A study on melanogenesis and catecholamine biosynthesis during Bufo bufo development

Tyrosinase and L-DOPA decarboxylase activities have been investigated during Bufo bufo development since catecholamines and melanin are formed from common substrates in homologous cells. Catecholamines first appear at stage 13 (neural plate), but tyrosinase, at a very low level, and L-DOPA decarboxylase are present throughout all of prior development. Hence, L-DOPA decarboxylase activity is not likely to be correlated with the control of catecholamine synthesis, although at stage 17 it is mainly localized in the nonneural part of the embryo. The distribution of young melanosomes and L-DOPA decarboxylase suggest a separation between melanogenesis and catecholamine synthesis.     

Striatal L-DOPA Decarboxylase Activity in Parkinson's Disease In Vivo: Implications for the Regulation of Dopamine Synthesis

Abstract: L-DOPA is a large neutral amino acid subject to transport out of, as well as into, brain tissue. Competition between dopamine synthesis and L-DOPA egress from striatum must favor L-DOPA egress if decarboxylation declines relatively more than transport in Parkinson's disease. To test this hypothesis, we injected patients with Parkinson's disease with a radidabeled analogue of L-DOPA and recorded regional brain radioactivity as a function of time by means of positron emission tomography. We simultaneously estimated the activity of the decarboxylating enzyme and the amino acid transport. In the striatum of patients, we found the L-DOPA decarboxylase activity to be reduced in the head of the caudate nucleus and the putamen. However, the rate of egress of the DOPA analogue was unaffected by the disease and thus inhibited dopamine synthesis more than predicted in the absence of L-DOPA egress.     

Production of L-DOPA by cell suspension cultures of Mucuna pruriens

The endogenous synthesis of 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) by cell suspension cultures of Mucuna pruriens was found to be influenced by several environmental parameters. The nature of the nitrogen source as well as the concentration of nitrogen containing salts, sucrose and phosphate in the culture medium were found to affect the biosynthesis of L-DOPA. Addition of 2, 4-dichlorophenoxyacetic acid to the medium suppressed L-DOPA production; continuous illumination of the cultures had a strong beneficial effect on L-DOPA production. L-DOPA was accumulated intracellularly by the cell suspension cultures. These observations further demonstrate that for certain products of plant cell suspensions product synthesis can be manipulated by a proper selection of specified nutrients.     

Dopamine synthesis by non-dopaminergic neurons of the rat fetus arquate nucleus

Our hypothesis was tested in respect to dopamine synthesis by non-dopaminergic neurons expressing individual complementary enzymes of the DA synthetic pathway. According to the hypothesis, L-dihydroxyphenylalanine (L-DOPA) synthesised in tyrosine hydroxylase(TH)-expressing neurons for conversion to dopamine. The mediobasal hypothalamus of rats on the 21st embryonic day was used as an experimental model. The fetal substantia nigra containing dopaminergic neurons served as control. Dopamine and L-DOPA were measured by high performance liquid chromatography in cell extracts and incubation medium in presence or absence of L-tyrosine. L-tyrosine administration increased L-DOPA synthesis in the mediobasal hypothalamus and substantia nigra. Moreover, L-tyrosine provoked an increase of dopamine synthesis in substantia nigra and a decrease in the mediobasal hypothalamus. This is, probably, due to an L-tyrosine-induced competitive inhibition of the L-DOPA transport to monoenzymatic AADC neurons after its release from the monoenzymatic TH neurons. This study provides a convincing evidence of dopamine synthesis by non-dopaminergic neurons expressing TH or AADC, in cooperation.     

Effect of catecholamines and serotonin on RNA-synthesizing activity in isolated nuclei and chromatin of the rat brain and liver

It has been shown that intraperitoneal injections of L-DOPA cause an increase in the matrix activity of chromatin and stimulate the incorporation of [3H]uridine into the nuclear fraction of rat brain cells by 35%. In vitro studies have shown that preincubation of brain chromatin with L-DOPA diminishes the inhibiting effect of actinomycin D on RNA synthesis. It has been found that the rate of RNA synthesis in vitro depends on concentrations of catecholamines (L-DOPA, dopamine, norepinephrine) and serotonin.     

Missing proof of cooperative synthesis of dopamine by non-dopaminergic neurons

L-DOPA accumulation in the extracellular medium was detected when the transfer of L-DOPA from the neurons containing tyrosine hydroxylase to the neurons containing aromatic L-amino acid decarboxylase was blocked, under conditions of inhibition of the L-DOPA degradation enzyme. Thus, the missing proof confirming the existence of cooperative synthesis of dopamine by neurons non-dopaminergic was obtained.     

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

(1) The treatment of choice for Parkinson’s disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.     

L-tyrosine, L-dopa, and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in Bomirski Ab amelanotic melanoma cells

In cultured cells of the Bomirski Ab amelanotic hamster melanoma line, the substrates of tyrosinase, L-tyrosine, and L-DOPA induce the melanogenic pathway. In this report, we demonstrate that these substrates regulate the subcellular apparatus involved in their own metabolism and that this regulation is under the dynamic control of one of the components of this apparatus, tyrosinase, via tyrosine hydroxylase activity. Culturing cells with nontoxic but melanogenically inhibitory levels of phenylthiourea (PTU; 100 microM) strongly inhibits induction of both the tyrosine hydroxylase and DOPA oxidase activities of tyrosinase by L-tyrosine (200 microM) but has no effect on the induction of either activity by L-DOPA (50 microM). De novo synthesis of premelanosomes precedes the onset of tyrosine-induced melanogenesis. Thereafter, increases in the population of melanosomes (likewise inhibited by PTU) correlate positively with increases in tyrosinase activity induced by L-tyrosine. Melanogenesis induced by L-DOPA in the absence of L-tyrosine is rate-limited not by tyrosinase but by inadequate melanosome synthesis. Our findings indicate that in Bomirski Ab amelanotic hamster melanoma cells the synthesis of the subcellular apparatus of melanogenesis is initiated by L-tyrosine and is regulated further by tyrosinase and L-DOPA, which serves as a second messenger subsequent to tyrosine hydroxylase activity.     

The simple and rapid quantification method for L-3,4-dihydroxyphenylalanine (L-DOPA) from plant sprout using liquid chromatography-mass spectrometry

L-3,4-dihydroxyphenylalanine (L-DOPA) is one of the important secondary metabolites of plants and has been used for various purposes, such as in clinical treatment for Parkinson’s disease and dopamine-responsive dystonia. In plants, L-DOPA is a precursor of many alkaloids, catecholamines, and melanin; the L-DOPA synthesis pathway is similar to that in mammals. L-DOPA acts as an allelochemical, has an important role in several biological processes, such as stress response and metabolism, in plants. L-DOPA is widely used in the clinical treatment as well as a dietary supplement or psychotropic drug, understanding of biosynthesis of L-DOPA in plant could lead to a stable supply of L-DOPA. This paper describes an improved method for simple and rapid quantification of L-DOPA content using liquid chromatography-tandem mass spectrometry. The standard quantitative methods for L-DOPA require multiple purification steps or relatively large amounts of plant material. In our improved method, quantification of L-DOPA was possible with extract of one–two pieces of cotyledon without any partitioning or column for purification. The endogenous L-DOPA (approximately 4,000 µg g⁻¹ FW (fresh weight)) could be detected from the one pieces of cotyledon of the faba bean sprout using this method. This method was also effective for samples with low endogenous amounts of L-DOPA such as broccoli, Japanese white radish, pea, and red cabbage sprouts. Therefore, this improved method will allow to measurement of L-DOPA content easily and accurately from a small amount of plant tissue and contribute to understanding biosynthesis, catabolism, and transport of L-DOPA.     

Effect of L-DOPA on cyclic adenosine-3',5'-monophosphate in neurogenically damaged cardiac muscle

During electric stimulation of the aortal reflexogenic zone in rabbits, administration of L-DOPA prevented the reduction of the level of cyclic adenosine-3',5'-monophosphate (cAMP) in the cardiac muscle and blood plasma. This is likely to be related to L-DOPA ability to participate in the biosynthesis of endogenous catecholamines, and thus to stimulate the synthesis of cAMP.     

Catechol-O-methyltransferase inhibition protects against 3,4-dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new insights into levodopa toxicity

Inhibition of catechol-O-methyltransferase (COMT) has protective effects on levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589]. Here, we extend our recent studies to elucidate the mechanisms of these protective effects. Thus, we investigated the effects of all main L-DOPA/DA metabolites on survival of tyrosine hydroxylase immunoreactive (THir) neurons in primary rat mesencephalic cultures. 3-O-Methyldopa, homovanillic acid, dihydroxyphenyl acetate and 3-methoxytyramine had no effects at concentrations up to 300 micro M after 24h, whereas DA was more toxic than L-DOPA with toxicity at concentrations of >or=1 micro M. The coenzyme of COMT, S-adenosyl-L-methionine (SAM), and its demethylated product S-adenosylhomocystein caused no relevant alteration of THir neuron survival or L-DOPA toxicity. In contrast, inhibition of SAM synthesis by selenomethionine showed time- and dose-dependent increase of THir neuron survival, but did not affect L-DOPA toxicity. L-DOPA-induced lipid peroxidation in mesencephalic cultures was not modified by the COMT inhibitor Ro 41-0960 (1 micro M). Increased contamination of the cultures with glial cells attenuated L- and D-DOPA toxicity, but caused significant enhancement of protection by COMT inhibitors against L-DOPA toxicity only. Investigations of L-DOPA uptake in rat striatal cultures using HPLC revealed a significant reduction of extracellular L-DOPA concentrations by Ro 41-0960. Our data confirm that L-DOPA toxicity towards DA neurons is mediated by an autooxidative process, which is attenuated by glial cells. In addition, we demonstrate a second mechanism of L-DOPA toxicity in vitro mediated by a COMT- and glia-dependent pathway, which is blocked by COMT inhibitors, most likely due to enhanced glial uptake of L-DOPA.     

Metabolic engineering of tomato fruit enriched in L-DOPA

L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is a non-standard amino acid, and the gold standard drug for the treatment for Parkinson's Disease (PD). Recently, a gene encoding the enzyme that is responsible for its synthesis, as a precursor of the coloured pigment group betalains, was identified in beetroot, BvCYP76AD6. We have engineered tomato fruit enriched in L-DOPA through overexpression of BvCYP76AD6 in a fruit specific manner. Analysis of the transgenic fruit revealed the feasibility of accumulating L-DOPA in a non-naturally betalain-producing plant. Fruit accumulating L-DOPA also showed major effects on the fruit metabolome. Some of these changes included elevation of amino acids levels, changes in the levels of intermediates of the TCA and glycolysis pathways and reductions in the levels of phenolic compounds and nitrogen-containing specialised metabolites. Furthermore, we were able to increase the L-DOPA levels further by elevating the expression of the metabolic master regulator, MYB12, specifically in tomato fruit, together with BvCYP76AD6. Our study elucidated new roles for L-DOPA in plants, because it impacted fruit quality parameters including antioxidant capacity and firmness. The L-DOPA levels achieved in tomato fruit were comparable to the levels in other non-seed organs of L-DOPA - accumulating plants, offering an opportunity to develop new biological sources of L-DOPA by widening the repertoire of L-DOPA-accumulating plants. These tomato fruit could be used as an alternative source of this important pharmaceutical.     

Stimulation of total phenolics, L-DOPA and antioxidant activity through proline-linked pentose phosphate pathway in response to proline and its analogue in germinating fava beans (Vicia faba)

The rationale behind the study was to enhance azetedine-2-carboxylate (A2C)-linked stress in the germinating seeds to which it responds by increased proline synthesis to overcome inhibition of proline dehydrogenase (PDH). A2C is a competitive inhibitor of proline that inhibits its transport from cytosol to the mitochondria for further metabolic recycling by binding on to the active sites of PDH. The enhanced synthesis of proline would increase the ratio of the cofactors NADP/NADPH₂. The increase in the cofactors would result in the over-expression of the phenypropanoid pathway required for the phenolic acids and L-DOPA synthesis via pentose phosphate pathway through the activity of glucose-6-phosphate dehydrogenase (G6PDH). Fava bean were chosen since it has high phenolic and L-DOPA levels and could be an important part of the diet especially for patients suffering from Parkinson's Disease. The objectives were investigated by assaying for total phenolic content, the corresponding antioxidant activity by β-carotene oxidation method, proline levels and enzymes such as G6PDH and guaiacol peroxidase (GPX) using spectrophotometric methods. L-DOPA was quantified using HPLC. The fava bean seeds were primed with water, 200 μM A2C, 0.25 mM proline and a combination of A2C and proline treatments. After the priming stage, seeds were dark germinated and grown for a period of 8 days, for biochemical analysis. L-DOPA levels did not change in comparison to the control treatments while total phenolic content, proline and G6PDH were all enhanced by the treatments. During the early stages of germination the phenolic acids were antioxidant in nature, which later was reduced as they become polymerized to lignins and lignans via the GPX activity. Total phenolic synthesis was both coupled and uncoupled to PLPPP depending on the treatments. The three treatments over-expressed PLPPP since large difference between control and the treatments were observed for all parameters, except L-DOPA content.     

Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin

Albino mammals have profound retinal abnormalities, including photoreceptor deficits and misrouted hemispheric pathways into the brain, demonstrating that melanin or its precursors are required for normal retinal development. Tyrosinase, the primary enzyme in melanin synthesis commonly mutated in albinism, oxidizes l-tyrosine to l-dopaquinone using l-3,4-dihydroxyphenylalanine (L-DOPA) as an intermediate product. L-DOPA is known to signal cell cycle exit during retinal development and plays an important role in the regulation of retinal development. Here, we have mimicked L-DOPA production by ectopically expressing tyrosine hydroxylase in mouse albino retinal pigment epithelium cells. Tyrosine hydroxylase can only oxidize l-tyrosine to L-DOPA without further progression towards melanin. The resulting transgenic animals remain phenotypically albino, but their visual abnormalities are corrected, with normal photoreceptor numbers and hemispheric pathways and improved visual function, assessed by an increase of spatial acuity. Our results demonstrate definitively that only early melanin precursors, L-DOPA or its metabolic derivatives, are vital in the appropriate development of mammalian retinae. They further highlight the value of substituting independent but biochemically related enzymes to overcome developmental abnormalities.     

Cooperative synthesis of dopamine in rat mediobasal hypothalamus as a compensatory mechanism in hyperprolactinemia

Dopamine (DA), synthesized in the mediobasal hypothalamus by dopaminergic neurons containing two enzymes of DA synthesis–tyrosine hydroxylase and decarboxylase of aromatic L-amino acids, or by monoenzymatic non-dopaminergic neurons containing one DA synthesis enzyme in cooperation, is known to have an inhibitory effect on prolactin secretion. Deterioration of this inhibitory control leads to an increase in prolactin concentration in the blood and to the development of hyperprolactinemia syndrome. In a rat model of hyperprolactinemia induced by administration of a neurotoxin causing degeneration of dopaminergic and noradrenergic neurons, the level of DA first decreases, leading to an increase in prolactin level (decompensation stage), while later both levels are restored to normal (compensation stage). However, the mechanism of such compensation is still not clear. The aim of the present study was to analyze whether the increase in cooperative synthesis of DA by monoenzymatic neurons during hyperprolactinemia is a manifestation of a compensatory mechanism representing a particular case of neuroplasticity. The level of cooperative synthesis in the hyperprolactinemia model and in the control was estimated as the level of synthesis of DA and L-dihydroxyphenylalanine (L-DOPA)–an intermediate product of DA synthesis, when L-DOPA transfer from neurons containing tyrosine hydroxylase into neurons containing aromatic L-amino acid decarboxylase is inhibited. The level of DA synthesis during the decompensation stage was not changed, while during the compensation stage it was lower than the control. Along with a reduction in DA level, during the compensation stage an increase in the extracellular L-DOPA level in the medium was detected. Thus, the compensation of DA deficiency after degeneration of dopaminergic neurons in the mediobasal hypothalamus is due to the increase in cooperative synthesis of DA by monoenzymatic neurons containing one of the complementary enzymes of the DA synthesis pathway.     

L-DOPA and glia-conditioned medium have additive effects on tyrosine hydroxylase expression in human catecholamine-rich neuroblastoma NB69 cells

The aim of this study was to investigate the effect of L-DOPA and glia-conditioned medium (GCM) on cell viability, tyrosine hydroxylase (TH) expression, dopamine (DA) metabolism and glutathione (GSH) levels of NB69 cells. L-DOPA (200 microM) induced differentiation of NB69 cells of more than 4 weeks in vitro, as shown by phase-contrast microscopy and TH immunocytochemistry, and decreased replication, as shown by 5-bromodeoxyuridine immunostaining. L-DOPA did not increase the number of necrotic or apoptotic cells, as shown by morphological features, Trypan Blue, lactate dehydrogenase activity, bis-benzimide staining and TUNEL assay. Furthermore, L-DOPA (200 microM) increased Bcl-xL protein expression. Incubation of cells with L-DOPA (50, 100, 200 microM) for 24 h resulted in an increase in TH protein levels (174, 196 and 212% versus control). Neither carbidopa, an inhibitor of L-aromatic amino acid decarboxylase enzyme, nor L-buthionine sulfoximine, which inhibits GSH synthesis, or ascorbic acid, an antioxidant, blocked the L-DOPA-induced effect on TH protein expression. L-DOPA (0, 50, 100 and 200 microM) plus GCM further increased the amount of TH protein (346, 446, 472 and 424%). L-DOPA (200 microM) increased TH protein levels to 132, 191 and 245% of controls after incubation for 24, 48 and 72 h. DA metabolism in NB69 cells was increased in cultures treated with either L-DOPA (200-300 microM) or GCM and these two agents had a synergistic effect on DA metabolism. In addition, L-DOPA (200 microM) or/and GCM-treated cells increased their GSH extracellular levels (223, 257, 300% of controls) after 48 h of treatment. The L-DOPA-induced increase of TH protein expression in NB69 cells was independent of DA production, free radicals and GSH up-regulation.     

Transplantation of Melanocytes Obtained from the Skin Ameliorates Apomorphine-Induced Abnormal Behavior in Rodent Hemi-Parkinsonian Models

Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson’s disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson’s disease.     

Biosynthesis of N-Acetyldopamine and N-Acetyloctopamine by Schistocerca gregaria Nervous Tissue

N-Acetyltyramine, N-acetyldopamine and N-acetyloctopamine were the major products when either L-[3H]tyrosine or [3H]tyramine were incubated with thoracic ganglia of the desert locust, Schistocerca gregaria. No label was incorporated into L-DOPA under these conditions, although 2-3% of the radioactivity could be recovered in dopamine and octopamine. Addition of the aromatic amino acid decarboxylase inhibitor, 3-hydroxybenzylhydrazine (NSD 1015), prevented the formation of N-acetylcompounds from L-[3H]tyrosine, without resulting in an accumulation of label in L-DOPA. In contrast, incubation of samples of haemolymph with L-[3H]tyrosine resulted in the recovery of 7% of label in L-DOPA, which was increased to 17% in the presence of NSD 1015. These results provide evidence that the initial step in the synthesis of dopamine and octopamine by S. gregaria nervous tissue is the conversion of L-tyrosine to tyramine, which is subsequently metabolised to N-acetyltyramine, N-acetyldopamine or N-acetyloctopamine.     

Expression of the enzymes of dopamine synthesis in non-dopaminergic neurons: functional significance and regulation

Dopamine(DA), the most widely distributed in the nervous system and functionally important chemical signal, is synthesized in DA-ergic neurons from L-tyrosine by means of two enzymes, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). Apart from the enzymes, specific DA transporter is an attribute of DA-ergic neurons. In the mid eighties of the last century, in addition to DA-ergic neurons, those expressing only one enzyme, TH or AADC, have been discovered. These "monoenzymatic" neurons occurred to be more numerous and more widely distributed in the brain compared to DA-ergic neurons that manifests their wide involvement to the brain functioning. It has been demonstrated that the monoenzymatic neurons expressing complementary enzymes of DA synthesis produce this neurotransmitter in cooperation. In this case, L-tyrosine is transformed to L-DOPA in TH containing neurons that is followed by L-DOPA release and uptake from the intercellular space to AADC containing neurons for DA synthesis. Moreover, the L-DOPA uptake to DA-ergic or serotoninergic neurons results either in the increase or the onset of DA synthesis in addition to serotonin, respectively. The expression of the enzymes of DA synthesis in non-dopaminergic neurons is one of the adaptive reactions serving to compensate the functional insufficiency of DA-ergic neurons. For instance, hyperprolactinemia and the deficiency of DA, prolactin-inhibiting hormone, which is developed under degeneration of DA-ergic neurons of the arcuate nucleus, are compensated with time due to the increase of the number of monoenzymatic neurons and cooperative synthesis of DA in the nucleus. It is supposed that the same compensatory cooperative synthesis of DA is turned on under the degeneration of DA-ergic neurons of the nigrostriatal system that is manifested by the appearance of non-dopaminergic neurons expressing enzymes of DA synthesis in the deafferentated striatum. The expression of the enzymes of DA synthesis in non-dopaminergic neurons is under the control by intercellular signals, catecholamines, neurotrophic (growth) factors and, perhaps, hormones. Thus, non-dopaminergic monoenzymatic neurons expressing enzymes of DA synthesis produce this neurotransmitter in cooperation that is a compensatory reaction under functional insufficiency of DA-ergic neurons, in neurodegenerative diseases, hyperprolactinemia and Parkinson's disease, in particular.     

Metabolism of Catecholamines in the Developing Spinal Cord of the Rat

The metabolism of 3,4-dihydroxyphenylethylamine (DA, dopamine) and norepinephrine (NE) both normally, and after the administration of levo-3,4-dihydroxyphenylalanine (L-DOPA), has been studied in several regions of the developing spinal cord of the rat from fetal day (FD) 16 to the young adult stage. During late fetal (from FD 16) and most of neonatal life [to neonatal day (ND) 20], dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were either just detectable or present in very low concentration in all regions in the untreated developing rat. However, the developing spinal cord possesses an enormous capacity to metabolize the large amounts of DA synthesized from injected L-DOPA. At the end of 1 h after 100 mg/kg i.p. of L-DOPA, DOPAC and HVA are 54 +/- 14 (n = 5) and 16 +/- 5 (n = 5) nmol/g, respectively, in the thoracic zona intermedia in the 12-h-old (ND 0.5) rat. This metabolic capability is already highly developed as early as FD 16, peaks during the first half of neonatal life (ND 4 for DOPAC, and ND 15 for HVA), and is considerably reduced toward the end of neonatal life (approximately ND 28) and in the young adult. Control experiments suggest that a substantial part of this synthesis (from L-DOPA) and metabolism of DA occurs in elements other than the descending monoaminergic nerve fibers. By comparison, the synthesis and metabolism of NE develop more slowly, peak in the latter half of neonatal life, and then decline to the level found in the young adult.(ABSTRACT TRUNCATED AT 250 WORDS)