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PubMed1982

Studies on the mechanism by which tyrosine raises urinary catecholamines.

The source of urinary catecholamines and the mechanisms by which tyrosine administration raises these compounds were investigated in rats. Adrenalectomy blocked the tyrosine-induced rise in urinary epinephrine but not dopamine or norepinephrine. Following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), the tyrosine-induced increase in urinary norepinephrine was diminished, but epinephrine and dopamine responses were unaffected. Cardiac norepinephrine, which is normally unchanged following tyrosine administration, became significantly elevated in 6-OHDA-pretreated animals. At the doses used in this study, tyrosine had no effect on the uptake or metabolic clearance of circulating catecholamines. We conclude that tyrosine augments the synthesis of the three catecholamines in sympathoadrenal cells by increasing the extent to which tyrosine hydroxylase is saturated with its amino acid substrate. Moreover, the effects of tyrosine on peripheral catecholamine synthesis may be enhanced under conditions of increased sympathetic activity.

Adrenal Glands↗
PubMed1988

Decreases in tyrosine and p-hydroxyphenylglycol caused by various antidepressants.

The effects of eleven different antidepressant drugs on brain p-hydroxyphenylglycol (pHPG) and on brain and plasma tyrosine concentrations were investigated in rats. Imipramine, amitriptyline, amoxapine, desmethylimipramine and iprindole (20 mg/kg each) and bupropion (50 mg/kg) decreased brain pHPG levels 4.5 or 6 hr after injection. Each of these drugs also significantly reduced plasma tyrosine levels 1.5 hr after injection. In contrast, zimelidine, amitriptylinoxide, trimipramine and trazodone had no significant effect on either brain pHPG or plasma tyrosine. Mianserin significantly lowered plasma tyrosine but produced a nonsignificant decrease in brain pHPG. The decreases in brain pHPG caused by the various drugs were significantly correlated with 3,4-dihydroxyphenylethyleneglycol. Moreover, decreases in brain pHPG and brain and plasma tyrosine concentrations were correlated with the potencies of these drugs to inhibit in vitro norepinephrine uptake. These results suggest the possibility that noradrenergic (or similar) mechanisms regulate both pHPG and tyrosine levels. However, the decreases in pHPG cannot be explained entirely by a deficiency in tyrosine, since the depletions in pHPG were much larger and longer lasting than those of tyrosine.

Animals↗
PubMed1984

Neurochemical and behavioral consequences of acute, uncontrollable stress: effects of dietary tyrosine.

Acute, uncontrollable stress increases norepinephrine (NE) turnover in the rat's brain (thereby depleting NE) and diminishes the animal's subsequent tendency to explore a novel environment. We determined whether supplemental dietary tyrosine could prevent some of these changes. Rats given a control diet or diets enriched with tyrosine or tyrosine plus valine were exposed to tail-shock stress or to no stress over a 60-min period. Exposure to the stress caused an increase in NE turnover, decreasing NE and increasing 3-methoxy-4-hydroxy-phenylethylene glycol sulfate (MHPG-SO4) concentrations within the locus coeruleus, hypothalamus and hippocampus. No changes were detected in serotonin (5-HT) levels or turnover. Behavioral deficits following the stress were observed using measures of locomotion and of exploration in a novel open-field environment: stressed animals displayed much less spontaneous motor activity, hole-poking or frequency of standing on their hind legs than control animals. Animals receiving the tyrosine-enriched diet displayed neither the stress-induced depletion of NE nor the behavioral depression. These preventive effects of tyrosine were abolished by co-administration of valine, a large neutral amino acid that competes with tyrosine for transport across the blood-brain barrier. Since tyrosine alone, in animals not subjected to stress, did not change NE turnover nor the behaviors studied, our observations affirm that catecholaminergic neurons respond to the precursor amino acid only when they are physiologically active. Supplementary tyrosine may be useful therapeutically in people exposed chronically to stress.

Animals↗
PubMed1985

Tyrosine accelerates catecholamine synthesis in hemorrhaged hypotensive rats.

Tyrosine, the amino acid precursor of catecholamines, increases blood pressure (BP) in rats made hypotensive by hemorrhage. Since this amino acid also accelerates catecholamine synthesis in and release from frequently-firing neurons, we tested the hypothesis that tyrosine's pressor action resulted from this mechanism. Male Sprague-Dawley rats (500 g) were anesthetized with chloralose (50 mg/kg) and urethane (500 mg/kg) and tracheostomized. The carotid artery was cannulated allowing BP to be recorded continuously. Blood was removed until systolic BP fell to half of each animal's starting value; 45 min later, animals received tyrosine or other treatments in volumes of 1 ml/kg. Tyrosine (100 mg/kg) increased BP by 58%, while saline caused an insignificant increase. Pretreatment with carbidopa, which inhibits tyrosine's conversion to catecholamines, blocked the amino acid's effect. Tyrosine also failed to increase BP in rats made hypotensive with phentolamine, suggesting that it acts via catecholamine receptors. Adrenal epinephrine significantly (P less than 0.02) and splenic norepinephrine slightly (P less than 0.07) increased in rats receiving tyrosine after 1 h of hypotension when compared with tissue-catecholamine contents in similar rats. These observations show that tyrosine increases BP during hemorrhagic hypotension by accelerating catecholamine synthesis.

Adrenal Glands↗
PubMed1996

Tyrosine hydroxylase expression within Balb/C and C57black/6 mouse locus coeruleus. I. Topological organization and phenotypic plasticity of the enzyme-containing cell population.

Tyrosine hydroxylase phenotype expression was investigated in the catecholaminergic population of the locus coeruleus neurons of two pure inbred mouse strains, Balb/C and C57Black/6. Therefore, we have characterized the precise organization of tyrosine hydroxylase-expressing perikarya population, in control animals and following RU24722 treatment, which is known to induce tyrosine hydroxylase expression. Serial coronal sections were selected along the caudo-rostral extent of the structure and were processed for tyrosine hydroxylase immunocytochemistry. Three days after the treatment, an increase in the number of cells which expressed tyrosine hydroxylase was observed all along the locus coeruleus in the Balb/C strain only. This increase equalized the catecholaminergic neuron populations of the two strains. In the caudal subdivision of the structure, these newly detected perikarya were intermingled with the perikarya which expressed tyrosine hydroxylase in control conditions. In the rostral half, the additional immunoreactive perikarya enlarged the mean coerulean space, defined as the area delimited by the tyrosine hydroxylase-containing perikarya. These results demonstrate a plasticity of the tyrosine hydroxylase phenotype expression, topologically organized and specific to the Balb/C strain.

Animals↗
PubMed1977

Studies on the depletion of brain amines by m-tyrosine.

The biochemical basis of the well-known physiological and pharmacological actions of m-tyrosine was examined by a detailed study of its effect on the brain biogenic amines. m-Tyrosine was injected i.p. and rat brain monoamine levels were measured. Endogenous levels of dopamine, norepinephrine and serotonin all showed approximately 50% reductions 1 h after the administration of L-m-tyrosine at 150 mg/kg. These actions of L-m-tyrosine could be blocked by the inhibition of the central dopa decarboxylase. Depletion of brain monoamines was also observed with the D-isomer of m-tyrosine, although this effect was less pronounced than that of the L-isomer. In vitro experiments with rat brain homogenates showed that L-m-tyrosine, m-tyramine and m-octopamine enhanced in efflux of exogenous labeled monamines from brain particles, whereas D-m-tyrosine was completely ineffective. From these results it is concluded that the observed decreased in brain monamine levels by L-m-tyrosine may be due to a m-tyramine-enhanced release of the amines which are quickly metabolized in vivo.

Animals↗
PubMed1985

Abnormal phenylalanine hydroxylation and tyrosine oxidation in a patient with acute fulminant liver disease with correction by liver transplantation.

Phenylalanine hydroxylation, tyrosine oxidation, and plasma appearance of phenylalanine and tyrosine were evaluated in a 49-yr-old woman with fulminant non-A, non-B hepatitis and encephalopathy using a continuous intravenous infusion of L-[ring-D5]phenylalanine and L-[U-14C]tyrosine. Despite marked elevations in plasma phenylalanine and tyrosine appearance and normal apparent albumin synthetic rates, phenylalanine clearance and hydroxylation to tyrosine were only 12% and 60%, respectively, of values observed in individuals with normal liver function. Three days after orthotopic liver transplantation, plasma phenylalanine and tyrosine appearances were not markedly changed. Phenylalanine clearance and conversion to tyrosine, however, were restored to normal. In addition, tyrosine oxidation and apparent albumin synthesis were increased. This case report represents the first in vivo demonstration of a selective diminution of enzyme function in an individual with fulminant liver disease. Liver replacement restored aromatic amino acid degradative capacity and increased albumin synthesis.

Female↗
PubMed1984

Whole-body tyrosine flux in relation to energy expenditure in weight-losing cancer patients.

Whole-body tyrosine flux was measured in seven weight-losing cancer patients and compared with that of seven noncancer patients with malnutrition. L[U-14C] tyrosine was infused intravenously (IV) after an overnight fast under resting conditions and flux rates, oxidation, and incorporation into proteins of tyrosine were calculated from plateau values of specific activity of tyrosine in plasma and of labeled expired carbon dioxide. Rates of protein synthesis were calculated from the flux rate of tyrosine after subtracting the proportion oxidized. Simultaneous measurements of whole-body carbon dioxide production and oxygen uptake were also performed in each subject. Cancer patients had elevated whole-body tyrosine flux, protein synthesis, and energy expenditure when expressed in relation to body weight and whole-body potassium while the differences in tyrosine kinetics became of borderline significance when expressed in relation to energy expenditure. Tyrosine incorporation into whole-body proteins corresponded to a synthesis rate of 2.70 +/- 0.17 protein/kg/d in cancer patients and 2.18 +/- 0.17 in control patients (P less than 0.025). The results show that elevated protein synthesis in weight-losing cancer patients may explain not more than one third of the elevated energy expenditure. Therefore, other systems that utilize energy must increase in activity.

Aged↗
PubMed1983

Participation of spinal monoaminergic and cholinergic systems in the regulation of adrenal tyrosine hydroxylase.

The role of spinal pathways in the regulation of tyrosine hydroxylase activity (ATHA) in the adrenal medulla was characterized in adult rats with surgical transection of the upper thoracic cord. The animals received injections of centrally active agonists, which could then act on the sympathoadrenal preganglionic neurons isolated from their supraspinal afferents. All agonists tested produced distinct increases of tyrosine hydroxylase activity in rats with a surgical sham operation. The injection of quipazine or oxotremorine into spinalized rats led to decreased tyrosine hydroxylase activity. Clonidine and several dopamine agonists did not affect tyrosine hydroxylase activity. Considering the mechanism of the observed changes in tyrosine hydroxylase activity it is concluded that the changes are mediated by neural pathways and that variations in the secretion of adrenocorticotrophic hormone (ACTH) do not play a role. The results suggest (a) that there are serotonergic and cholinergic (muscarinic) receptors in the lower thoracic cord generating a net inhibitory action on tyrosine hydroxylase activity; and (b) that increases of tyrosine hydroxylase activity mediated by dopaminergic drugs probably originate from areas rostral to the thoracic cord. It is possible that an alpha-adrenergic system participates in the regulation of tyrosine hydroxylase activity in the adrenal medulla.

Adrenal Medulla↗
PubMed1986

Tyrosine influence on amphetamine self-administration and brain catecholamines in the rat.

Earlier work had shown that L-tyrosine administration, precursor to both dopamine (DA) and norepinephrine (NE), could increase brain DA metabolite concentrations after amphetamine treatment and restore amphetamine-induced decreases in whole brain NE. Both monoamines have been suggested to participate in some aspects of continued drug abuse. Rats trained to self-administer IV d-amphetamine were treated with IP tyrosine during test sessions to examine the behavioral and neurochemical response. In animals with less than 35 days of amphetamine exposure, L-tyrosine treatments did not alter amphetamine self-administration. Experiments using a computer-controlled injection apparatus which administered IV amphetamine to naive rats in patterns mimicking those of self-administration animals indicated tyrosine could antagonize amphetamine-induced NE depletions. The increases in DA metabolite dihydroxyphenylacetic acid (DOPAC) were found limited to the striatum, an area not involved in the positive reinforcing effects of amphetamine. Concentrations of DOPAC in nucleus accumbens septi were unchanged by the amphetamine or the amphetamine-tyrosine regimen. In rats with 4-6 months of chronic amphetamine exposure, however, L-tyrosine administration significantly reduced daily drug self-injection. While neurochemical responses to tyrosine could not be performed, it is speculated that chronic long-term amphetamine abuse might alter the tyrosine-induced changes in DA and/or NE synthesis and release compared to that in the acute or short-term amphetamine abuse animals. These data suggest that the success or failure of an experimental pharmacologic treatment strategy in psychomotor stimulant abusers might be dependent on the subjects history of drug abuse.

Animals↗
PubMed1996

Activation of tyrosine hydroxylase by pituitary adenylate cyclase-activating polypeptide (PACAP-27) in bovine adrenal chromaffin cells.

The effect of pituitary adenylate cyclase-activating polypeptide (PACAP-27) on tyrosine hydroxylase activity has been studied in intact, cultured, bovine adrenal chromaffin cells. Tyrosine hydroxylase activity was determined in situ by measuring the production of 14CO2 following the hydroxylation and rapid decarboxylation of [14C]tyr offered to the cells. PACAP-27 increased tyrosine hydroxylase activity 3-fold over 10 min. With an EC50 of 10-20 nM. PACAP-38 was approximately 2-fold less potent. Removing extracellular Ca2+ reduced basal tyrosine hydroxylase activity and the activation produced by both PACAP-27 and forskolin by about 20%. In the absence of extracellular Ca2+, chelation of intracellular Ca2+ by treating cells with BAPTA-AM (50 microM) caused a consistent 40-50% reduction in basal tyrosine hydroxylase activity and in the responses to forskolin and PACAP-27. The tyrosine hydroxylase activation produced by PACAP-27 was unaffected by the protein kinase C inhibitor Ro 3l-8220 (3 microM), but was reduced by 85% by the protein kinase A inhibitor H89 (10 microM). PACAP-27 increased cellular cyclic AMP levels 3-fold at 100 nM. The results suggest that PACAP-27 activates tyrosine hydroxylase in bovine chromaffin cells through cyclic AMP formation and protein kinase A activation, and that both extracellular and intracellular Ca2+ modulate the effect of the adenylate cyclase/cyclic AMP/protein kinase A signalling pathway on tyrosine hydroxylase activity.

Animals↗
PubMed1989

Human neutrophils contain distinct cytosolic and particulate tyrosine kinase activities: possible role in neutrophil activation.

Tyrosine protein kinase activities were partially purified from circulating human neutrophils. Purification steps involved sequential chromatography on DEAE-Sephacel, gel filtration and affinity chromatography on a column composed of a glutamine:tyrosine copolymer linked to AH-Sepharose. The results indicate that human neutrophils contain a tyrosine kinase activity in the 150,000 x g cytosolic fraction which is distinct from the activity in a detergent extractable 150,000 x g particulate fraction. These enzyme activities are dependent on the divalent cations Mn2+ and Mg2+. Kinetics for the phosphorylation of a glutamine:tyrosine copolymer substrate demonstrated an apparent Km for the cytosolic tyrosine kinase activity of 22.3 +/- 0.3 microM, and an apparent Km for the particulate extract activity of 42.7 +/- 6.0 microM. By gel filtration chromatography, the cytosolic and particulate tyrosine kinase activities have approximate molecular masses of 80-90 and 50-60 kDa, respectively. The particulate but not the cytosolic neutrophil tyrosine kinase activity was inhibited by a novel tyrosine kinase inhibitor ST638. ST638 inhibited superoxide production in intact neutrophils stimulated with the chemotactic peptide F-Met-Leu-Phe, opsonized zymosan particles, and sodium fluoride. ST638 did not, however, inhibit superoxide production in neutrophils stimulated with phorbol myristate acetate or the calcium ionophore, A23187.

Cations, Divalent↗
PubMed1984

Phosphorylation of tyrosine hydroxylase in the superior cervical ganglion.

We studied the phosphorylation of tyrosine hydroxylase in the superior cervical ganglion of the rat. Ganglia were preincubated with [32P]Pi and were then incubated in non-radioactive medium containing a variety of agents that are known to activate tyrosine hydroxylase in this tissue. Tyrosine hydroxylase was isolated from homogenates of the ganglia by immunoprecipitation followed by polyacrylamide gel electrophoresis. 32P-labelled tyrosine hydroxylase was visualized by radioautography, and the incorporation of 32P into the enzyme was quantitated by densitometry of the autoradiograms. Veratridine produced a concentration-dependent increase in the incorporation of 32P into tyrosine hydroxylase, with 50 microM veratridine producing a 5-fold increase in 32P incorporation. The nicotinic agonist, dimethylphenylpiperazinium (100 microM), caused a 7-fold increase in the phosphorylation of tyrosine hydroxylase. The effect of dimethylphenylpiperazinium was maximal within 1 min and decreased upon continued exposure of the ganglia to this agent. The actions of dimethylphenylpiperazinium and of veratridine were dependent on extracellular Ca2+. Muscarine, 8-Br-cAMP, forskolin, vasoactive intestinal peptide, isoproterenol, deoxycholate and phospholipase C also stimulated the incorporation of 32P into tyrosine hydroxylase. These data support the hypothesis that phosphorylation plays a role in activation of tyrosine hydroxylase produced by all of these agents.

Animals↗
PubMed1994

Activation of the macrophage respiratory burst by phorbol myristate acetate: evidence for both tyrosine-kinase-dependent and -independent pathways.

We have investigated the relationship between tyrosine phosphorylation and respiratory-burst activity in murine bone-marrow-derived macrophages (BMM) stimulated with phorbol myristate acetate (PMA). In unprimed BMM, a good correlation was observed between the net level of tyrosine phosphorylation and the activity of the respiratory burst. The phosphotyrosine phosphatase inhibitor, vanadate, enhanced both tyrosine phosphorylation and respiratory-burst activity triggered by PMA. Furthermore, the tyrosine kinase inhibitor, ST638, abolished both tyrosine phosphorylation and respiratory-burst activity stimulated by PMA. However, in BMM primed by preexposure to TNF alpha, the correlation between net tyrosine phosphorylation and respiratory-burst activity triggered by PMA was not maintained. ST638 was found to only partially inhibit the PMA-triggered respiratory burst under conditions where PMA-stimulated tyrosine phosphorylation was abolished. We conclude that PMA can activate the macrophage respiratory burst by both tyrosine-kinase-dependent and -independent pathways.

Animals↗
PubMed1988

Gastric mucosal tyrosine kinase activity during aging and its relationship to cell proliferation in rats.

The relationship between tyrosine kinase activity and cellular proliferative activity was investigated in the gastric mucosa. For the purpose of comparison, the liver and the pancreas were also included. Groups of 2-, 14- and 22-month-old male Fischer-344 rats were used. Tyrosine kinase activity was determined in the membrane fraction (30,000 x g pellet) utilizing a synthetic polymer, Glu-Tyr (4:1), as substrate. Cellular proliferative activity was assessed by measuring ornithine decarboxylase in the 20,000 x g supernatant. In all age groups, gastric mucosal tyrosine kinase activity was found to be 10-20-fold higher than in the liver or pancreas. In addition, gastric mucosal tyrosine kinase activity in 22-month-old rats was 35-70% higher than in their 2- and 14-month-old counterparts. Gastric mucosal ornithine decarboxylase activity also followed essentially the same pattern as that of tyrosine kinase in that the highest activity was observed in 22-month-old rats. Increased gastric mucosal proliferative activity in 22-month-old rats was also associated with increased tyrosine-phosphorylation of a mucosal membrane protein with an apparent Mr of 53,000. An opposite phenomenon occurred in the pancreas whose proliferative activity was found to be the lowest. It is concluded that the age-associated changes in gastric mucosal proliferative activity are accompanied by parallel alterations in tyrosine kinase activity. Tyrosine-phosphorylation of a 53 kDa membrane protein may play a role in the regulation of cell proliferation.

Aging↗
PubMed1984

Olfactory bulb dopamine neurons survive deafferentation-induced loss of tyrosine hydroxylase.

Peripheral deafferentation of the rodent olfactory bulb results in loss of dopamine content, tyrosine hydroxylase activity and immunocytochemical staining for tyrosine hydroxylase in juxtaglomerular dopamine neurons. Reinnervation of the bulb by afferent neurons results in the return of all parameters to control levels suggesting that the dopamine neurons did not degenerate but that the expression of tyrosine hydroxylase enzyme was transneuronally regulated in a static population of juxtaglomerular cells. To evaluate this possibility, we determined the activity and immunocytochemical localization of the second enzyme in the dopamine biosynthetic pathway, DOPA decarboxylase. At a time when tyrosine hydroxylase activity was reduced to 25% of control values, DOPA decarboxylase activity in the lesioned bulb was maintained at about 65% of that in the unlesioned bulb. Immunocytochemical staining with antibodies to both enzymes, performed sequentially in the same sections, demonstrated that in the unlesioned bulb tyrosine hydroxylase and DOPA decarboxylase are co-localized in the same population of juxtaglomerular neurons. Similar results were obtained in adjacent sections each stained with one of the two antibodies. In contrast, in the deafferented bulb, about three times as many neurons were stained with DOPA decarboxylase as with tyrosine hydroxylase antibodies. The DOPA decarboxylase activity measurements and immunocytochemistry argue for the continued presence, in the lesioned olfactory bulb, of a population of tyrosine hydroxylase deficient dopamine neurons. The data suggest that olfactory receptor cell innervation transneuronally regulates the expression of tyrosine hydroxylase by mechanisms separate from those controlling the levels of DOPA decarboxylase.

Afferent Pathways↗
PubMed1988

Morphometrical evidence for a complex organization of tyrosine hydroxylase-, enkephalin- and DARPP-32-like immunoreactive patches and their codistribution at three rostrocaudal levels in the rat neostriatum.

Tyrosine hydroxylase-like, dopamine- and cyclic AMP-regulated phosphoprotein (Mr = 32,000)-like and enkephalin-like immunoreactive profiles and their codistribution have been evaluated at three rostrocaudal levels of the rat neostriatum by means of a computer-assisted morphometrical method, which allows an objective definition of high density/intensity patches using specific antibodies in combination with the peroxidase-antiperoxidase technique. Our results show that both tyrosine hydroxylase-like, dopamine- and cyclic AMP-regulated phosphoprotein-like and enkephalin-like profiles are organized in patches in the rat neostriatum. In the marginal zone, the tyrosine hydroxylase-like immunoreactive and dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive patches both occupied a large part of the total area. Moreover, in this zone, these putative markers for pre- and postsynaptic elements of dopaminergic synapses also showed a complete spatial overlap. In contrast, the enkephalin-like immunoreactive patches in the marginal zone occupied a smaller area, and showed only an incomplete, albeit significant overlap with the tyrosine hydroxylase-like immunoreactive/dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive system. In the central zone, tyrosine hydroxylase-like immunoreactive, dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive and enkephalin-like immunoreactive patches occupied a much smaller part of the total area than did those in the marginal zone. Within the central zone, enkephalin-like immunoreactive patches occupied a significantly larger area than did the tyrosine hydroxylase-like immunoreactive and dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive patches. No consistent pattern of overlap between the three different staining patterns could be seen in the central zone, probably due to the small, inconsistent size of the patches. Trend analysis showed a consistent trend of more tyrosine hydroxylase-like immunoreactive and dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive patches in the dorsal than in the ventral striatum, and a trend of more enkephalin-like immunoreactive patches in the rostral than in the caudal striatum. Our data thus demonstrate that, by using computer-assisted morphometrical techniques, it is possible to describe a non-homogenous but overlapping distribution of tyrosine hydroxylase-like immunoreactive and dopamine- and cyclic AMP-regulated phosphoprotein-like immunoreactive patches in the rat neostriatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Convergent regulation by ciliary neurotrophic factor and dopamine of tyrosine hydroxylase expression in cultures of rat substantia nigra.

Ciliary neurotrophic factor and dopamine were found to enhance the expression of tyrosine hydroxylase immunoreactivity in cultured neurons from the substantia nigra of 16-day-old rat fetuses. The number of tyrosine hydroxylase-positive cells decreased progressively to approximately 30% by 96 h. Treatment with 5 microM dopamine maintained the tyrosine hydroxylase-positive neurons at 60% for 48 h, but not for longer. Concurrent treatment with 5 microM dopamine and 20 trophic units/ml ciliary neurotrophic factor had a greater impact on tyrosine hydroxylase-positive cells, resulting in the maintenance of 70% of the initial number for up to 72 h, but not beyond that time. When dopamine or dopamine/ciliary neurotrophic factor treatments were applied for 24 h after a 48-h delay, the number of tyrosine hydroxylase-positive cells was restored to 60 and 80%, respectively, but not restoration was observed with 96-h delayed treatments. These results suggest that dopamine and ciliary neurotrophic factor, alone or in combination, are not able to support the survival of tyrosine hydroxylase-positive neurons, but reduce their apparent numerical loss by enhancing the expression of tyrosine hydroxylase. The effects of dopamine, alone or in combination with ciliary neurotrophic factor, were predominantly mediated by D2 receptors, since they were blocked by selective D2 receptor antagonists and since the D2 receptor agonist quinpirole was able to substitute for dopamine. The effects of dopamine and ciliary neurotrophic factor were similar in astroblast-rich and in astroblast-depleted cultures, suggesting that they were not mediated through glial cells. These results extend our previous observations on locus coeruleus cultures, in which the concurrent treatment with ciliary neurotrophic factor and norepinephrine was shown to enhance tyrosine hydroxylase expression (but not survival) of noradrenergic neurons. They also consolidate the view that ciliary neurotrophic factor and the neuron's own transmitter act in convergence and in an autocrine/paracrine mode as regulators of the corresponding neurotransmitter phenotype.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗