamine is a catecholamine derived from L-tyrosine. Tyrosine hydroxylase converts L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), which is then converted to dopamine via DOPA decarboxylase. Further metabolism of dopamine by dopamine beta-hydroxylase produces norepinephrine, which is metabolized to epinephrine by phenylethanolamine N-methyltransferase.

Dopamine transporters are responsible for reuptake of dopamine following release from a presynaptic neuron. Clearance of dopamine from the synapse terminates dopaminergic signaling. The dopamine active transporter (DAT) is the primary synaptic transporter terminating dopamine signaling. The vesicular monoamine transporter (isoforms VMAT1 and VMAT2) loads dopamine (as well as other monoamines) into presynaptic vesicles. Imaging ligands that bind to dopamine transporters has become an important non-invasive measure of dopaminergic function in the brain.

Dopamine is degraded by catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO). Monoamine oxidase degrades dopamine and other monoamines including serotonin, norepinephrine, and epinephrine. Both MAO type A and type B are able to degrade dopamine. Dopamine can also have cytoxic effects: the monoamine oxidase metabolite was found to mediate dopamine's cytotoxic effects (Burke et al., 2003), and likely plays a role in the selective vulnerability of dopamine nigral neurons in Parkinson's disease (Galvin et al., 2006).