IN VIVO INHIBITION OF DOPAMINE -HYDROXYLASE BY 1-PHENYL-3-(2-THIAZOLYL)-2-THIOUREA (U-14,624)

¹ Central Nervous System Research, The Upjohn Company, Kalamazoo, Michigan

Inhibition of dopamine -hydroxylase by U-14,624 results in a specific depletion of norepinephrine (NE) in both mouse brain and rat brain. A single dose of 25 mg/kg significantly reduced brain NE in both species. Maximum depletion of mouse brain NE, to less than 20% of control levels, was detected 18 hours after U-14,624, 200 mg/kg. NE levels returned to control level by 48 hours. Rat brain NE was lowered to approximately 10% of control 18 hours after U-14,624, 200 mg/kg, and brain NE concentrations were not fully restored after 24 hours. Although the initial fall in mouse brain NE was accompanied by a marked increase in brain dopamine (DA), brain DA levels in both species were at control levels or only slightly elevated at times of maximal NE depletion. Pretreatment of rats with U-14,624 slowed the incorporation of tyrosine-C¹⁴ into NE. The effectiveness of the block in the synthesis of endogenous NE was also demonstrated by the accumulation of DA resulting from 1) loading rats with L-dopa and 2) monoamine oxidase inhibition. NE levels were not changed concurrently with the increases in DA. Although U-14,624 did not deplete myocardial NE levels upon acute or chronic administration, it did block the in vivo synthesis of NE from exogenous DA in rat hearts depleted of NE by metaraminol. However, U-14,624 effectively lowered myocardial NE stores in adrenalectomized rats within six hours. The decrease in heart NE was very likely due to inhibition of NE synthesis, since U-14,624 did not alter the uptake or retention of H³-NE, nor did it release the amine from mouse heart