Inhibition of striatal tyrosine hydroxylase by low concentrations of apomorphine

The inhibitory effect of apomorphine on tyrosine hydroxylase (TH) was tested using enzyme preparations from rat striatum, neuroblastoma clone N1E-115 and pheochromocytoma clone PC-12. When the striatal enzyme preparation was incubated at pH 7.2 with (6R,S)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) as cofactor (100-1,000 mumol/l), the IC50 for apomorphine was found to be in the 0.1-1 mumol/l range depending on the BH4-concentration used. Changing the incubation medium to pH 6.0 yielded an IC50 of about 2.5 mumol/l (BH4 = 100 mumol/l). Apomorphine was even less effective when 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine (100 mumol/l) was used as cofactor (IC50 approximately 10 mumol/l). Similar results were obtained with the enzyme preparations of the two cell clones. These experiments show that, even in low concentrations, apomorphine inhibits TH directly, provided more physiological test conditions are used. The relevance of these results for the autoreceptor-mediated mechanism of the apomorphine action on catecholamine synthesis is discussed.