Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels

Abstract

The relationship between limited tyrosine availability, DA (dopamine) synthesis and DA levels in the medial prefrontal cortex (MPFC) of the rat was examined by in vivo microdialysis. We administered a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA(−)) IP to lower brain tyrosine, and the norepinephrine transporter inhibitor desipramine (DMI) 10 mg/kg IP to raise MPFC DA levels without affecting DA synthesis. For examination of DOPA levels, NSD-1015 20 μM was included in perfusate. Neither NSD-1015 nor DMI affected tyrosine levels. LNAA(−) lowered tyrosine levels by 45%, and lowered DOPA levels as well; this was not additionally affected by concurrent DMI 10 mg/kg IP. In parallel studies DMI markedly increased extracellular levels of DA (420% baseline) and norepinephrine (NE) (864% baseline). LNAA(−) had no effect on baseline levels of DA or NE but robustly lowered DMI-induced DA (176% baseline) as well as NE (237% baseline) levels. Even when DMI (20 μM) was administered in perfusate, LNAA(−) still lowered DMI-induced DA and NE levels. We conclude that while baseline mesocortical DA synthesis is indeed dependent on tyrosine availability, the MPFC maintains normal extracellular DA and NA levels in the face of moderately lower DA synthesis. During other than baseline conditions, however, tyrosine depletion can lower ECF DA and NE levels in MPFC. These data offer a potential mechanism linking dysregulation of tyrosine transport and cognitive deficits in schizophrenia.