Dopamine synthesis

Genetic disruption of dopamine synthesis in mice lacking TH shows that dopamine is not essential for development. However, dopamine deficient mice do not survive long after weaning unless treated with l-DOPA. These mice display severe aphagia and adipsia and loss of motor function. While these mice have a major reduction in dopamine levels some residual dopamine can be detected that is generated through the action of tyrosinases. 

There are few reports on the effects of nitrous oxide on dopaminergic neurotransmission. A study in mice showed that nitrous oxide inhalation produced a significant increase in locomotor activity that was antagonized in a dose-dependent fashion by the dopamine synthesis inhibitor a-methyl-/)-tyrosine (Hynes and Berkowitz 1983). Moreover, administration of the D2 antagonist haloperidol also reduced the locomotor activity induced by nitrous oxide (Hynes and Berkowitz 1983). These results suggest that excitatory effects induced by nitrous oxide may be also mediated by dopaminergic neurotransmission. However, other studies have reported that exposure to nitrous oxide resulted in decreased dopamine release by neurons in the striatum (Balon et al. 2002 Turle et al. 1998). 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

Trulson, ME., and Ulissey. J.J. Chronic cocaine administration decreases dopamine synthesis rate and increases [ H] spiroperidol binding in rat brain. Brain Res Bull 19 35-38, 1987. 

Kogan, F.J., and Gibb, J.W. Influence of dopamine synthesis on methamphetamine-induced changes in striatal and adrenal tyrosine hydroxylase activity. N-S Arch Pharmacol 310 185-187, 1979. 

Figure 7.1 Schematic of the prototypical dopaminergic synapse. Pre- and post-synaptic components of a dopaminergic synapse summarizing molecular pathways for dopamine synthesis, metabolism, and second messenger effects following Dl-like or D2-like receptor activation. (See also Plate 6.)...

Spampinato, U., Espisito, E., and Samainin, R., Serotonin agonists reduce dopamine synthesis in the striatum only when the impulse flow of nigro-striatal neurons is intact, J. Neurochem., 45, 980, 1985. 

Tsukada H., Harada N., Nishiyama S., Ohba H., Kakiuchi T. Dose-response and duration effects of acute administrations of cocaine and GBR 12909 on dopamine synthesis and transporter in the conscious monkey brain PET studies combined with microdialysis. Brain Res. 860 141, 2000. 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

These patients suffer from a genetic defect of dopamine synthesis, caused by reduced GTP cyclohydrolase activity. This enzyme is rate-limiting in the biosynthesis of tetra-hydrobiopterin, a cofactor of the dopamine-synthesizing enzyme tyrosine hydroxylase (see Fig. 40-2). 

Waldmeier, P. C. (1991) The GABAb antagonist, CGP 35348, antagonizes the effects of baclofen, gamma-butyrolactone and HA 966 on rat striatal dopamine synthesis. Naunyn Schmiedebergs Arch. Pharmacol. 343,173-178. 

These enable a logical, mechanistic understanding and will be discussed individually. 4.4.2.1 Dopamine Synthesis Inhibitors... 

Dopamine synthesis inhibitors interfere with the enzymes involved, and are identical to those discussed in section 4.3.5 (e.g., a-methyltyrosine (4.74), a tyrosine hydroxylase inhibitor). In this case, aj-adrenergic receptor effects are irrelevant, and only the classical competitive inhibitory effect is of any consequence. 

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