Giovanni Umberto Corsini

Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism

TRYPTOPHAN (Try) is the only amino acid circulating in plasma which is bound to serum proteins (MCMENAMY & ONCLEY, 1958). Previous studies from our (TAGLIAMONTE et al., 1971a; GESSA et al., 1972; TAGLIAMONTE et al., 1973a; 1973b) and Curzons laboratories (KNOTT & CURZON, 1972) have shown that the concentration of free Try in serum parallels in many instances the concentration of Try in brain which, in turn, parallels the synthesis rate of brain serotonin (TAGLIAMONTE et al., 1971~; TAGLIAMONTE, et al., 1971b). On the other hand, studies on transport of amino acids from blood to brain on uptake of amino acids by brain slices GUROFF & UDENFRIEND, 1962; OLDENWRF, 1971; &HEN & LAJTHA, 1972) or synaptosomes (GRAHAME-SMITH & PARFITT, 1970) have shown that many of the aromatic acids share the same transport mechanism from blood to brain and that a high concentration of one can lower the uptake or transport of others. These considerations suggest that Try concentration in brain may depend not only on the concentration of free serumTry but also, as suggested by FERNSTROM & WURTMAN (1971), on the plasma concentration of the other amino acids competing for the same transport mechanism. In order to test this hypothesis, we studied the effect of the intragastric administration of different amino acid mixtures not containing Try, on brain Try level and serotonin metabolism. Results show that certain amino acid combinations produce a dramatic fall in Try, serotonin and 5-h ydroxyindoleacetic acid in brain and in free and total Try in serum. MATERIALS AND METHODS

SELECTIVE INCREASE OF BRAIN DOPAMINE SYNTHESIS BY SULPIRIDE

—Sulpiride (5–200 mg/kg) increases brain HVA and DOPAC levels, causes no change in dopamine concentration, does not interfere with the outflow of HVA from the CNS and enhances the disappearance of brain dopamine after inhibition of tyrosine hydroxylase. The compound influences neither 5‐HT nor NE metabolism. The central action of sulpiride differs from that of classic neuroleptics in that this drug stimulates dopamine turnover without producing catalepsy.

Decreased conversion of tyrosine to catecholamines in the brain of rats treated with p‐chlorophenylalanine

Repeated treatment with p‐chlorophenylalanine (100 mg kg−1) daily for 5 days impairs the transport of amino‐acids from plasma into the brain and decreases the rate of conversion of [3H]tyrosine to [3H] catecholamines in the rat brain. The possible mechanisms involved are discussed.

Effect of estrogens on dopamine autoreceptors in male rats.

There is biochemical and pharmacological evidence indicating that estrogens are capable of substantially modulating post-synaptic dopamine (DA) receptor sensitivity in experimental animals. Recent electrophysiological data, showing that estrogens significantly attenuate the ability of apomorphine to inhibit the firing activity of type B dopamine neurons in the rat substantia nigra, suggest that these hormones may also induce subsensitivity of DA autoreceptors. In accord with this hypothesis, estrogen-treated rats showed no marked decrease of motility counts when challenged with apomorphine (20-50 micrograms/kg) from 24 to 72 h after the last hormone administration. Similarly, the decrease of dihydroxyphenylacetic acid (DOPAC) levels induced by apomorphine (20 micrograms/kg) in the caudate nucleus, in oil-treated control rats was almost completely counteracted by estrogen treatment. Dopamine agonists, such as 2-alpha-bromocriptine, piribedil, 3 hydroxyphenylpropylpiperidine and n-propylnorapomorphine, failed to induce hypomotility when administered to estrogen-treated rats. These behavioural and biochemical results, along with the electrophysiological data, indicate that estrogen treatment is able to induce hyposensitivity of DA autoreceptors. These results may be relevant to the clinical findings indicating that the activity of dopamine receptor agonists varies in relation to sex or hormonal treatments.

Involvement of monoamine oxidase enzymes in the action of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, a selective neurotoxin, in the squirrel monkey: binding and biochemical studies.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a new neurotoxin that causes degeneration of the dopaminergic nigrostriatal neurons and induces a Parkinson-like state in several species, including humans and monkeys. The present study was designed to better characterize the properties of [3H]MPTP binding sites and to evaluate the interaction of MPTP with the oxidation of dopamine by monoamine oxidase (MAO) in an animal species (Saimiri Sciureus) shown to be lesioned by MPTP. Our data confirm the presence of high affinity and saturable binding sites for [3H]MPTP in the squirrel monkey. Specific binding with analogous characteristics also occurs in peripheral tissues. Various substances failed to inhibit the [3H]MPTP binding, whereas only MAO inhibitors (MAOI) were able to antagonize this binding to brain and peripheral tissues. In particular, deprenyl, a selective inhibitor of MAO type B enzyme, was relatively more potent as a displacer of [3H]MPTP from its binding sites both in brain and in peripheral tissues. Our results further suggest a correspondence between [3H]MPTP sites and MAO, particularly MAO-B, in monkey brain. Moreover, our data show that the oxidative deamination of dopamine is inhibited by MPTP in vitro. In conclusion, these data are consistent with the hypothesis of the involvement of MAO in the neurotoxic effects of MPTP, even though further experiments are necessary to better clarify the molecular mechanism of MPTP neurotoxicity.

Increase of brain homovanillic acid level induced by metoclopramide

Abstract Metoelopramide (1 to 10 mg/kg) increased brain homovanillic acid but not 5-hydroxyindoleacetic acid levels and caused no change in dopamine or norepinephrine concentrations. The metoclopramide-induced elevation of homovanillic acid levels is likely to be the result of an accelerated dopamine turnover. These results, in conjunction with the sedative and cataleptigenic action of this compound, support evidence for a neuroleptic activity of metoclopramide.

High affinity binding sites for 1-methyl-4-phenyl-pyridinium ion (MPP+) are present in mouse brain.

The possible involvement of 1-methyl-4-phenyl-pyridinium ion (MPP+) in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prompted us to search for and characterize [3H]MPP+ binding sites in the mouse. Our data show that [3H]MPP+ binds saturably and with high affinity to mouse brain membranes. Scatchard analysis resulted in one straight line. The apparent KD was 15 +/- 1 nM and the Bmax 245 +/- 30 fmol/mg protein. The distribution of [3H]MPP+ binding sites shows a regional variation: the hypothalamus having highest binding and the cerebellum the lowest. Several compounds failed to inhibit [3H]MPP+ binding whereas only analogues of MPP+, MPTP and paraquat were able to antagonize this binding to brain. Specific binding with analogous characteristics also occurs in peripheral tissues. Considering the postulated role of MPP+ in MPTP neurotoxicity, further studies on [3H]MPP+ binding sites might be relevant to elucidate the mechanisms of this toxicity.

Increased paroxysmal activity of partial seizures in man by apomorphine.

In order to studh the role of dopamine (DA) in the regulation of seizure mechanisms in man, a non-emetic dose of apomorphine, a direct stimulant of DA receptors, was administered to eight patients effected by different types of epilepsy.The EEG changes induced by apomorphine administration in comparison to those elicited by promazine or placebo were evaluated in a double blind cross-over study. Similarly to promazine treatment, apomorphine worsened the EEG recordings of some patients. The apomorphine-induced increase in paroxysmal activity was observed in patients affected by partial epilepsy and was not related to the sleep-inducing properties of the drug.This effect is interpreted as being the result of a stimulation of DA autoreceptors, mediating a decrease of dopaminergic activity in the central nervous system. The use of apomorphine as an EEG activating agent is suggested.

Treatment of Sydenham's chorea with a combination of L-dopa and a peripheral dopa decarboxylase inhibitor.

Two male patients suffering from Sydenhams chorea were treated with a combination of l-Dopa and a peripheral decarboxylase inhibitor. This treatment markedly reduced in one patient and totally suppressed in the other the abnormal involuntary movements present in this disease.

Effects of Copper-chelating Agents and Alcohol-sensitizing Drugs on MPTP-induced Neurotoxicity in Mice

1-Methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages nigrostriatal dopaminergic (DA) neurons in several animal species including mice (Burns et al., 1983; Heikkila et al., 1984a). MPTP biotransformation is essential for the neurotoxic mechanism, as evidenced by the finding that inhibitors of monoamine oxidase (MAO) prevent the MPTP-induced DA-damage in monkeys and mice (Langston et al., 1984; Cohen et al., 1984; Heikkila et al., 1984b).