In vivo regulation of DOPA decarboxylase by dopamine receptors in rat brain

To test the hypothesis that dopamine (DA) receptors influence cerebral DOPA-decarboxylase (DDC) activity in vivo, we used HPLC to measure the kinetics of the cerebral uptake and metabolism of [³H]DOPA in carbidopa- treated rats, and in rats also treated acutely with a DA receptor antagonist (flupenthixol, 2 mg/kg, intraperitoneally) or a DA receptor agonist (apomorphine, 200 μg/g, subcutaneously). The unidirectional blood-brain clearance of [³H]DOPA (K₁(DOPA), 0.030 mL g^-1 min^-1) increased by 50% after flupenthixol. The magnitudes of the relative DDC activity (k₃(DOPA) in striatum (0.20 min^-1), olfactory tubercle (0.11 min^-1), and hypothalamus (0.15 min^-1) of carbidopa-treated rats were doubled with flupenthixol, but conical DDC activity was unaffected (0.02 min^-1). Apomorphine reduced the magnitude of k₃(DOPA) in striatum by 20%. The rate constant for catabolism of [³H]DA formed in brain (k₇', monoamine oxidase [MAO] activity), which ranged from 0.025 min^-1 in striatum to 0.08 min^-1 in hypothalamus of carbidopa-treated rats, globally increased 2- to 4-fold after flupenthixol, and decreased to 0.003 min^-1 in striatum after apomorphine. These in vivo results confirm the claim that acute blockade of DA receptors with flupenthixol stimulates the synthesis of [³H]DA from [³H]DOPA, and that this [³H]DA is subject to accelerated catabolism. Conversely, activation of the DA receptors with apomorphine inhibits DDC activity and DA catabolism.