Increased tyrosine availability increases brain regional DOPA levels in vivo

Tyrosine hydroxylation is considered to be the rate-limiting step in catecholamine synthesis. It is also assumed that under usual conditions, tyrosine 3-monooxygenase (EC 1.14.16.2) (tyrosine hydroxylase - TH) is close to full saturation with its l-tyrosine substrate and hence that raising the availability of l-tyrosine does not substantially increase 3,4-dihydroxyphenylalanine (DOPA) synthesis. We evaluated this in vivo by reverse dialysis of the aromatic-l-amino-acid decarboxylase (EC 4.1.1.28) inhibitor NSD-1015 (20μM) and selected concentrations of l- or d-tyrosine. In striatum, extracellular DOPA levels increased linearly (maximum 250% control) as l-tyrosine concentrations were raised from 0-1000μM. In medial prefrontal cortex, DOPA levels reached a maximum (300% control) at l-tyrosine 62.5-125μM but still remained significantly elevated (200% control) at higher l-tyrosine concentrations (250-500μM). At the l-tyrosine concentrations tested, DOPA levels were never below those of controls. d-tyrosine (62.5μM) did not affect DOPA levels. The degree to which the elevation of DOPA levels represents a net increase in tyrosine hydroxylation as opposed to heteroexchange of l-TYR for intracellular DOPA remains to be determined. However, one interpretation of the data is that under usual in vivo conditions brain TH may not be near full saturation with l-tyrosine and that mechanisms other than tyrosine hydroxylation may be more important in the acute regulation of brain catecholamine synthesis than previously appreciated. This would have implications for the pathophysiology and treatment of neuropsychiatric conditions in which dysregulation of DA transmission and l-tyrosine transport have been implicated.