A. Tagliamonte

Free tryptophan in serum controls brain tryptophan level and serotonin synthesis

Abstract Tryptophan (Try) is the only aminoacid present in plasma bound to serum proteins. The administration of Try to rats increased free and total Try in serum. Changes in free Try were much more pronounced and longer lasting than in total Try. Brain Try and 5-hydroxyindoleacetic acid (5-HIAA) underwent changes, parallel and proportional to the changes in free Try in serum. Rats fasted for 24 hours had higher concentrations of free serum tryptophan, brain tryptophan and 5-HIAA than rats fed for 2 hours. In contrast, total serum tryptophan was lower in fasted than in fed rats. These results indicate that brain tryptophan and serotonin turnover are controlled by free serum tryptophan and that free serum tryptophan levels are independent from total serum tryptophan concentrations.

Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet.

Abstract Rats were trained for 20 days to eat their normal daily meal in a period of 2 hours. On the twentyfirst day they received a diet in which tryptophan was omitted instead of the usual balanced diet. The ingestion of the tryptophan-free diet produced a marked depletion of free serum tryptophan (90%), brain tryptophan (85%), brain 5-HT (58%) and brain 5-HIAA (76%). These changes were almost maximal within 2 hours after food presentation and persisted for more than 24 hours. The mechanism of these changes is discussed.

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

Role of brain monoamines in male sexual behavior

Publisher Summary This chapter describes the role of brain monoamines in male sexual behavior. The effects of p-chlorophenylalanine (PCPA) administration on the homo- and heterosexual behavior are suppressed in rats, rabbits and cats by 5-hydroxytryptophan, the direct precursor of serotonin. This amino acid also abolishes the spontaneous copulatory behavior of normal rats with receptive females. This inhibition is potentiated by inhibitors of extracerebral decarboxylase, suggesting that 5-HTP acts centrally. The monoamineoxidase inhibitor, pargyline, suppresses the spontaneous copulatory behavior of male rats with receptive females at the time when brain serotonin is maximally increased and inhibition, as well as serotonin accumulation, is prevented by PCPA. Marked homosexual mounting behavior has been observed in male rats after other treatments that lower brain serotonin, such as p-chloro-N-methyl-amphetamine and the intraventricular injection of 5,6 dihydroxytryptamine and furthermore, in testosterone-treated male rats, after different inhibitors of serotonin receptors such as mesorgydine, methysergide and Wa 335-BS . Inhibition of heterosexual copulatory behavior has been observed after the administration of LSD which is considered a direct stimulant of central serotonin receptors.

The striatal dopaminergic function is mediated by the inhibition of a nigral, non-dopaminergic neuronal system via a strio-nigral gabaergic pathway

Abstract The unilateral, intranigral administration of muscimol produced a spontaneous circling, contralateral to the injected side, lasting from 90 min to several h, according to the dose (5, 25, 50 ng/s.n.). This contralateral circling was potentiated by haloperidol (0.2 mg/kg) and antagonized by apomorphine. The bilateral injection of muscimol in the s.n. resulted in stereotyped movements which were resistant to haloperidol administration. Moreover, haloperidol (up to 5 mg/kg) failed to produce catalepsy in these bilaterally injected rats. Picrotoxin, injected unilaterally in the nigra in a dose of 20 ng, produced ipsilateral turning, which was potentiated by apomorphine (0.2 mg/kg) and antagonized by haloperidol administered in the contralateral striatum. The bilateral injection of the same dose of picrotoxin induced rigid catalepsy, which was not sensitive to apomorphine treatment (0.20 mg/kg). Both the contralateral turning and the stereotypes induced by the acute, intranigral administration of muscimol were very similar to the chronic effects elicited by intranigral kainic acid (k.a.) observed from 24 h to several days after treatment, a compound that destroys rather selectively the neurons of the pars reticulata. Conversely, the acute effect of the unilateral injection of k.a., which is supposed to be initially stimulatory, recalled the effect of intranigral picrotoxin. The following neuronal model is proposed: the nigral, k.a. sensitive neurons control posture in a manner opposite to striatal dopamine. The function of the nigro-striatal dopamine system is to inhibit these neurons by activating a strio-nigral GABAergic pathway.

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.

EVIDENCE THAT METHADONE BLOCKS DOPAMINE RECEPTORS IN THE BRAIN

Abstract— This study has shown that methadone shares with phenothiazine and butyro‐phenoneneuroleptics several pharmacological and biochemical actions:thus, D,L‐methadone causes catalepsy and hypothermia, blocks apomorphine‐induced gnawing, increases brain homovanillic acid levels and stimulates brain dopamine synthesis. The dextro isomer of methadone is inactive. α‐Methyl‐tyrosine potentiates and apomorphine reverses methadone‐induced catalepsy. The data suggest that methadone, like butyrophenone and phenothiazine neuroleptics, blocks dopamine receptors in brain.

Intranigral kainic acid: evidence for nigral non-dopaminergic neurons controlling posture and behavior in a manner opposite to the dopaminergic ones.

The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nigro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turning, while haloperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.

Role of Brain Monoamines in Male Sexual Behavior

Publisher Summary This chapter describes the role of brain monoamines in male sexual behavior. The effects of p-chlorophenylalanine (PCPA) administration on the homo- and heterosexual behavior are suppressed in rats, rabbits and cats by 5-hydroxytryptophan, the direct precursor of serotonin. This amino acid also abolishes the spontaneous copulatory behavior of normal rats with receptive females. This inhibition is potentiated by inhibitors of extracerebral decarboxylase, suggesting that 5-HTP acts centrally. The monoamineoxidase inhibitor, pargyline, suppresses the spontaneous copulatory behavior of male rats with receptive females at the time when brain serotonin is maximally increased and inhibition, as well as serotonin accumulation, is prevented by PCPA. Marked homosexual mounting behavior has been observed in male rats after other treatments that lower brain serotonin, such as p-chloro-N-methyl-amphetamine and the intraventricular injection of 5,6 dihydroxytryptamine and furthermore, in testosterone-treated male rats, after different inhibitors of serotonin receptors such as mesorgydine, methysergide and Wa 335-BS . Inhibition of heterosexual copulatory behavior has been observed after the administration of LSD which is considered a direct stimulant of central serotonin receptors.

Increase of brain tryptophan and stimulation of serotonin synthesis by salicylate

Indirect evidence indicates that the rate‐limiting step in the synthesis of brain 5‐HT is the concentration of tryptophan in brain and not, as previously considered (Green and Sawyer, 1966), tryptophan hydroxylase. In fact this enzyme has a Km for its substrate much higher than the concentration of tryptophan normally present in the mammalian brain (Jequier, Lovenberg and Sjoerdsma, 1967; Jequier, Robinson, Lovesberg and Sjoerdsma, 1969; Mcgeer, Peters and Mcgeer, 1968). Tryptophan is the only amino acid circulating in plasma which is highly bound to serum proteins (Mcmenamy and Oncley, 1958). We have previously shown that the free fraction of serum tryptophan controls the concentration of brain tryptophan and, therefore, 5‐HT synthesis as well (Tagliamonte, Biggio and Gessa, 1971d; Gessa, Biggio and Tagliamonte, 1972). Salicylate has been shown to displace tryptophan from its protein binding in plasma and to raise the free tryptophan concentration (Mcarthur and Dawkins, 1969; Smith and Lakatos, 1971). These considerations prompted us to study the effect of salicylate on tryptophan concentrations and 5‐HT metabolism in brain.