Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transmitter dopamine reduces electrotonic coupling between retinal horizontal cells and increases their sensitivity to glutamate. Since in other systems single afferents establish mixed electrotonic and chemical excitatory synapses with their targets, dopamine might be expected there to depress one component of excitation while enhancing the other. This hypothesis was tested by applying dopamine locally in the vicinity of the lateral dendrite of the goldfish Mauthner cell (M cell) and monitoring the composite electrotonic and chemical excitatory postsynaptic potentials and currents evoked by ipsilateral eighth nerve stimulation. Dopamine produces persistent enhancements of both components of the postsynaptic response while it also increases input conductance. All these dopamine actions are prevented by superfusing the brain with saline containing the dopamine D1 receptor antagonist SCH-23390. Postsynaptic injections of the cAMP-dependent protein kinase inhibitor (Walsh inhibitor, or PKI5-24) block the dopamine-induced changes in synaptic transmission, implicating a cAMP-dependent mechanism. Furthermore, there is a dopaminergic innervation of the M cell, as demonstrated immunohistochemically with antibodies against dopamine and the rate-limiting enzyme in its synthetic pathway, tyrosine hydroxylase. Varicose immunoreactive fibers lie in the vicinity of the distal part of the lateral dendrite between the large myelinated club endings that establish the mixed synapses. As determined with electron microscopy, the dopaminergic fibers contain small vesicles, and they do not have synaptic contacts with either the afferents or the M cell, remaining instead in the synaptic bed. Taken together, these results suggest that dopamine released at a distance from these terminals increases the gain of this primary sensory input to the M cell, most likely through a phosphorylation mechanism.
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PMID:Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses. 133 56

Dopamine and selective agonists of D1 [(1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, SKF 38393] and D2 [(3-[2-[N-(3-hydroxyphenylethyl)-N-propylamino]ethyl] phenol, RU 24926] receptors were examined as inhibitors of the activity of tyrosine hydroxylase in the striatum of the guinea pig. In soluble enzyme preparations, the agonists were weak inhibitors of the activity of tyrosine hydroxylase. However, the catechol-containing agonists dopamine (EC50 = 44.7 microM) and SKF 38393 (EC50 = 35.5 microM) were more potent than the non-catechol agonist RU 24926 (EC50 = 447 microM). All of the agonists were much more potent in synaptosome-rich preparations of guinea pig striatum, where stimulation of autoreceptors mediated inhibition of the enzyme (SKF 38393, D1, EC50 = 27 nM; RU 24926, D2, EC50 = 30 nM; dopamine, non-selective, EC50 = 1.5 microM). The D1 antagonist, SCH 23390 [(R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine hydrochloride], did not significantly reduce the action of SKF 38393 or dopamine. Furthermore, the D2 antagonist, (-)-sulpiride, significantly antagonized the inhibitory activity of both RU 24926 and dopamine. Studies in synaptosome-rich preparations from the striatum of the rat showed that both SKF 38393 (EC50 = 398 nM) and RU 24926 (EC50 = 58 nM) were also effective autoreceptor-mediated inhibitors of the activity of tyrosine hydroxylase in the rat. However, in the rat, SCH 23390 and (-)-sulpiride were equally effective in attenuating the inhibitory actions of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine D2 synthesis-modulating receptors are present in the striatum of the guinea pig. 134 5

The present study shows that during the time course of the action of single doses, L-dopa induces multiphasic opposing effects on pain, recorded as vocalization during the presentation of electrical stimulation applied to the tail of normal rats. This indicates that two or more functional systems contribute to produce the net response. A small dose (15 mg/kg) of L-dopa facilitates pain slightly, whereas larger doses (100-200 mg/kg) can produce an antinociceptive effect following an initial hyperalgesia. Moreover, profound hyperalgesia is revealed by either dopamine (DA) D1 and D2 receptor blockade by means of SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H- 3-benzazepine hydrochloride] or (-)-sulpiride, respectively, as well as after a reduction of the presynaptic synthesis of catecholamines after pretreatment of the animals with the tyrosine hydroxylase inhibitor alpha-methyl-DL-p-tyrosine (alpha-MPT). The enhancement of L-dopa's hyperalgesic effect after SCH 23390 treatment is maximal already at the onset of the effects, whereas (-)-sulpiride or alpha-methyl-DL-p-tyrosine precipitates the hyperalgesia after a certain temporal delay during defined phases of the time course of the effects of large L-dopa doses. The D1 receptor agonist (+)-SKF 38393 potentiates both the hyperalgesic and antinociceptive effects of 100 mg/kg of L-dopa. It is suggested that L-dopa's net effect on pain is modulated from concentration-dependent, opposing effector systems involving both DA stimulatory and inhibitory receptor mechanisms. At high dosing, activation of D2 receptors enhancing DA functional activity produces an antinociceptive response that normally outweighs the hyperalgesia, but this effect becomes dissociable with inhibition of central DA activity.
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PMID:L-dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses. 143 83

The anatomical and functional characteristics of dopamine neuron-rich grafts implanted into rat pups were compared with those of identical grafts implanted into adult hosts. The host nigrostriatal dopaminergic pathway was unilaterally destroyed by an intrahypothalamic injection of 6-hydroxydopamine. This was followed five days later by the implantation of a cellular suspension obtained from rat embryonic mesencephali. Identical operations were carried out on adult and infant (PD3) rats. The survival rate of implanted tyrosine hydroxylase-positive cells was lower in the neonates. On the other hand, in the neonate hosts, surviving immunoreactive cells migrated extensively throughout the host striatum coursing preferentially below the corpus callosum and towards the subependymal zone. The structural integrity of the host parenchyma was well maintained after the neonatal implantation, in contrast to that observed in the adults. Despite a difference in the cell survival rate, there was no major difference in reinnervation density between the two types of host. The functional capacities of the implants were evaluated by measuring the rotational responses of the animals to dopaminergic agonists. The implants compensated the lesion-induced contralateral rotational response to the mixed agonist apomorphine and the D1 agonist SCH-38393 in both neonates and adults. However, the response to the D2 agonist LY-171555 was not significantly attenuated by the implant. The ipsilateral rotational response to amphetamine observed in the lesioned animals was also compensated and even reversed by the graft. It is concluded that with respect to rotational behavior, similar functional benefits were observed following adult stage or neonatal implantation, despite differences in their anatomical development.
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PMID:Anatomical and behavioral comparison of unilateral dopamine-rich grafts implanted into the striatum of neonatal and adult rats. 167 13

The effect of alpha-methyl-p-tyrosine (alpha-MT), FLA-63, amphetamine, apomorphine and quinpirole on the concentration of thyrotropin-releasing hormone (TRH) in the striatum and nucleus accumbens was studied in rats. It has been found that the TRH content was increased in both those structures after alpha-MT, an inhibitor of tyrosine hydroxylase which reduced the concentration of both dopamine (DA) and noradrenaline (NA), but not after FLA-63, an inhibitor of DA-beta-hydroxylase which decreased the NA level without affecting DA. On the other hand, the indirectly acting dopaminomimetic amphetamine, the non-selective DA receptor agonist apomorphine, and the selective D2 receptor agonist quinpirole reduced the TRH level in the striatum, but not in the nucleus accumbens. Moreover, the decrease in the striatal peptide content induced by DA-mimetics was antagonized by the selective D2-receptor antagonist sulpiride, but not by the selective D1 receptor antagonist SCH 23390. The effect of amphetamine was not modified by the selective alpha 1-adrenoceptor antagonist prazosin. These results indicate that DA and D2 receptors play a significant role in the regulation of the striatal TRH.
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PMID:The role of dopamine in regulation of thyrotropin-releasing hormone in the striatum and nucleus accumbens of the rat. 168 Feb 23

Incubation of turtle or Xenopus retinas in 0.1 nM [125I]SCH 23982, a dopamine D1 receptor antagonist for 30-45 min and subsequent fixation in paraformaldehyde/glutaraldehyde resulted in strong blue formaldehyde-induced fluorescence of inner retinal neurons. On the basis of their morphological features, the labeled cells were classified as dopaminergic cells, an identification which was confirmed by double-labeling experiments using an antiserum against tyrosine hydroxylase. The whole experiment can be conducted in less than 2 h (whole mount), the label is very stable and allows the use of high-magnification objectives for detailed morphological investigation of dopaminergic retinal neurons.
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PMID:[125I]SCH 23982, a new tool for rapid visualization of dopaminergic neurons in lower vertebrate retinas. 170 84

Young adult female rats received a 6-hydroxydopamine lesion in the left substantia nigra and, 3 weeks later, some of them were grafted with a cell suspension from the ventral mesencephalon of rat embryos (14-15 days old). Six months after transplantation, some grafted rats, following injection of amphetamine, had switched to turning only toward the intact side (type 1), whereas others turned toward the intact side only during the first half of the test (type 2). Levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid were, respectively, 2%, 15% and 35% of the intact side in the denervated striatum of 6-hydroxydopamine rats. Dopamine concentrations were restored to 13% and 10% of the intact side in the grafted striatum of type 1 and type 2 animals, respectively. Levels of homovanillic acid were unchanged following grafts whereas those of dihydroxyphenylacetic acid increased by 209% and 247% in the grafted striatum of type 1 and type 2 animals, respectively. The ratios of dihydroxyphenylacetic acid/dopamine as well as homovanillic acid/dopamine were low in the intact striatum whereas they increased in the denervated striatum with or without graft. The tyrosine hydroxylase immunoreactivity decreased by about 80% in the denervated striatum of 6-hydroxydopamine rats. In type 1 rats, tyrosine hydroxylase immunoreactivity revealed that the graft was localized in the dorsomedial part of the denervated striatum, whereas in type 2 animals, it was also in the medial striatum but it overlapped the dorsal and ventral parts of it equally. D1 as well as D2 dopamine receptors were measured throughout the striatum (9.0-7.6 rostral-caudal coordinates), by autoradiography, using [3H]SCH 23390 (D1 antagonist) and [3H]spiperone (D2 antagonist) binding. Supersensitive D2 receptors were normalized in the dorso- and ventromedial parts of the grafted striatum. D2 receptor density was higher in type 2 than in type 1 rats, more specifically at 8.6-8.2 rostral-caudal coordinates, where the graft was. D1 receptor supersensitivity was modest compared to D2 receptors in the striatum of 6-hydroxydopamine rats and decreased following grafts. DA receptors changes in the striatum, following fetal mesencephalic grafts, may explain the behavioral recovery seen in grafted rats.
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PMID:Regional changes of striatal dopamine receptors following denervation by 6-hydroxydopamine and fetal mesencephalic grafts in the rat. 183 95

The postnatal development of D1 dopaminergic receptors (D1 receptors) was investigated in the rat striatum in relation to distribution of mu opiate receptor patches and islandic tyrosine hydroxylase (TH)-immunoreactive fibers. The possible influence of dopaminergic (DA) fibers originating from the substantia nigra on the postnatal distribution of striatal D1 and mu receptors was also examined by producing an early 6-hydroxydopamine (6-OHDA) lesion of DA fibers. D1 and mu receptors were labeled with selective ligands: [3H]SCH 23390 and [3H]DAGO, respectively. During the first postnatal week, control rats showed patches of dense D1 binding sites in the entire rostro-caudal extension of the striatum. The localization of D1 receptor patches corresponded to striosomes identified by TH-immunoreactive islands. The striatal distribution of mu receptors was relatively homogeneous at postnatal day 0 (P0) but was clearly patchy at P3-P4. During the second postnatal week the striosomal pattern of D1 binding sites disappeared along a dorso-ventral gradient whereas mu binding sites remained distributed in patches. Densitometric measurements showed that there was a parallel increase of D1 binding sites in both striosomes and the surrounding matrix from P0 to P4. The disappearance of D1 receptor patches observed in the dorsal striatum at P9 was due to a faster increase of D1 binding sites in the matrix than in striosomes between P4 and P9 whereas a significant difference was still observed between these two compartments in the ventral striatum of P9 rats. During the third postnatal week, the density of D1 binding sites still increased but became progressively uniform in the whole striatum. The intrastriatal injection of 6-OHDA in 2-day-old rats produced a local disappearance of TH-immunoreactive fibers in the striatum and a distal degeneration of TH-immunoreactive cell bodies in the substantia nigra. However an early lesion of striatal DA fibers did not modify the pattern of development or the density of D1 binding sites during the postnatal period examined (1 and 3 weeks after the lesion). The distribution of mu receptors was unchanged 1 week after the lesion but showed a clear disorganization 3 weeks after the lesion. We discuss the differential influence of DA fibers on the distribution of D1 and mu receptors in the rat striatum and the possible role of DA in the regulation of the expression of mu receptors.
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PMID:Comparative development of D1-dopamine and mu opiate receptors in normal and in 6-hydroxydopamine-lesioned neonatal rat striatum: dopaminergic fibers regulate mu but not D1 receptor distribution. 184 2

Presynaptic autoreceptor-mediated modulation of dopamine (DA) synthesis was evaluated as the inhibition of tyrosine hydroxylase activity by enantiomeric mono- and dihydroxyaporphines with minced striatal tissue from rat brain. The isomers of N-n-propylnorapomorphine (NPA) both inhibited tyrosine hydroxylase activity [IC50 = 0.3 and 1.0 microM for (R)-(-)- and (S)-(+)-NPA, respectively; R/S potency = 3.6]. Their effects were fully blocked by the nonselective DA receptor antagonist fluphenazine, as well as by the D2-selective antagonist spiperone, but not by the D1 antagonist SCH-23390. These results suggest a D2-type autoreceptor-mediated inhibition of DA synthesis, with limited enantiomeric selectivity of this catechol-aporphine. The corresponding monohydroxy analogs, (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) were about 100 times less potent (IC50 = 42 and 87 microM, respectively) than the NPA isomers in fully inhibiting the enzyme activity in normal tissue but, after depletion of endogenous DA by acute in vivo pretreatment with reserpine (which did not alter the number of D1 or D2 specific binding sites), (R)-(-)-11-OH-NPa was a highly potent but partial agonist (IC25 = 7 nM). Fluphenazine and spiperone fully antagonized the inhibition of tyrosine hydroxylase by (R)-(-)-11-OH-NPa in reserpinized tissue, but SCH-23390 was ineffective. Actions mediated by endogenous DA probably contribute to the effect of high concentrations of (R)-(-)-11-Oh-NPa to evoke a full inhibition of DA synthesis, but its high potency partial agonist effects appear to be mediated by D2-autoreceptors. (S)-(+)-11-OH-NPa was a very weak partial agonist in reserpinized tissue, with an IC25 = 30 microM (essentially the same as normal tissue); thus, (R)-(-)-11-OH-NPa was greater than 4,000 times more potent than its S-(+)-enantiomer in the absence of endogenous DA. These results demonstrate that NPA, which contains a catechol moiety, acts as a full agonist to inhibit striatal DA synthesis via a presynaptic autoreceptor of the D2 type, with only slight stereoselectivity, and that its monohydroxy analog is a very potent but partial D2 autoreceptor agonist, with very high stereoselectivity.
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PMID:Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines. 197 25

The effects of the D1 dopamine agonists SKF 38393 and CY 208-243 on the activity of tyrosine hydroxylase within tuberoinfundibular dopamine neurons were studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence in vivo after inhibition of DOPA decarboxylase. SKF 38393 (5-20 mg/kg) and CY 208-243 (5-20 mg/kg) alone did not alter the accumulation of DOPA in the median eminence of male rats. However, the haloperidol-, reserpine- and neurotensin-induced increases in DOPA formation in the median eminence were antagonized dose-dependently by SKF 38393 (5-20 mg/kg i.p.) and/or CY 208-243 (5-20 mg/kg i.p.). Treatment of rats with SCH 23390 (0.5 mg/kg i.p.), a selective D1 antagonist, or loxapine (5 mg/kg i.p.), a dopamine antagonist with high affinity for D1 receptors, prevented the inhibitory effect of CY 208-243 on the haloperidol-induced activation of tyrosine hydroxylase in the median eminence. SKF 38393 did not inhibit the basal activity or the haloperidol-induced increase in activity of tyrosine hydroxylase in the striatum or nucleus accumbens. It is concluded that D1 receptor activation results in little or no effect on the basal rate of dopamine synthesis within tuberoinfundibular dopamine neurons, but under conditions in which the activity of tyrosine hydroxylase is increased D1 receptor stimulation results in a marked inhibition of the rate of dopamine synthesis within these neurons.
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PMID:D1 receptors function to inhibit the activation of tuberoinfundibular dopamine neurons. 197 47


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