Effects of neuroleptics on striatal tyrosine hydroxylase: changes in affinity for the pteridine cofactor

We assayed tyrosine hydroxylase activity in various brain regions and in adrenal glands of rats receiving reserpine or other neuroleptics which are chemically related to dibenzothiepines (methiothepin), butyrophenones (haloperidol), or diphenylbutylamines (pimozide). These drugs reduced the interaction of brain dopamine with specific postsynaptic receptors by various mechanisms. Intraperitonal administration of haloperidol (24 µmoles/kg), methiothepin (10 µmoles/kg), pimozide (11 µmoles/kg), or reserpine (8 µmoles/kg) increased the affinity of striatal tyrosine hydroxylase for the pteridine cofactors 2-amino-4-hydroxy-6,7-dimethyltetrahydropteridine (DMPH) and 2-amino-4-hydroxy-6-methyltetrahydropteridine (6MPH 4 ) within 30 min. When reserpine or the other neuroleptics were added to striatal enzyme preparations they changed neither the K m for DMPH 4 nor that for 6MPH 4 . A dose of cycloheximide (70 µmoles/kg intraperitoneally) that reduced the rate of brain protein synthesis by about 90% failed to reduce the increased affinity of tyrosine hydroxylase for pteridines elicited by injections of reserpine or methiothepin. Intraperitoneal doses of apomorphine (32 µmoles/kg) or trivastal (70 µmoles/kg) that stimulate brain dopaminergic postjunctional receptors reduced the increased affinity of striatal tyrosine hydroxylase for pteridines produced by injection of methiothepin or reserpine. The injection of haloperidol reduced the K m of the striatal enzyme for DMPH 4 from 0.69 to 0.13 mM but failed to change the K m for tyrosine (0.054 mM). The injection of reserpine also reduced the K m of striatal tyrosine hydroxylase for 6MPH 4 from 0.5 to 0.13 mM. In the same animals the properties of tyrosine hydroxylase from hypothalamus, brain stem, and adrenals were unchanged. Addition of dopamine to striatal tyrosine hydroxylase preparations from rats receiving 0.9% NaCl exhibited sigmoidal kinetics in addition to competitive inhibition of 6MPH 4 binding. The addition of dopamine to preparations of striatal tyrosine hydroxylase from rats receiving reserpine yielded simple competitive inhibition. Since the blockade of dopaminergic receptors by neuroleptics increases the firing rate of dopaminergic neurons, these results suggest that the affinity of striatal tyrosine hydroxylase for the cofactor is enhanced when the activity of dopaminergic neurons is increased.