MODULATION OF RAT-BRAIN ENDOGENOUS DOPAMINE METABOLISM BY NEW INHIBITORS OF CATECHOL O-METHYLTRANSFERASE

The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/k g), respectively. Additional metabolic effects of two inhibitors of ca techol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake2 inhibitor (CGP 28014 (30 mg/kg)) were a ssessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The latt er two effects were reversed by tolcapone and CGP 28014, but not by en tacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances al so decreased striatal HVA levels. Striatal 3-methoxytyramine levels we re significantly lowered only by tolcapone. Our results show that enha nced central dopamine metabolism is modified by the inhibition of cate chol O-methyltransferase even in the absence of L-3,4-dihydroxyphenyla lanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltr ansferase.