Alpha-methyl tyrosine (~-MT) has been shown in vitro (NAGATSU et al., 1964) and in vivo in rat and guinea pig (Sev.cTo~ et aI., 1965a; WV, ISSMAN and Ko~, 1965; MAIT~]~, 1965; Moog]~, 1966; R]~cH et at., 1966) to be a potent and specific competitive inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine (DA) and noradrenaline (NA). The same is true of the methylester hydrochloride of ~-MT (H 44/68), as has been demonstrated in cats, rats and mice (HANso~, 1965; COm~ODI and HANSON, 1966). UDENFI~IE~D et al. (1965) found 3-iodo tyrosine to be much more active than c~-MT in vitro, in vivo the activity was quite reduced a phenomenon, which was related to a rapid dehalogenation (SPEcrog et al., 1965b). ~-MT is by itself a substrate of tyrosine hydroxylase and the conversion by hydroxylation to a-methyl-DOPA is not negligible (MAIT~V,, 1965; UDEN]~IE~ -D et al., 1966). This compound interferes with the synthesis via enzymatic inhibition in the formation of catecholamines (CA) (for review see SOURKES, 1965; MVSCHOLL, 1966). Further, ~-methyl-DOPA is decarboxylated to ~-methyl-DA and fl-hydroxylated to ~-methyl-NA, which both deplete the monoamine neurons of the natural CA by displacement (CA~LSSON and Lr~DQVlSr, 1962). The ~-methylated amines work as false transmirrors, but their central behavioural effect seems to be low (HAnsoN and HEN~r~G, 1967). H 44/68, the methylester hydrochloride of ~-MT, is probably hydrolyzed in vivo by esterase to form the corresponding amino acid (CoI~ODI, unpublished), and thus the foregoing argument is true also of this drug. However, 3,cr tyrosine ~ is not converted to displacing amines (CoRI~ODI, unpublished) and is consequently a more convenient tool for studying the pure functional significance of the inhibition of tyrosine hydroxylase, lq[ 59/64 has been shown to be a potent inhibitor of the latter enzyme in vitro (l~oss, unpublished) and in vivo by Fuxv, and MALMFORS (unpublished). The present study was designed to evaluate the effects of H 59/64 in comparison with those of H 44/68 on the brain CA levels and a negatively reinforced, conditioned avoidance response (CAR) in rat and cat.
1 The compound generously supplied by Hassle Ltd., Gbteborg, Sweden, in the form of 3,ce-dimethyl tyrosine methylester-HC1 (H 59/64).