Dopamine is a catelcholamine and acts as a neurotransmitter activating dopamine receptors of which five types exist with D1 and D2 predominating. Aside from functioning as a neurotransmitter, dopamine is also the precursor to noradrenaline in all central and peripheral noradrenergic neurons. Dopamine is made from the precursor Tyrosine which is converted to DOPA by the enzyme tyrosine hydroxylase, and DOPA is then converted to dopamine by the enzyme dopa decarboxylase. This enzyme has a much higher activity in comparison to tyrosine hydroxylase so under normal conditions there is little or no endogenous DOPA found in most cells.
The first line of treatment for a patient is to replenish their dopamine stores, which have diminished due to loss of dopaminergic neurones. As dopamine cannot cross the blood-brain barrier it is of no use to simply administer dopamine, instead its precursor L-DOPA is given. This is able to cross the blood-brain barrier upon which it is then converted to dopamine by aromatic amino acid decarboxylase. However L-DOPA can also be converted to dopamine in the periphery, which can cause unwanted effects and so to prevent this a decarboxylase inhibitor is given. Not only does this reduce adverse effects but also lowers the effective dose.
Dopamine is rapidly taken up into storage vesicles by an energy-dependent transporter-mediated process, achieving high local concentrations within the storage vesicles by complexing with adenosine triphosphate and vesicular proteins. This mechanism can be impaired by reserpine, which depletes presynaptic storage of dopamine by binding with high affinity to the vesicular monamine transporter (VMAT), preventing the incorporation of monoamines into storage vesicles. The terminals cannot concentrate or store amines and so the amines leak out and are deaminated by monamine oxidase, which is found attached to the membrane of intraneuronal mitochondria. It has been shown that compounds that release dopamine from vesicular stores are less active in the presence of reserpine whereas compounds that release dopamine from cytoplasmic stores are unaffected.
Once dopamine is released from the neuron, it is removed from the synaptic extracellular space by a transporter protein located in the presynaptic membrane. This transporter helps to control the extracellular concentration of dopamine. However, amphetamines can disrupt this process as they are similar in structure to dopamine, and so can enter the terminal button of the presynaptic neuron via its dopamine transporters.
They are also capable of diffusing through the neural membrane directly. Once inside the presynaptic neuron, amphetamines force the dopamine molecules out of their storage vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse. This results in a large concentration of dopamine in the cytoplasm.
