Tyrosine hydroxylase, aromatic L-amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (+/-)-SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3 -benzazepine-7, 8-diol) [DA D-1-like]; bromocriptine, [DA D-2 selective]; quinpirole, [DA D-2/D-3 preferring]; (+/-)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D-3/D-2 preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), [DA D-1-like]; and haloperidol, [DA D-2-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic L-amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well. as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D-1-like agonists had no effect on TH or AAAD activity, while D-2-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D-2-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D-1-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D-2-like, but not DA D-1-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinson's patients on L-DOPA therapy. (C) 1999 Elsevier Science B.V. All rights reserved.