There are several dopamine-containing pathways in the CNS. The nigrostriatal dopamine pathway accounts for approximately 70% of the dopamine in the brain. Cells bodies in this pathway are located in the substantia nigra pars compacta and project to the caudate, putamen, and the globus pallidus (Fig. 1). An interesting characteristic of these dopamine neurons is that they contain extensive dendritic trees, which extend ventrally into the substantia nigra pars reticu-lata. Dopamine release occurs from these dendrites in addition to the axon terminals. Deterioration of the nigrostriatal pathway underlies Parkinson's disease (PD).
The mesocorticolimbic dopaminergic pathway originates in the ventrotegmental area (VTA) and innervates the olfactory tubercle, nucleus accumbens, septum, amygdala, and adjacent cortical structures (medial frontal, anterior cingulate, entorhinal, peri-rhinal, and piriform cortet pallidus) (Fig. 1).
The substantia nigra and VTA dopamine cell bodies are often referred to as the A-9 and A-10 nuclear groups, respectively, following the original designation of Dahlsstrom and Fuxe from their pioneering rodent studies using a novel technique that made dopamine neurons fluorescent. However, more detailed immunohistochemical studies suggest that the A-9 and A-10 nuclear groups are a continuum, with laterally situated cells innervating the striatum and medial cells innervating mesolimbic and meso-cortical areas.
The tuberoinfundibular dopamine pathway originates in the arcuate and periventricular nuclei of the hypothalamus and projects to the intermediate lobe of the pituitary and the median eminence. Dopamine released from these neurons is secreted into the hypophysed and portal blood regulates prolactin secretion from the pituitary through inhibitory D2 receptor on nanotrophic cells.
Other pathways containing dopamine include (i) the incertohypothalamic neurons, which connect the dorsal and posterior hypothalamus with the dorsal anterior hypothalamus and lateral septal nuclei; (ii) the medullary periventricular group, which includes dopamine cells of the dorsal motor nucleus of the vagus nerve, the nucleus tractus solitarius, and the tegmentum radiation in the periaqueductal gray matter; (iii) the interplexiform amacrine-like neurons, which link the inner and outer plexiform layers of the retina; and (iv) the periglomerular dopamine cells in the olfactory bulb, which link mitral cell dendrites in adjacent glomeruli.
In dopamine-secreting cells, the first step in dopamine synthesis is the conversion of dietary tyrosine into l-3,4-dihydroxyphenylalanine (l-DOPA) (Fig. 2). This reaction is catalyzed by the rate-limiting enzyme tyrosine hydroxylase (TH). l-DOPA is then converted to dopamine via the enzyme l-aromatic amino acid decarboxylase.
TH is composed of four identical subunits and contains iron ions, which are required for its activity. The cofactors oxygen and tetrahydrobiopterin are also required for its activity. A single gene encodes TH, although in humans four isoforms have been shown to result from alternative splicing of the primary transcript. TH is present in both soluble (cytoplasmic) and membrane-bound forms.
Under basal conditions TH is nearly saturated by-tyrosine. The observation that pharmacological agents
known to block TH activity have greater effects on extracellular dopamine levels than agents that block dopa-decarboxylase indicates that the rate-limiting step for dopamine synthesis is tyrosine hydroxylation of tyrosine to l-DOPA by TH. Thus, increasing levels of tyrosine by dietary modifications may also regulate dopamine synthesis.
The conversion of l-DOPA to dopamine by dopamine b-hydroxylase results from the removal of a hydroxyl group and requires pyridoxal 5-phosphate (vitamin B6) as a cofactor.
Dopamine synthesis is regulated in a variety of ways. End product inhibition is the major regulator when dopamine neuronal activity and release are low. In contrast, when dopaminergic fibers are electrically stimulated, TH activity is increased. This increase appears to be a function of enhanced enzyme substrate kinetics, in part caused by TH phosphorylation. This results in a net decrease in affinity of TH for dopamine, which overrides end product inhibition.
B. Storage and Release
There are two release mechanisms for dopamine. The first is calcium-dependent, tetrodotoxin (TTX)-sensi-
tive, vesicular release at the axon terminal that occurs following an action potential. The second is calcium and TTX independent and occurs following the administration of stimulant drugs that reverse the direction of the dopamine transporter (DAT). Under normal, nondrug conditions the DAT carries released dopamine from the extrasynaptic space back into the terminal region.
Pharmacological studies indicate that dopamine exists in three pools or compartments within the axon terminal. Two of these are vesicular dopamine stores, one containing newly synthesized dopamine and the second containing a longer term store of dopamine. A cytoplasmic pool has also been identified, and it consists of dopamine newly taken up by the dopamine transporter.
Dopamine inactivation is accomplished by a combination of reuptake and enzymatic catabolism. Dopamine uptake is an energy-dependent process that requires sodium and chloride. Catabolism occurs through two enzymatic pathways (Fig. 3). Although it is not clear how much dopamine is catabolized in each of these
pathways in the human brain, almost 90% of catabo-lism in the rat striatum takes place via the monoamine oxidase (MAO) pathway. In the rat, the level of 3,4-dihydroxylphenylacetic acid is thought to reflect catabolism of intraneuronal dopamine, which includes dopamine that is taken back up by the dopamine transporter, whereas 3-methoxytyramine levels are thought to reflect metabolism of extracellular dopa-mine. Cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) are often used as an indicator of dopaminergic activity in humans.
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