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Dopamine | nature, metabolism and re-uptake

Studies into the regulation of the dopamine (DA) system and its postsynaptic actions are often stymied by of actions that this neurotransmitter can produce. Thus, DA has been found to exert actions on the neurons it innervates both directly and via G-protein–coupled receptors.
DA plays multiple functions in the brain

Moreover, this transmitter can modulate afferent input within these target regions, as well as alter intercellular communication via its actions on gap junctions. Finally, DA can potently modulate its own dynamics, acting via autoreceptors on DA nerve terminals and on DA neuron somata.

Dopamine (DA) is a neuromodulator that originates from small groups of neurons in the mesencephalon (the ventral tegmental area (A10), the substantia nigra (A9) and A8) and in the diencephalon (area A13, A14 and A15). Dopaminergic projections are in general very diffuse and reach large portions of the brain. The time scales of dopamine actions are diverse from few hundreds of milliseconds to several hours.

DA plays multiple functions in the brain. Calabresi et al. reported the role of DA in the modulation of behavior and cognition; voluntary movement; motivation; punishment and reward; inhibition of prolactin production; sleep; dreaming; mood; attention; working memory; and learning.

DA can be a precursor in the biosynthesis of other related catecholamines such as norepinephrine and epinephrine. Norepinephrine is synthesized from DA by the catalytic action of DA-hydroxylase in the presence of Lascorbic acid and molecular oxygen (O2). Norepinephrine then acted upon by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine (SAMe) as a cofactor to produce epinephrine.

Dopamine Receptors

In the synapse, DA binds to either postsynaptic or presynaptic DA receptors or both. This bond, regardless of the receptor, generates an electric potential in the presynaptic cell In the case of postsynaptic DA receptors, the signal is propagated to the postsynaptic neuron, while, in the case of presynaptic DA receptors, the signal can either excite the presynaptic cell or inhibit it.

Presynaptic receptors with an inhibitory potential, also known as auto receptors, inhibit the synthesis and release of neurotransmitters and thus function to maintain normal levels of DA. After carrying out its synaptic function, DA is taken up again into the cytosol by presynaptic cells through the actions of either high-affinity DA transporters (DAT) or low-affinity plasma membrane monoamine transporters.

Once in the synaptic neuron, amphetamine exercises a reverse influence on the action of DA transporters (DAT) and forces DA molecules out of storage vesicles and into the synaptic gap.The DA transporter is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal DA in the brain. The DA now in the cytosol is then repackaged into vesicles by the action of vesicular monoamine transport, VMAT2

Metabolism of DA

The enzymatic breakdown of DA to its inactive metabolites is carried out by catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO). This degradative action can be performed by the MAO isoforms MAO-A and MAO-B. It should be noted that COMT is predominantly expressed by glial cells. In neurons, this enzyme is either missing or found at very low levels. MAO-B is mainly found in astrocytes, whereas MAO-A predominates in catecholaminergic neurons like the cells of the SN. MAO breaks down dopamine to 3, 4-dihydroxyphenylacetaldehyde (DOPAL), which in turn is degraded to form 3, 4-dihydroxyphenylacetic acid (DOPAC) by the action of the enzyme aldehyde dehydrogenase

Another pathway for the metabolism of DA involves the enzyme COMT, which converts it to 3-methoxytyramine (3-MT). Then, 3-MT is reduced by MAO to HVA and eliminated in the urine. As a result, the inhibition of monoamine oxidase has been considered as an adjunctive therapy in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (PD). However, MAO inhibitors are used to increase DA levels and not to decrease hydrogen peroxide production.

The Reuptake

DA reuptake can be inhibited by cocaine and amphetamines, but each has a different mechanism of action. Cocaine is a DA transporter and norepinephrine transporter blocker. It inhibits the uptake of DA, which results in an increase in DA lifetime, thereby producing an overabundance. Disruptions in these mechanisms following chronic cocaine use contribute to addiction, due, in part, to the unique architecture of themesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at extrasynaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus induces long-lasting maladaptive plasticity

Dopamine and Parkinson’s disease

The loss of the dopamine neurons in the mid-brain of the human brain is the main feature of Parkinson’s disease. Approximately 50%-60% of the dopamine neurons are damaged, when a person is detected with Parkinson’s disease. These dopamine neurons, present in the substantia nigra of the mid-brain, releases a neurotransmitter known as dopamine which is circulated into different areas of the brain. The primary regions of this neurotransmitter are the Putamen and the Caudate nucleus. 

The long projections of the dopamine neurons called axons, extends the brain to the putamen and caudate nucleus. In Parkinson’s disease these axon extensions that project to the putamen and caudate nucleus gradually disappear. It occurs due to the disappearance of the dopamine neurons of the substantia nigra. As a result, the amount of activity in the indirect pathway increases and the thalamus is kept inhibited. Due to this condition of the thalamus, the overlying motor cortex has trouble in getting excited. The motor system is unable to work properly and hence, a person with Parkinson’s disease has trouble in movement of their limbs.

The loss of dopamine-containing neurons in the midbrain affects different parts of the nigral complex up to various levels. This loss increases with disease progression. The most severe loss occurs in the ventrolateral part of the substantia nigra pars compacta. In-debt knowledge of the patterns of depletion of dopamine-containing neurons in Parkinson’s disease is crucial to understand its pathogenesis. Ron levy worked on high- frequency oscillations (HFO) at 15-30 Hz and explored how HFOs are modulated by voluntary movements and by dopaminergic medication. 

The clinical trial of transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson’s disease has proved to be very much beneficial for all the clinicians and researchers working on this neurodegenerative disorder. However, this intervention would be more effective than sham surgery in a controlled trial is yet to be explored.


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