The inhibition of catecholamine biosynthesis by apomorphine

Apomorphine stimulates the dopamine receptors in the striatum (Ernst, 1967; Ernst & Smelik, 1966; AndCn, Rubenson & others, 1967). More recently, apomorphine was also used in the treatment of parkinsonism (Cotzias, Papavasiliou & others, 1970). Biochemical studies have shown that apomorphine retards the depletion of the central dopamine stores, but not noradrenaline stores, in animals pretreated with tyrosine hydroxylase inhibitors (AndCn & others, 1967). Apomorphine reduces the impulse flow of the dopamine neurons, probably by a negative feedback mechanism arising from dopamine receptor stimulation. But no evidence exists on whether apomorphine has a direct effect on tyrosine hydroxylase activity. Apomorphine contains a catecho1 group and catechols are known to be inhibitors of tyrosine hydroxylase (Nagatsu, Levitt & Udenfriend 1964; Goldstein, Gang & Anagoste, 1967). We have now investigated the effects of apomorphine on tyrosine hydroxylase activity and on dopamine biosynthesis in vitro and in vivo. Male Sprague-Dawley rats, 250-300 g, were decapitated and the striata immediately dissected, sliced and incubated at 37" in Krebs-Henseleit medium. The incubation procedure and the determination of [14C]catecholamines was done as previously described (Goldstein, Ohi & Backstrom, 1970). In some experiments the animals were treated with apomorphine 25 mg/kg subcutaneously and 30 min later [14C]~-tyrosine (U) (6.25 @/rat ; specific activity 450 mCi/mol) was administered intracisternally. Haloperidol (2mg/kg, i.p.) was given 30 min before the apomorphine. Tyrosine hydroxylase activity was measured according to Nagatsu & others (1964). The effects of apomorphine on tyrosine hydroxylase activity at different concentrations of the substrate 2-amino-4-hydroxy-6,7-dimethyltetrahydropteridine (DMPH,) are in Table 1. Apomorphine 10"'~ significantly inhibits tyrosine hydroxylase activity. At lower concentrations of the pteridine the inhibition by apomorphine is more effective. However, at 10-6~, apomorphine does not inhibit significantly tyrosine hydrolyase activity even at low DMPH, concentrations. Apomorphine inhibits effectively the biosynthesis of [14C]dopamine from [14C] tyrosine in slices of rat striatum (Table 2) even at and ~O-'M. Thus, striatal slices are more sensitive to the inhibition of [14C]dopamine biosynthesis by apomorphine than tyrosine hydroxylase preparations obtained either from bovine adrenal glands or from the striatum of rats. The addition of haloperidol to the media in which the striatal slices were incubated did not affect the inhibitory activity of apomorphine. In separate experiments the effects of apomorphine on [14C]catecholamines were investigated after intraventricular injection of [14C]tyrosine. Treatment with apomor-