Effects of isomers of hydroxyaporphines on dopamine metabolism in rat brain regions.
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.
Baldessarini
R J
RJ
Department of Psychiatry, Harvard Medical School, Boston, MA.
Marsh
E R
ER
Kula
N S
NS
Zong
R S
RS
Gao
Y G
YG
Neumeyer
J L
JL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001060:Aporphines; D015102:3,4-Dihydroxyphenylacetic Acid; C009074:N-n-propylnorapomorphine; C008081:11-hydroxy-N-(n-propyl)noraporphine; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid