Dopamine. Dopamine is both a neurotransmitter and a precursor of the neurotransmitters epinephrine and norepinephrine. Dopamine is synthesized from the amino acid tyrosine, which is transported across the blood-brain barrier and taken up by dopaminergic neurons. In the first and rate-limiting step in dopamine synthesis, the enzyme tyrosine hydroxylase (TH) converts tyrosine to 3,4-dihydroxy-L-phenylalanine (l-DOPA). l-DOPA, in turn, is converted into dopamine by L-aromatic amino acid decarboxylase. Because the levels of tyrosine in the brain normally exceed the processing capacity of TH, increasing the availability of tyrosine in the brain does not significantly increase dopamine synthesis. Instead, the amount and activity of TH determine the rate of dopamine biosynthesis.
As the rate-limiting step, TH is a key target for pharmacologic modulation of dopamine availability in the brain. For example, the tyrosine analog a-methylparatyrosine competes with tyrosine as a substrate for T and thereby reduces or prevents dopamine synthesis.
Dopamine is released from presynaptic nerve terminals upon cell membrane depolarization. The amount of release depends on the rate and pattern of neuronal firing and can be modulated by extracellular dopamine. Dopaminergic terminals contain high-affinity sodium- and chloride-dependent dopamine transporters (DAT), which function to actively pump extracellular dopamine back into the nerve terminal. As with adenosine, the transport of dopamine across neuronal membranes is bidirectional, depending on the concentration gradient. Dopamine autoreceptors are present on soma, dendrites, and the nerve terminals of most dopamine neurons and negatively regulate dopamine release. These autoreceptors are categorized as D2R and are coupled to Gi.
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Stimulation of autoreceptors in the somatodendritic region of the neuron reduces the firing rate of dopamine neurons, whereas stimulation of autoreceptors on terminals inhibits dopamine release.
As the rate-limiting step, TH is a key target for pharmacologic modulation of dopamine availability in the brain. For example, the tyrosine analog a-methylparatyrosine competes with tyrosine as a substrate for T and thereby reduces or prevents dopamine synthesis.
Dopamine is released from presynaptic nerve terminals upon cell membrane depolarization. The amount of release depends on the rate and pattern of neuronal firing and can be modulated by extracellular dopamine. Dopaminergic terminals contain high-affinity sodium- and chloride-dependent dopamine transporters (DAT), which function to actively pump extracellular dopamine back into the nerve terminal. As with adenosine, the transport of dopamine across neuronal membranes is bidirectional, depending on the concentration gradient. Dopamine autoreceptors are present on soma, dendrites, and the nerve terminals of most dopamine neurons and negatively regulate dopamine release. These autoreceptors are categorized as D2R and are coupled to Gi.
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Stimulation of autoreceptors in the somatodendritic region of the neuron reduces the firing rate of dopamine neurons, whereas stimulation of autoreceptors on terminals inhibits dopamine release.
Figure 4. Dopamine and adenosine receptor interactions in striatum.
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