Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recently alleged neurotoxicity of the D1 receptor agonist, SKF 38393, was investigated in rat striatum by measuring the enzymes acetylcholinesterase (AChE) and glutamate decarboxylase (GAD). First, unilateral intrastriatal microinjection of the excitotoxin kainic acid (2 micrograms in 1 microliter) was shown to evoke vigorous contraversive circling, followed 1 or 2 weeks later by profound decreases in striatal AChE (24 and 54%), GAD (51 and 75%), and protein (36 and 47%), as well as loss of GAD (45% at 2 weeks) in the ipsilateral substantia nigra. Similar striatal treatments with SKF 38393 (30 micrograms in 0.5-1 microliter), the related benzazepines SKF 82526 (D1 agonist, 30 micrograms in 1 microliter) and SCH 23390 (D1 antagonist, 5 micrograms in 1 microliter), or the phenanthridine D1 agonist CY 208-243 (5 micrograms in 1 microliter) failed to affect the rats' behaviour or their striatal levels of AChE, GAD, and protein. Intrastriatal SKF 38393 (30 micrograms in 0.5 microliter) also had no influence on these enzymes in the substantia nigra. It is concluded that none of the D1 dopaminergic compounds examined here was neurotoxic toward the many different cell groups that contain AChE and/or GAD in the striatum.
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PMID:Putative neurotoxicity of SKF 38393 and other D1 dopaminergic drugs investigated in rat striatum. 134 81

Purposeless chewing in rats was dose dependently increased by acute administration of the dopamine D-1 receptor agonist SKF 38393 (5-20 mg/kg), the D-2 receptor antagonist sulpiride (10-100 mg/kg) and the D-2 receptor agonist quinpirole (0.05-0.25 mg/kg). Only high doses of the D-1 receptor antagonist SCH 23390 (1 and 5 mg/kg) induced purposeless chewing. SCH 23390 (0.05 mg/kg) blocked SKF 38393 (20 mg/kg)-induced purposeless chewing, but had no effect on the purposeless chewing induced by sulpiride (100 mg/kg) or quinpirole (0.1 mg/kg). A dose of SKF 38393 (5 mg/kg) which did not itself induce chewing, potentiated the increase in purposeless chewing observed after administration of sulpiride (100 mg/kg). Administration of SKF 38393 (20 mg/kg) and quinpirole (0.1 mg/kg) did not induce purposeless chewing but stereotyped licking was observed. Administration of sulpiride (100 mg/kg) with quinpirole (0.1 mg/kg) produced an incidence of purposeless chewing not different from that observed when either compound was administered alone. Acute administration of the cholinergic agonist pilocarpine (0.5-4.0 mg/kg) or the cholinesterase inhibitor physostigmine (0.05-0.2 mg/kg) increased the frequency of purposeless chewing in rats. Co-administration of pilocarpine (0.5 mg/kg) with sulpiride (100 mg/kg) increased the frequency of purposeless chewing above that seen when either compound was administered alone. Co-administration of pilocarpine (0.5 mg/kg) with SKF 38393 (20 mg/kg) increased the frequency of purposeless chewing in an additive manner. Co-administration of physostigmine (0.1 mg/kg) with sulpiride (100 mg/kg) but not SKF 38393 (20 mg/kg), increased the frequency of purposeless chewing above that observed when either compound was administered alone. Quinpirole (0.1 mg/kg)-induced purposeless chewing was not affected by co-administration with either pilocarpine (0.5 mg/kg) or physostigmine (0.1 mg/kg). The anticholinergic agent scopolamine (0.1 mg/kg) blocked the purposeless chewing induced by either SKF 38393 (20 mg/kg) or sulpiride (100 mg/kg), but had no effect on the purposeless chewing induced by quinpirole (0.1 mg/kg). Contrary to previous reports, acute manipulation of D-1 or D-2 receptor function can both enhance purposeless chewing behaviour in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Drugs acting at D-1 and D-2 dopamine receptors induce identical purposeless chewing in rats which can be differentiated by cholinergic manipulation. 167 28

The dopaminergic regulation of striatal cholinergic activity was studied using in vivo microdialysis to measure interstitial concentrations of acetylcholine (ACh) and choline in the striata of freely moving rats. The quaternary acetylcholinesterase inhibitor neostigmine (100 nM) was included in the perfusion solution to increase the recovery of ACh. d-Amphetamine (2 mg/kg, s.c.) and nomifensine (5 mg/kg, s.c.) increased the concentration of ACh in the striatal dialysate by 40 to 60%. Interstitial choline concentrations were reduced by both drugs. Administration of the selective D1 receptor antagonist SCH 23390 (0.3 mg/kg, s.c.) decreased the concentration of ACh in the striatal dialysate by 15 to 20%; in contrast, the selective D2 antagonist raclopride (1 mg/kg, s.c.) increased striatal ACh release by 50 to 60%. Raclopride also briefly increased the extracellular concentration of choline. Raclopride blocked the increase in locomotor activity produced by d-amphetamine, but did not further enhance ACh release. In contrast, SCH 23390 completely antagonized the increases in locomotion and striatal ACh release produced by d-amphetamine. These results indicate that d-amphetamine increases ACh release in the striatum via a D1 receptor mechanism. Consistent with this hypothesis, the selective D1 receptor agonist CY 208-243 (1 mg/kg, s.c.) increased striatal ACh release by approximately 60%. In contrast, local application of CY 208-243 (10 microM) and SCH 23390 (10 microM) failed to alter ACh concentrations in the striatal dialysate. Inclusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (10 microM) in the striatal perfusion solution significantly attenuated the increase in striatal ACh release produced by systemic CY 208-243.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopaminergic regulation of striatal acetylcholine release: importance of D1 and N-methyl-D-aspartate receptors. 183 58

The pharmacology of SK&F R-105058 and SK&F R-106114, N-ethyl carbamate ester prodrugs of fenoldopam, was evaluated in pentobarbital-anesthetized dogs. The selective dopamine 1 (DA1) antagonist, SCH 23390, significantly attenuated the renal vasodilator effects of SK&F R-82526, the active enantiomer of fenoldopam. This dose of SCH 23390 also significantly attenuated the increase in renal blood flow and decrease in renal vascular resistance induced by the administration of either SK&F R-106114 or SK&F R-105058. The cholinesterase inhibitor, physostigmine, at a dose that significantly enhanced the renal effects of acetylcholine, did not alter the in vivo renal vasodilator effects of SK&F R-105058 or prevent conversion of SK&F R-105058 to fenoldopam. Thus, these data indicate that the renal vasodilator activity of fenoldopam prodrugs involves activation of DA1 receptors and that, unlike other carbamate ester prodrugs, conversion to the parent compound is unlikely to involve cholinesterase.
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PMID:Pharmacology of SK&F R-105058 and R-106114, N-ethyl carbamate ester prodrugs of fenoldopam. 198 34

The autoradiographic distribution of D1 dopaminergic binding sites was studied in the human ventral mesencephalon using the D1 antagonist [3H]SCH 23390. [3H]SCH 23390 binding was characterized by a single class of sites with a Kd of 2.5 nM and a Bmax of 31 fmol/mg of tissue. The density of [3H]SCH 23390 binding sites was high in the substantia nigra, moderate in the ventral tegmental area and low in the peri- and retrorubral field (catecholaminergic region A8). Binding densities were similar in pars compacta and pars reticulata of the substantia nigra, except for a peak value of high [3H]SCH 23390 in the pars reticulata, at a level just ventral to a zone of hyperdensity of melanized dopaminergic neurons in the pars compacta. The anatomical organization of the human ventral mesencephalon was analysed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase, substance P, dynorphin B, somatostatin and methionine-enkephalin immunohistochemistry, respectively. The similarity in distribution of [3H]SCH 23390 binding sites and substance P or dynorphin B immunoreactivity suggests that D1 binding sites are mainly located on the striatonigral projections. In accordance with these results: (1) the density of [3H]SCH 23390 binding sites was reduced in the substantia nigra of a patient with Huntington's chorea, a disease associated with a degeneration of striatonigral neurons; (2) the density of [3H]SCH 23390 binding sites was unaffected in the substantia nigra of a patient with Parkinson's disease, a disorder characterized by a marked loss in nigral tyrosine hydroxylase-positive neurons. [3H]SCH 23390 binding sites showed a characteristic, heterogeneous distribution within the human ventral mesencephalon, confirming data obtained in other species. The preferential localization of D1 dopamine receptors on striatonigral projections in human brain suggests that pharmacological manipulation of these receptors modulates the activity of striatonigral pathways, thereby affecting the various outputs of the nigral complex.
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PMID:Microtopography of D1 dopaminergic binding sites in the human substantia nigra: an autoradiographic study. 198 69

The effects of cholinesterase inhibitors, cholinergic agonists, dopaminergic agonists and dopaminergic antagonists on the hyperactivity produced by the muscarinic cholinergic antagonist scopolamine were evaluated in mice. Scopolamine (0.3-10 mg/kg) produced a dose-related increase in locomotor activity, with a peak effect at 3.0 mg/kg. The cholinesterase inhibitor physostigmine (0.03-0.175 mg/kg) was without effect on locomotor activity when administered alone, whereas the cholinesterase inhibitor tetrahydroaminoacridine hydrate (0.3-10 mg/kg) decreased locomotor activity. Both physostigmine and tetrahydroaminoacridine hydrate attenuated the effects of scopolamine. Administered alone, the cholinergic agonists oxotremorine (0.01-0.3 mg/kg) and RS86 (0.1-3.0 mg/kg) produced dose-related decreases in locomotor activity, whereas pilocarpine (0.3-10 mg/kg) had no effect on locomotor activity. None of these three muscarinic agonists significantly attenuated the hyperactivity produced by scopolamine. Administered alone, the dopaminergic agonists quinpirole (0.003-0.1 mg/kg), S-(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (0.3-10 mg/kg) and SKF 38393 (8-64 mg/kg) had no significant effect on activity, whereas apomorphine (0.3-10 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) increased activity. Quinpirole, apomorphine and S-(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine produced dose-related reversals of the increases in locomotor activity produced by scopolamine. The hyperactivity effects of d-amphetamine were approximately additive with scopolamine, whereas SKF 38393 did not significantly affect scopolamine. The mixed D1/D2 dopaminergic antagonist haloperidol (0.003-3.0 mg/kg) and the selective D1 antagonist SCH 23390 (0.01-0.3 mg/kg) produced dose-related decreases in locomotor activity when administered alone, and also produced dose-related reversals of the hyperactivity produced by scopolamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A comparison of the effects of cholinergic and dopaminergic agents on scopolamine-induced hyperactivity in mice. 224 41

The development of dopamine D1-receptors in rat striatum during the early postnatal period is examined, using autoradiography and [3H]SCH 23390 as ligand. Dopamine D1-receptors are present in striatum at birth and are more dense than in any adjacent region. The receptors are preferentially localized in striosomes and to some extent in a subcallosal streak. The density of D1-receptors in the matrix increases with age so that by two weeks postnatally the striosomal pattern is no longer evident, and the overall dense labelling is the same as seen in adults. Dopamine D1-receptor development seems to take place earlier than that of dopamine terminals but at the same time as or somewhat later than that of acetylcholinesterase. The D1-defined striosomes move from ventrolateral towards dorso-medial striatum with increasing age and from anterior to posterior striatum. This direction is nearly perpendicular to the direction of development of several other markers, including dopamine terminals and D2-receptors. The present studies indicate that for markers appearing in the striosomal compartment there are different patterns of development with respect to time and spatial pattern. Regulation of striatal development by interaction of neuronal systems with one another and with other factors is complex and will require extensive study to clarify the mechanisms involved.
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PMID:Dopamine D1 receptor development in the rat striatum: early localization in striosomes. 252 49

Rats made tolerant to morphine show neither a change in brain opiate receptor number nor altered sensitivity to the inhibitory effect of opiates on striatal adenylate cyclase (AC) activity. Interestingly, SCH 23390, a selective blocker of D1 dopamine (DA) receptors which, given chronically to rats, induces a 32% increase in D1 receptor number and increases the Vmax of D1-stimulated striatal AC, resulted in marked resistance to acute morphine effects. In particular, rats chronically treated with SCH 23390 failed to show muscular rigidity and increased striatal dihydroxyphenylacetic acid (DOPAC) concentration after morphine. Moreover, basal striatal AC activity in these animals had a significantly reduced sensitivity to opiate inhibition. On the other hand, decreased AC sensitivity to acetylcholine (ACh) inhibition observed in the striatum of rats chronically treated with DFP, an irreversible blocker of acetylcholinesterase, appeared to be secondary to the downregulation of muscarinic receptors and thus did not modify the opiate inhibitory capacity. It was concluded that although a potentiation of striatal AC impairs opiate action, such mechanism is not involved in morphine tolerance.
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PMID:Resistance to extrapyramidal effects of opiates in rats chronically treated with SCH 23390. 253 Dec 33

The distribution of D1 dopamine receptors was studied autoradiographically in the basal ganglia of the cat, monkey and human. These receptor binding sites were labeled directly with the D1-selective antagonist [3H]SCH 23390, and ligand-binding assays were performed concurrently. Serial- or same-action analysis permitted comparisons among D1 binding distributions, acetylcholinesterase staining and tyrosine hydroxylase immunoreactivity. In all species studied, the dorsal striatum exhibited patches of particularly dense D1 binding in correspondence with acetylcholinesterase-poor striosomes. Highly patterned binding was present in the ventral striatum. Distinctions in binding density were observed among the subdivisions of the globus pallidus and of the substantia nigra. The external segment of the pallidum was extremely sparse in D1 binding, whereas the internal segment (or entopeduncular nucleus in the cat) was a site of high D1 binding density. The binding density was greatest in the core of the internal segment, and tyrosine hydroxylase-positive fibers surrounded and weakly dispersed themselves through this core. Weak binding was present in the ventral pallidum. In the substantia nigra, the pars reticulata demonstrated the densest binding, particularly medially. The pars compacta showed much sparser binding, though some of its tyrosine hydroxylase-positive neurons had dendrites extending ventrally into the zone of dense D1 binding in the pars reticulata. We conclude that [3H]SCH 23390-defined D1 binding is compartmentalized in the dorsal striatum and that, particularly in relation to the reported distributions of striatal D2 dopamine receptors, this is likely to be of functional significance in the dopaminergic modulation of intrastriatal neurotransmission as well as of afferent and efferent neurotransmission. The segregated localizations of D1 receptors in the substantia nigra suggest predominant activation of the pars reticulata, including ventral and medial regions adjacent to the densocellular zone. Specific pathways from compartments in the striatum to subdivisions of the pallidum may also be differentially modulated by dopamine acting via distinct receptor subtypes. At the level of the pallidum, such D1 modulation appears to be restricted to the internal segment, which projects to the thalamus, rather than to the external pallidum, which projects to the subthalamic nucleus.
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PMID:[3H]SCH 23390 binding to D1 dopamine receptors in the basal ganglia of the cat and primate: delineation of striosomal compartments and pallidal and nigral subdivisions. 290 90

The distribution and density of dopamine D-1 and D-2 receptors were studied in the basal ganglia of adult turtles, pigeons, rats, cats, and monkeys. Dopamine receptors were measured in vitro by quantitative autoradiography in alternate sections processed for D-1 and D-2 receptor subtypes and compared to adjacent sections stained for acetylcholinesterase (AChE) activity. [3H]-SCH 23390 and [3H]-spiroperidol were used to label the D-1 and D-2 dopamine receptor subtypes, respectively. The anatomic distribution of both D-1 and D-2 receptors in the basal ganglia was remarkably similar across all species examined. Whereas the absolute number of D-1 and D-2 receptors in the basal ganglia varied between species, the percentage of D-1 and D-2 receptors in a region was quite similar among species. The pattern of binding to the D-1 and D-2 receptor varied among the different species. The adult turtles, pigeons, and rats demonstrated nonpatchy D-1 and D-2 receptor binding in the striatum and pallidum. The adult cat and monkey caudate nucleus and putamen demonstrated mildly heterogeneous receptor binding in a pattern that differed from that seen with AChE staining, but did occasionally demonstrate similar patterns of the D-1 and D-2 receptor subtypes. The immature cat striatum was characterized by heterogeneous D-1 receptor binding that corresponded to heterogeneous AChE rich patches, whereas D-2 receptor binding was homogeneous. Heterogeneous binding was seen in other basal ganglia structures including the nucleus accumbens, olfactory tubercle, and substantia nigra pars compacta and reticulata. Complementary D-1 and D-2 receptor binding patterns were seen in the pallidum and substantia nigra of the mammals. The results of this study indicate that both D-1 and D-2 dopamine receptors are present in the basal ganglia of five different vertebrates. A common feature of dopamine receptors in the basal ganglia is their heterogeneity in distribution and density. The heterogeneity of dopamine receptors has similarities to and differences from the distribution of presynaptic dopamine and other neurotransmitter markers of the basal ganglia.
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PMID:Comparative distribution of dopamine D-1 and D-2 receptors in the basal ganglia of turtles, pigeons, rats, cats, and monkeys. 295 17


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