Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of AP-1 transcription factors was assessed in the dopamine-depleted rat striatum over a 1 week period of repeated apomorphine injections. A single injection of apomorphine increased the expression of a 35 kDa Fos-related antigen and Jun proteins and their expression continued to increase until day 3 of repeated apomorphine treatment in dopamine-depleted striata. Apomorphine induces AP-1 transcription factors which may be involved in modulating gene expression in the striatum.
Brain Res Mol Brain Res 1992 Sep
PMID:Apomorphine induction of AP-1 DNA binding in the rat striatum after dopamine depletion. 133 62

Gonadotropin (GTH) release in static incubations of dispersed goldfish pituitary cells was stimulated by chicken GTH-releasing hormone II (cGnRH-II), salmon (s)GnRH, phospholipase A2, phospholipase C, phospholipase D, and arachidonic acid (AA). Coincubations with nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraenoic acid, and indomethacin did not alter the GTH responses to cGnRH-II. In contrast, NDGA reduced sGnRH-stimulated GTH release. Incubation with Ca(2+)-deficient medium abolished the GTH responses to cGnRH-II, reduced sGnRH-stimulated GTH release, but did not alter AA actions on GTH secretion. Apomorphine, a dopamine agonists that had been shown to partially inhibit the GTH responses to sGnRH and to abolish those induced by cGnRH-II, did not affect the hormone response to AA. However, the partial inhibitory actions of NDGA and apomorphine on sGnRH-induced GTH release were additive. These findings suggest the existence of a major difference in cGnRH-II and sGnRH stimulation of GTH release--AA metabolism is not involved in cGnRH-II, as opposed to sGnRH actions. This difference in second messenger activation may also explain the differential sensitivity of the two GnRH peptides to dopamine inhibition and manipulations of extracellular Ca2+ availability. The results further suggest that dopamine and AA affect GTH release via non-overlapping signal transduction pathways.
Mol Cell Endocrinol 1991 Aug
PMID:Lack of involvement of arachidonic acid metabolism in chicken gonadotropin-releasing hormone II (cGnRH-II) stimulation of gonadotropin secretion in dispersed pituitary cells of goldfish, Carassius auratus. Identification of a major difference in salmon GnRH and chicken GnRH-II mechanisms of action. 193 48

Activation of synthesis-modulating dopamine autoreceptors by dopamine or its agonists has been shown to inhibit dopamine synthesis in the rat striatum. However, systemic administration of the direct-acting dopamine agonist apomorphine failed to inhibit dopamine synthesis in striata from rats that had received local unilateral administration of pertussis toxin. Apomorphine did reduce dopamine synthesis by greater than 50% in sham injected control rats as well as in the striata opposite to the side of pertussis toxin injection. Examination of G proteins in striatal tissue revealed that 61% of the G proteins were ADP-ribosylated in vivo by direct pertussis toxin injection. These data suggest that guanine nucleotide regulatory proteins mediate the effects of activation of striatal synthesis-modulating dopamine autoreceptors.
Mol Pharmacol 1988 Dec
PMID:The effects of pertussis toxin on autoreceptor-mediated inhibition of dopamine synthesis in the rat striatum. 297 20

Phenoxybenzamine, the classic alpha-adrenergic receptor alkylating agent, also acts as an irreversible antagonist of the binding of [3H]spiroperidol, a D-2-selective dopaminergic ligand, to bovine caudate membranes. Doses completely eliminating the binding of this ligand leave the binding of [3H]dopamine to D-3 sites virtually unaffected. The binding sites for these two ligands thus represent distinct subtypes of dopamine receptors, not interconverting states of a single receptor. This phenoxybenzamine-mediated inhibition proceeds via a dose-dependent (pseudo-IC50 = 1 microM) decrease in Bmax with little or no change in affinity for 3H-ligands at the D-2 site. The effect is site-directed, as the dopaminergic agonists dopamine and apomorphine and the antagonist domperidone are able to protect against phenoxybenzamine-mediated attack in proportion to their affinities for D-2 sites. Epinephrine, norepinephrine, and serotonin are much less effective in protecting these sites. The sensitivity of [3H]apomorphine binding is intermediate to that of [3H]spiroperidol and [3H]dopamine. [3H]Apomorphine binding can be resolved into a phenoxybenzamine-labile population of binding sites which have equal phenoxybenzamine sensitivity, selectivity among protecting agents, and butyrophenone affinity to those of D-2 sites labeled by 3H-butyrophenones, and a separate phenoxybenzamine-stable population of sites which have an affinity for dopamine comparable to that of D-3 sites labeled by [3H]dopamine. [3H]Apomorphine therefore appears to label a portion of D-2 receptor sites in addition to D-3 receptors.
Mol Pharmacol 1982 Jan
PMID:Phenoxybenzamine treatment differentiates dopaminergic 3H-ligand binding sites in bovine caudate membranes. 612 21

In male and female rat anterior pituitary homogenates dopamine inhibited basal adenylate cyclase by 30% and 50%, respectively. Dopamine also inhibited vasoactive intestinal peptide-stimulated adenylate cyclase by 50% in both sexes. Sulpiride, a specific D2 antagonist, stereospecifically blocked with high affinity the dopamine inhibition in both males and females. RU 24926, a specific, non-catechol, non-ergot D2 agonist, also inhibited basal adenylate cyclase of female pituitary with a higher apparent affinity than dopamine (KDapp 20 nM and 450 nM, respectively). This effect was also stereospecifically antagonized by sulpiride. Apomorphine was also more potent (KDapp 100 nM) than dopamine, whereas norepinephrine and SKF 38393, a specific D1 agonist, were poorly active; isoproterenol and clonidine were inactive. Ergots derivatives such as CB 154, LY 14865, pergolide, and lergotrile were potent agonists. alpha-Dihydroergocryptine was a partial agonist of the dopamine receptor negatively coupled with an adenylate cyclase. Because of the slow association kinetics of this drug with the dopamine receptor, its KDapp (0.7 nM) for adenylate cyclase inhibition could be correctly determined only after a 30-min incubation period. All classical dopaminergic antagonists blocked dopamine inhibition of pituitary adenylate cyclase, pimozide (KI 1 nM) and spiperone (KI 0.8 nM) being the more potent. There were good correlations between the affinities of large series of agonists and antagonists for the anterior pituitary dopamine receptors negatively coupled with an adenylate cyclase on one hand, and for either D2 dopamine receptors labeled with [3H] dihydroergocryptine or [3H]spiroperidol in both pituitary and striatum, or D2 pituitary receptors involved in prolactin secretion on the other hand. It is concluded that the pituitary dopamine receptors negatively coupled with an adenylate cyclase are the classical D2 receptors involved in prolactin secretion.
Mol Pharmacol 1983 May
PMID:Pharmacological characterization of the D2 dopamine receptor negatively coupled with adenylate cyclase in rat anterior pituitary. 630 29

The present study is an attempt to find sites of dopaminergic inhibition along the transduction cascades culminating in gonadotropin (GtH) release in a teleost fish, tilapia. Experiments were carried out on perifused pituitary fragments and in primary culture of trypsinized pituitary cells. Salmon GnRH, chicken GnRH I and II stimulated GtH release in culture with estimated ED50 values of 15.56 pM, 2.55 nM and 8.65 pM, respectively. Apomorphine (APO; 1 microM) totally abolished this stimulation. Dopamine (DA; 1 microM) reduced both basal and GnRHa-stimulated GtH release from perifused pituitary fragments but did not alter the formation of cAMP. In a similar perifusion experiment DA abolished GtH release in response to forskolin (10 microM) with no reduction in cAMP formation. This indicates that one site of the dopaminergic inhibition is distal to cAMP formation, an indication not compatible with the classic characteristic of DA D2 type mode of action. The inhibition of GtH release in culture, caused by 1 microM APO, the specific DA D2 agonists LY 171555 (LY) or bromocryptine (BRCR) could not be reversed by activating protein kinase C (PKC) by DiC8 or the phorbol ester TPA. This would indicate a site for DA action distal to PKC. However, the stimulatory effect of arachidonic acid (AA; 50 microM) in perifusion was not reduced by DA (1 microM) or by APO, LY or BRCR in culture, which suggests a site for DA action proximal to AA formation. APO, LY and BRCR reduced GtH release in response to the Ca2+ ionophore A23187, however, their inhibitory effect was reversed by 10 microM ionomycin.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Mar
PMID:Possible sites of dopaminergic inhibition of gonadotropin release from the pituitary of a teleost fish, tilapia. 778 19

The effects of in vivo administration of dopamine receptor agonists or antagonists on the mRNA levels encoding for the two isoforms of glutamate decarboxylase, GAD65 and GAD67, and for preproenkephalin were studied in regions of the rat dorsal striatum by radioactive in situ hybridization histochemistry. Changes in striatal mRNA levels after drug treatment were quantified by computerized densitometry on X-ray films. Chronic administration of the dopamine receptor agonist apomorphine or the D1 dopamine receptor agonist SKF-38393 resulted in increased GAD65 mRNA levels in the dorsomedial, ventromedial, dorsolateral and ventrolateral sectors of the striatum. Apomorphine or SKF-38393 treatment did not induce significant effects on GAD67 and preproenkephalin mRNA levels in striatum. On the other hand, chronic administration of the D2 dopamine receptor agonist quinpirole significantly decreased GAD67 in the dorsolateral and ventrolateral and preproenkephalin in the ventrolateral sectors of the striatum. Quinpirole treatment did not induce significant changes in GAD65 mRNA levels. Chronic administration of the dopamine receptor antagonist haloperidol resulted in a significant increase in GAD67 and preproenkephalin mRNA levels in the dorsomedial, dorsolateral and ventrolateral striatal sectors. Chronic treatment with the D2/D3 dopamine receptor antagonist sulpiride resulted in a significant increase in GAD67 in the ventromedial and ventrolateral and PPE in the dorsomedial and ventrolateral striatal sectors. Haloperidol or sulpiride did not induce significant changes in striatal GAD65 mRNA levels. Chronic administration of the D1 dopamine receptor antagonist SCH-23390 had no significant effect on GAD67, GAD65 or preproenkephalin mRNA levels. In the present experimental conditions, stimulation of dopamine receptors with apomorphine or SKF-38393 resulted in increased GAD65 mRNA levels whereas blockade of dopamine receptors with haloperidol or sulpiride resulted in increased GAD67 mRNA levels. These results indicate that striatal GAD65 and GAD67 mRNA levels are differentially regulated by dopamine receptor subtypes.
Brain Res Mol Brain Res 1995 Dec 01
PMID:Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. 875 Aug 62

The present study examined the hypothesis that mu-opioid receptors contribute to a behavioral stimulation produced by stimulation of dopamine receptors by comparing responses in mu-opioid receptor knockout and wild type mice. Apomorphine-induced climbing behavior was augmented by 65%, in wild type mice, but not in mu-knockout, following subcutaneous administration of morphine (15 mg/kg). Moreover, pretreatment with either naloxone (an opioid receptor antagonist) or haloperidol (a mixed D(1)/D(2) receptor antagonist) eliminated the enhancement by morphine of climbing behavior in wild type mice. These results indicate that expression of mu-opioid receptors plays an important role in the enhancement of climbing behavior induced by the dopamine receptor agonist, apomorphine. Furthermore, this augmentation is mediated by interaction between dopamine and mu-opioid receptors.
Brain Res Mol Brain Res 2000 May 31
PMID:Involvement of mu-opioid receptors in potentiation of apomorphine-induced climbing behavior by morphine: studies using mu-opioid receptor gene knockout mice. 1089 3

Gene transfer of glial cell line-derived neurotrophic factor (GDNF) in rodent models of Parkinson's disease (PD) has been shown to protect against neurodegeneration either prior to or immediately after neurotoxin-induced lesions; however, the nigrostriatal pathway was largely intact when gene delivery was completed in these models, which may not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, replication-incompetent adenoviral vectors encoding the rat GDNF gene were administered into the striatum 4 weeks following 6-hydroxydopamine (6-OHDA) injection in the unilateral striatum, more closely resembling fully developed PD. Apomorphine-induced rotational behavior testing was performed every week following 6-OHDA injection. At the 10th week after gene transfer, the striatal dopamine concentrations were measured by HPLC with an electrochemical detector and the number of tyrosine hydroxylase (TH)-positive dopamine neurons in the substantia nigra (SN) was determined by immunohistochemistry. Injection of 6-OHDA into the striatum produced stable increases in rotation, which reached a plateau between 4 and 5 weeks post-injection. The number of TH-positive neuron in the SN and dopamine levels in the striatum was significantly lower in the 6-OHDA group compared to the normal group. Gene transfer of GDNF, but not beta-galactosidase, significantly increased the number of TH-positive neurons and dopamine levels, with a subsequent behavioral recovery between 5 and 10 weeks following GDNF transduction. These findings demonstrate that adenovirus-mediated gene transfer of GDNF is efficacious even in the late stages of 6-OHDA-induced PD rats. They also provide further evidence on the effectiveness of GDNF-based gene therapy for experimental Parkinson's disease.
Brain Res Mol Brain Res 2005 Mar 24
PMID:Delayed gene therapy of glial cell line-derived neurotrophic factor is efficacious in a rat model of Parkinson's disease. 1579 May 39

Apomorphine is a potent molecule for the treatment of Parkinson's disease (PD). It can be obtained in both the R and S forms, and it is the former that is the therapeutically active form. Due to its structural similarity with 3,4-dihydroxyphenethylamine, dopamine, apomorphine can function as an agonist in the treatment of PD as it can stimulate both the D1 and D2 receptors of the striatum. The clinical efficacy of apomorphine is similar to that of 3,4-dihydroxyphenylalanine, levodopa (L-dopa), the cornerstone drug in dopaminergic therapy. (R)-Apomorphine is efficacious for one of the most challenging aspects in the management of PD, namely, managing the unpredictable "on-off" period as a rescue medication after oral administration of a therapeutic drug such as L-dopa. The effectiveness is due to its rapid control of the wearing-off period of the orally administered medicine. This short review will trace the progress of apomorphine use starting with its initial discovery and the first indications for which it was used, discovery of its "cure" for PD, and the studies that led to demonstrating its therapeutic efficacy. The key structural features of apomorphine responsible for its activity are illustrated along with major issues of chemical stability. From a drug delivery point of view, the current form of administration of apomorphine and some of the potential alternate methods of delivery are reviewed.
Mol Pharm
PMID:Apomorphine in dopaminergic therapy. 1688 31


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