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

Abstract

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.