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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
3
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pubmed:dateCreated |
1990-9-11
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pubmed:abstractText |
The effects of isomers of di- and monohydroxyaporphines on cerebral dopamine (DA) metabolism were evaluated in representative extrapyramidal (corpus striatum) and limbic (nucleus accumbens septi) tissues of rat brain by three methods: (1) changes in the ratio of homovanillic acid (HVA) to DA, (2) accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting its decarboxylation to DA under "open-loop" conditions, as well as (3) after gamma-butyrolactone (GBL) pretreatment to provide selective effects at presynaptic DA autoreceptors. The DA-agonist R(-) isomers of the aporphines apomorphine (APO), N-n-propylnorapomorphine (NPA), and 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) showed consistent dose-dependent inhibition of DA synthesis in both brain regions with all models; the neuroleptic haloperidol had the opposite effect in the first two models only, as expected. The S(+) isomers of NPA and 11-OH-NPa have shown behavioral evidence of antidopaminergic activity, especially in the limbic system. Unlike the neuroleptic, S(+)NPA did not show DA-synthesis enhancing actions in accumbens or striatal tissue but, instead, inhibited DA synthesis like its R(-) antipode in all three test paradigms. S(+)11-OH-NPa given alone produced minor changes in the HVA/DA ratio and did not antagonize R(-)11-OH-NPa, weakly increased accumulation of DOPA in the second model, and had no effect in the third--all without regional selectivity. In the test of autoreceptor functioning, the dihydroxyaporphine S(+)NPA, but not S(+)11-OH-NPa, inhibited DA synthesis and this effect, in turn, was largely reversed by haloperidol, as were the inhibitory effects of the three R(-)aporphines tested. In this model, however, neither S(+)NPA nor S(+)11-OH-NPa antagonized the DA-synthesis inhibiting effect of R(-)APO as haloperidol did. Overall, these results are consistent with evidence that R(-)NPA and 11-OH-NPa have high affinity at D-2 receptor sites in rat brain and show behavioral effects of typical DA agonists. The non-stereoselective inhibitory effects of NPA on DA synthesis may reflect its activity as a weak DA agonist with very low intrinsic activity, but may also include a direct "catechol-effect" on tyrosine hydroxylase. In contrast, R(-)11-OH-NPa appears to be a stereoselective D-2 agonist, active at autoreceptors as well as postsynaptic receptors, that lacks the nonstereospecific effects on DA metabolism of its catechol-aporphine congener. It may be a useful probe for the further characterization of dopamine receptors and autoreceptors.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/11-hydroxy-N-(n-propyl)noraporphine,
http://linkedlifedata.com/resource/pubmed/chemical/3,4-Dihydroxyphenylacetic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Apomorphine,
http://linkedlifedata.com/resource/pubmed/chemical/Aporphines,
http://linkedlifedata.com/resource/pubmed/chemical/Homovanillic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/N-n-propylnorapomorphine
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0006-2952
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
417-23
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:2383279-3,4-Dihydroxyphenylacetic Acid,
pubmed-meshheading:2383279-Animals,
pubmed-meshheading:2383279-Apomorphine,
pubmed-meshheading:2383279-Aporphines,
pubmed-meshheading:2383279-Brain,
pubmed-meshheading:2383279-Dopamine,
pubmed-meshheading:2383279-Homovanillic Acid,
pubmed-meshheading:2383279-Male,
pubmed-meshheading:2383279-Rats,
pubmed-meshheading:2383279-Rats, Inbred Strains,
pubmed-meshheading:2383279-Stereoisomerism,
pubmed-meshheading:2383279-Structure-Activity Relationship
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pubmed:year |
1990
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pubmed:articleTitle |
Effects of isomers of hydroxyaporphines on dopamine metabolism in rat brain regions.
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pubmed:affiliation |
Department of Psychiatry, Harvard Medical School, Boston, MA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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