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The present study has examined whether MAO-B has a role in DA metabolism in the primate CNS in situ. Eleven macaques (macaca facicularis) were used in this study to examine the effects of (-)-deprenyl (1 mg/kg, i.v., 2 and 24 hours). (-)-Deprenyl administration completely and selectively blocked MAO-B activity and blocked DA metabolism in the caudate nucleus and frontal cortex. DA metabolism in the substantia nigra was not affected by MAO-B inhibition. Changes in DA metabolism were accompanied by changes in 5-hydroxytryptamine (5HT) turnover: 5-hydroxyindole acetic acid (5HIAA) levels increased in the caudate and decreased in the frontal cortex. Levels of 2-phenylethylamine (PE), a putative modulator of dopaminergic transmission, were increased by MAO-B inhibition in all three brain regions examined. It is concluded that in some regions of the primate brain, in contrast to the rat, MAO-B has an important role in DA metabolism.

1. (-)-Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (-)-deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19-6327, whose only common effect with (-)-deprenyl is an inhibition of monoamine oxidase-B (MAO-B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism. 2. Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19-6327 was found to produce a dose-dependent potentiation of striatal neurone responses to dopamine but not gamma-aminobutyric acid. 3. Neurochemical investigations revealed that this occurred at doses (0.25-1 mg kg-1) which, while not affecting levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid or homovanillic acid, did cause a significant, dose-dependent, elevation in striatal levels of the putative neuromodulator, 2-phenylethylamine (PE). 4. Inhibition of PE synthesis by i.p. injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327. 5. Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg-1) selective for reduction of elevated PE levels. 6. These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO-B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO-B inhibition.

These studies were carried out to determine whether the greater abundance of monoamine oxidase B in the guinea pig affects the actions of (-)-deprenyl on dopamine metabolism in whole tissue or in extracellular fluid. The administration of (-)-deprenyl in doses that do not affect monoamine oxidase A activity (1-4 mg kg-1, 2 h) increases striatal 2-phenylethylamine and dopamine concentrations and reduces 3,4-dihydroxyphenylacetic acid. No effects were observed on striatal homovanillic acid, 5-HT and 5-hydroxyindole acetic acid. Inhibition of monoamine oxidase A with clorgyline with doses up to 8 mg kg-1 (2 h) does not affect striatal 2-phenylethylamine but increases dopamine and 5-HT concentrations and reduces 3,4-dihydroxyphenyl-acetic acid and 5-hydroxyindole acetic acid. (-)-Deprenyl (2-4 mg kg-1) did not change the extracellular concentrations of dopamine but the higher dose produced a limited reduction in extracellular 3,4-dihydroxyphenylacetic acid. Inhibition of monoamine oxidase A and monoamine oxidase B with pargyline (75 mg kg-1, 2 h) significantly increased the levels of extracellular dopamine and reduced those of their acid metabolites. These results show that in the guinea pig striatum inhibition of monoamine oxidase B by (-)-deprenyl impairs the metabolism of dopamine in the whole tissue but does not produce a marked increase in extracellular dopamine.

The purpose of this study was to examine whether monoamine oxidase type B (MAO-B) has a role in striatal dopamine metabolism in animals with a unilateral lesion of the medial forebrain bundle, and whether 2-phenylethylamine (PE) could have a role in amplification of dopamine (DA) responses in DA depleted striatum. Inhibition of MAO-B did not alter DA metabolism in lesioned striata. PE accumulation decreased with loss of DA as long as there was no DA dysfunction. In lesioned striata with dysfunction of DA transmission at the synaptic level, PE accumulation increased, suggesting a compensatory increase in PE synthesis. This increase in PE levels does not appear to be mediated by an increase in the total striatal aromatic L-amino acid decarboxylase (AADC) activity. We conclude that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that PE could be involved in the antiparkinsonian action of MAO-B inhibitors.

Dopamine depleting lesions of the substantia nigra result in a reduction of the striatal accumulation of 2-phenylethylamine following monoamine oxidase inhibition. It is established that this effect may not be due to a change in availability of aromatic L-amino acid decarboxylase in striatum. Nevertheless, the possibility remains that striatal concentrations of phenylalanine (the precursor of 2-phenylethylamine) may be altered by dopamine-depleting lesions. The present experiments assessed the effects of dopamine depletion induced by 6-OHDA (7 days following 8 micrograms/4 microliters unilateral substantia nigra injection) on striatal concentrations of phenylalanine, dopamine, 5-hydroxytryptamine and their metabolites. In addition, the effects of reserpine-induced (10 mg kg-1, 2h, sc) amine depletion on these striatal levels were also assessed. Under equivalent conditions reserpine is reported to increase striatal accumulation of 2-phenylethylamine. 6-OHDA induced a significant unilateral depletion of dopamine, DOPAC and HVA and increased 5-HIAA but had no significant effect on phenylalanine levels. Reserpine decreased dopamine and 5-hydroxytryptamine and increased DOPAC, HVA and 5-HIAA levels, no changes in phenylalanine were observed. This pattern of results was also observed when lesioned animals or reserpine-treated animals were pretreated with (-)-deprenyl (2 mg kg-1, 2 hr, sc), the treatment previously used to induce accumulation of 2-phenylethylamine. These data indicate that changes in 2-phenylethylamine previously observed under these conditions may not simply be secondary to a change in striatal phenylalanine concentrations.

This report describes experiments designed to determine whether (-)-deprenyl potentiates dopaminergic transmission and whether its mechanism involves the inhibition of dopamine catabolism. Intraperitoneal administration of (-)-deprenyl (0.5-8 mg kg-1) produced a dose-dependent inhibition of striatal monoamine oxidase type B activity whereas monamine oxidase type A activity in the striatum was inhibited only by 8 mg kg-1 of (-)-deprenyl. Intraperitoneal administration of (-)-deprenyl (0.5-4 mg kg-1) did not alter the striatal concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid. DOPAC concentrations were decreased by 8 mg kg-1 of (-)-deprenyl. In contrast, administration of clorgyline (2 mg kg-1), a monoamine oxidase type A inhibitor, increased the striatal concentrations of DA and decreased the striatal concentrations of DOPAC and homovanillic acid. The striatal concentrations of 2-phenylethylamine (PE), a putative modulator of striatal DA transmission, were increased by (-)-deprenyl (1-8 mg kg-1) but were unaffected by clorgyline (2 mg kg-1). In electrophysiological studies, single caudate neuron responses to iontophoretically applied (-)-apomorphine and (+/-)-2-(N-phenethyl-N-propyl) amino-5-hydroxytetralin were potentiated by intracarotid injections of PE (30 micrograms kg-1) and i.p. injections of (-)-deprenyl (2 mg kg-1). Both PE and (-)-deprenyl reduced the IT50 of responses to apomorphine and (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The highest concentrations of dopamine were observed in the sheep coronary interventricular artery (1.0 micrograms/g) and the lowest in the aorta (0.15 micrograms/g). Varying proportions of noradrenaline was also present in the arteries examined with dopamine:noradrenaline ratios ranging from 0.08 to 1.11. 2. p-Tyramine is the trace amine present in highest concentration in both the lung and the caudate nucleus (21.3 and 10.5 ng/g, respectively) while the levels of beta-phenylethylamine, m-tyramine and tryptamine are lower and range between 1.6 and 4.2 ng/g. 3. The results show that sheep arteries, lung and duodenum contain considerable amount of dopamine that is presumably associated with chromaffin cells. It is most likely that these cells also contain 5-hydroxytryptamine while the localization of trace amines remains to be elucidated.

This is an investigation of the effect of nutritional stress at various ages on the levels of the p- and m-isomers of tyramine in the caudate nucleus of the rat. For comparison, the effects of nutritional stress on the concentration and turnover of dopamine were also studied. Nutritional stress induced in pre-weaning (3 weeks of age) or post-weaning (up to 9 weeks of age) rats resulted in a decrease in the concentration of p-tyramine and an increase in the concentration of m-tyramine in the caudate nucleus. Dopamine concentration or turnover in the caudate nucleus was not affected by pre-weaning undernutrition; in the olfactory tubercles, however, a significant decrease was observed in dopamine turnover, calculated from the decrease in homovanillic acid levels after monoamine oxidase inhibition. The results suggest the changes observed are dependent on the availability of the amino acid precursors p- and m-tyrosine and their competition towards aromatic-L-amino acid decarboxylase.

Recent studies have demonstrated that selective monoamine oxidase inhibition may induce changes in brain beta-phenylethylamine availability following lesions. The present study used this approach to re-assess the possible effects of reserpine on striatal concentrations of beta-phenylethylamine and of other amines and selected metabolites. Mice were injected with pargyline (2,200 mg kg-1, 4 h), clorgyline (2 mg kg-1, 2 h) or (-)deprenyl (2 mg kg-1, 2 h) alone or in combination with reserpine (1, 10 mg kg-1, 2 h). Increases in beta-phenylethylamine accumulation were observed in the presence of both (-)deprenyl or pargyline respectively after reserpine except in the case of combined 200 mg kg-1 of pargyline plus 1 mg kg-1 of reserpine. In this condition, a minimal dopamine decrease was observed (to 80% of the concentration of pargyline-treated controls). Increases in beta-phenylethylamine concentration were not observed with reserpine alone (1 or 10 mg kg-1). In the latter condition, the concentrations of beta-phenylethylamine remained at control values due to the activity of monoamine oxidase B. Changes in p-tyrosine, 5-hydroxytryptamine or tryptophan did not consistently accompany increases in beta-phenylethylamine accumulation. Increased beta-phenylethylamine accumulation was always accompanied by the decreases in dopamine induced by reserpine in mice with either non-selective (200 mg kkg-1 pargyline) or type B monoamine oxidase inhibition (2 mg kg-1 pargyline or deprenyl). These data suggest that although the changes in beta-phenylethylamine accumulation may not be due simply to p-tyrosine availability they are related to dopamine levels in the intact striatum.

The concentration of homovanillic acid and p-tyramine in the female corpus striatum were increased after ovariectomy. The increases were reversed by chronic administration of estradiol benzoate and potentiated by progesterone. It is proposed that these changes are the consequence of concomitant variations in p-tyrosine availability.

Earlier work has shown that diabetic rats possess lower concentrations of brain p-tyrosine; these animals also show a decrease in the rate of accumulation of striatal DOPA after decarboxylase inhibition and an increase in striatal binding sites for dopamine. These findings suggested that diabetic rats show a reduction in the metabolism of brain dopamine. This is an investigation of the effects of streptozotocin-induced (65 mg/kg, intracardially) diabetes on rat striatal concentrations of p-tyrosine, p-tyramine, m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. Also, the effects of insulin administration (0.5-4 IU/kg, intraperitoneally) to normal and diabetic rats were studied. The onset of diabetes or effect of insulin treatment was determined by the changes produced in blood glucose. Streptozotocin produced a significant reduction in the striatal concentration of p-tyrosine, 3,4-dihydroxyphenylacetic acid and homovanillic acid observed 7 or 14 days after injection. The treatment produced a reduction in p-tyramine and an increase in m-tyramine. Insulin administration significantly increased rat striatal p-tyrosine, p-tyramine, 3,4-dihydroxyphenylacetic acid and homovanillic acid while m-tyramine was decreased. The concentrations of p-tyrosine, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum of insulin-treated diabetic rats were within the range of control values. The results indicate that streptozotocin-diabetic rats possess a reduced striatal dopamine metabolism and that this is counteracted by insulin administration. These changes are probably the consequence of changes in the availability of some amino acid precursors and in tyrosine hydroxylase activity.

Striatal amine levels were measured six weeks after unilateral injections of 6-OHDA (8 micrograms) into the substantia nigra in male Wistar rats pretreated with monoamine oxidase inhibitors. After (-) deprenyl.HCl pretreatment (2 mg.kg-1 SC 2hr), beta-phenylethylamine, m- and p-tyramine ipsilateral to the 6-OHDA lesion decreased to 50, 18 and 25% of contralateral levels. DA, DOPAC and HVA also decreased on the lesioned side. Ipsilateral concentrations of tryptamine, 5-HT, 5-HIAA, p-tyrosine and L-tryptophan concentrations were equivalent to contralateral values in this condition. In animals pretreated with pargyline.HCl (200 mg.kg-1 IP 2hr) m- and p-tyramine and tryptamine ipsilateral to the lesion decreased to 48, 59 and 57% of contralateral levels. Ipsilateral DA decreased to 26% of the contralateral value. Under these conditions no change in concentrations of beta-phenylethylamine or of the above acid metabolites or amino acids was observed. The masking of lesion-induced changes in beta-phenylethylamine by pargyline is attributed to the lipophilic nature of of this molecule and consequent diffusion of this amine from other areas after maximal monoamine oxidase inhibition. Conversely the failure to demonstrate lesion-induced changes in tryptamine with (-) deprenyl pretreatment is attributed to the nonselectivity of monoamine oxidase for tryptamine and activity of monoamine oxidase A under these conditions. These results indicate that for further assessment of lesion-induced changes in beta-phenylethylamie and of tryptamine the respective (-) deprenyl and pargyline pretreatments used in this study are appropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.

1 The concentrations of p- and m-tyramine, dopamine and homovanillic acid were measured in the mouse striatum following the subcutaneous injection of gamma-hydroxybutyrate; their control levels were 19.8, 6.3, 9600 and 1130 ng/g respectively. 2 The administration of 500-1000 mg/kg of gamma-hydroxybutyrate produced a reduction in p-tyramine that lasted at least 8 h. m-Tyramine and dopamine were significantly increased for at least 4 h. The levels of homovanillic acid were increased at 1 and 2 h after drug administration. 3 There experiments strongly suggest that the increases in dopamine turnover produced by gamma-hydroxybutyrate caused reciprocal changes in striatal tyramine that are similar to those produced by drug or treatment that increase dopamine turnover and tyrosine hydroxylase activity.

This is an investigation of the effects of electrolytic lesions (1 mA, 10s, anodal) on the median and dorsal raphé nuclei of Wistar rats on the striatal concentrations of p-tyrosine, p-tyramine, m-tyramine, DA, DOPAC, and HVA. The extent of the lesions was estimated in terms of the depletion of 5-hydroxytryptamine and 5-hydroxyindole acetic acid as well as histological examination of the lesioned area. The results show that the raphé nuclei lesions increased rat striatal levels of DOPAC and HVA while levels of DA were unaffected, an effect that was observed within the first day after the lesions were made. The increases in DOPAC and HVA were accompanied by a reduction in striatal p-tyramine and an increase in m-tyramine. The results further support the existence of a reciprocal relationship between p- and m-tyramine concentrations and dopamine metabolism. Previous experiments have demonstrated depletion of p-TA following nigral lesions. The present results are, therefore, important in relation to tyramine distribution in brain. The p- and m-tyramine concentrations were not reduced at 7 days after the raphé nuclei lesions indicating that if the striatal tyramine-containing neurons exist, they do not originate in or pass through the dorsal or median raphé nuclei.

1 The concentrations of p- and m-tyramine, dopamine and homovanillic acid were measured in the mouse striatum following the subcutaneous administration of amfonelic acid, (+)-amphetamine or nomifensine.2 The administration of 2.5-25 mg/kg of amfonelic acid produced a reduction in p-tyramine that lasted at least 8 h. m-Tyramine was significantly increased and this was observed between 2 and 24 h after drug treatment. The levels of homovanillic acid were increased within 4 h after amfonelic acid administration.3 (+)-Amphetamine treatment (5 mg/kg) produced a reduction in p-tyramine observed up to 4 h after its administration and no significant changes in m-tyramine.4 The administration of 10 mg/kg of nomifensine produced no significant changes in p-tyramine, m-tyramine or homovanillic acid. By increasing the dose to 20 mg/kg, nomifensine produced an increase in p-tyramine and homovanillic acid.5 The present results support the view that amfonelic acid and (+)-amphetamine would respectively release granular or newly synthesized dopamine, both actions being accompanied by an increase in tyrosine hydroxylase activity and dopamine turnover which in turn reduces p-tyramine but produces no change or an increase in m-tyramine.6 The effects of nomifensine were observed after the administration of a relatively high dose (20 mg/kg), that was lethal to some mice (about 20%, at 2 h), and more likely to posses unspecific actions.

Following electric stimulation of the substantia nigra for 1 h there was a substantial increase in dopamine (DA) turnover in the rat caudate nucleus evidenced by an increase in its acid metabolite homovanillic acid (HVA). Concurrently there was an increase in striatal m-tyramine (mTA) and a substantial decrease in p-tyramine (pTA). Lesioning the substantia nigra to decrease impulse flow resulted in a buildup of striatal DA and mTA, but again a decrease in pTA. Following pretreatment with a tyrosine hydroxylase inhibitor, the effects of stimulation of the nigra on mTA were reversed, there being a significant decrease in this amine. The decrease of pTA in response was partially prevented by tyrosine hydroxylase inhibition. The effects of stimulation or substantia nigra lesions on pTA levels were reversed, however, by tyrosine hydroxylase inhibition, a significant increase in this amine being recorded. mTA and DA levels were largely unaffected by a combination of lesion and tyrosine hydroxylase inhibition. The results provide insight into the possible biosynthetic interrelationships between DA and the tyramine isomers in the rat caudate nucleus.

Administration of phenelzine (100 mg/kg. i.p., 18 hr) increased rat striatal concentrations of pTA, mTA and DA by 30, 6.7 and 1.5 fold, respectively. Lesions of the medial forebrain bundle prevented these increases, permitting the conclusion that the phenelzine-induced amine increases were localized in the synaptic terminals. The release of endogenous pTA, mTA and DA from striatal slices obtained from phenelzine-treated rats was investigated, 50 mM KC1l elicited releases of pTA, mTA and DA which were significantly greater than their respective basal releases. These K+-stimulated releases were antagonized significantly by 15 mM MgCl2, suggesting that they are calcium-dependent in nature. We have concluded, therefore, that mTA and pTA, as well as DA, are released from striatal nerve terminals in vivo. The total amounts of mTA and DA, but not pTA, released in the release experiments were greater than those found in the nonincubated tissue. It appears, therefore, that the biosynthesis of mTA and DA was stimulated during the incubation of the striatal slices.

1. Bovine coronary and other arteries contain more dopamine (DA) [1400-520 ng g-1] than noradrenaline (NA) [120-500 ng g-1] with high DA/NA ratios (1.8-4.3). Arteries from other species, (pigs, rats, mice or guinea-pigs), contain far less DA (20-60 ng g-1) and have lower DA/NA ratios (0.01-0.06). 2. Bovine arteries also have 3,4-dihydroxyphenylacetic acid (80-290 ng g-1) but not homovanillic acid (less than 20 ng g-1). 3. It remains to be elucidated whether, in the bovine arterial wall, DA is a transmitter or it is associated with chromaffin-like cells.

1. In the avian brain, a high concentration of dopamine was found in a sharply contoured region of the nucleus basalis which may or may not have included the nucleus entopeduncularis, and therefore lay within the palaeostriatum of the nomenclature of Crosby and Huber. This was thus the only region which may be considered biochemically homologous to the mammalian corpus striatum. For purposes of macroscopic identification only, the region is described here as the ;anterior part of the nucleus basalis'. The concentration of dopamine was 3 mug/g in the pigeon, about the same in the duck and chicken, and 7.5 mug/g in the finch. In the pigeon this region also contained some noradrenaline; the quantity of 5-hydroxytryptamine (1.4 mug/g) and 5-hydroxyindolylacetic acid (0.6 mug/g) was larger than in any other part of the brain.2. In the brain of the pigeon and the chicken, the highest concentrations of noradrenaline (1.5 and 1.4 mug/g) were found in the hypothalamus.3. The concentration of adrenaline was higher in the avian than in the mammalian brain. In the hypothalamus, it ranged from 0.4 mug/g in the pigeon to 1 mug/g in the chicken.4. Fluorescence microscopy, using the formaldehyde condensation method, showed, in the anterior part of the nucleus basalis, a large area of diffuse green-yellow fluorescence, similar in appearance to the fluorescence of the striatum of the rat. In addition this part of the brain contained a small region of fluorescent fibres and varicosities. It is suggested that the diffuse fluorescence was produced by dopamine. It was absent from brains of reserpine-treated pigeons.5. In the pigeon, reserpine, tetrabenazine and prenylamine produced a decrease in the concentration of brain monoamines, an effect which was comparable to that seen in mammals. Yet, none of these drugs raised the concentration of homovanillic acid, but they increased that of 5-hydroxyindolylacetic acid; these drugs raise the concentration of both acids in mammalian brain.6. In the pigeon beta-tetrahydronaphthylamine decreased the concentration of all monoamines and their metabolites, an action quite different from that produced in the mammalian brain.7. The main effect of morphine and of M 99 (6,14-endoetheno-7-(2-hydroxy-2-pentyl)-tetrahydro-oripavine hydrochloride) was a lowering of the noradrenaline concentration.8. As in mammals, chlorpromazine affected only the dopamine metabolism.9. In the guinea-pig and the pigeon, the administration of alpha-methyl-DOPA led to a substitution of much of the cerebral noradrenaline by alpha-methyl-noradrenaline, sometimes in excess of the lost noradrenaline. However, although the loss of dopamine was severe in both pigeon and guinea-pig, only little alpha-methyl-dopamine accumulated in the pigeon brain, so that it did not consitute a replacement for the lost dopamine; in the guinea-pig, alpha-methyl-dopamine was found in quantities similar to, or exceeding those, of the lost dopamine.

1. Dopamine was found in the tortoise brain; the highest concentration (3.7 mug/g) occurred in a region of the telencephalon containing the nucleus basalis and cortex olfactoria. This region may be considered similar to the mammalian and avian corpus striatum with respect to dopamine.2. The administration of reserpine or prenylamine substantially decreased the concentration of dopamine in the tortoise brain. This effect appeared later and lasted longer than in birds or mammals. When these drugs were given in doses which nearly depleted brain dopamine the characteristic signs observed in birds or mammals were not present.