Life Sciences Vol. 18, pp. 925-934 Printed in the U.S.A.
Pergamon Press
THE EFFECTS OF QUIPAZINE ON SEROTONIN METABOLISM IN RAT BRAIN Ray W. Fuller, Harold D. Snoddy, Kenneth W. Perry, Betty W. Roush, Bryan B. Molloy, Frank P. Bymaster, and David T. Wong The L i l l y Research Laboratories, Eli L i l l y and Company Indianapolis, Indiana 46206 (Received in final form March 15, 1976)
Summary Quipazine, 2-(l-piperazinyl)-quinoline, is a drug that has been reported to stimulate serotonin receptors in brain. We therefore studied the effect of quipazine on several parameters of serotonin metabolism in rat brain. Quipazine caused a s l i g h t , dose-related elevation of serotonin levels and decrease in 5-hydroxyindoleacetic acid levels for 2-4 hrs after i t was administered. The decrease in 5-hydroxyindoleacetic acid levels was probably due primarily to a depression of 5-hydroxyindole synthesis, since quipazine also decreased the rate of 5-hydroxytryptophan accumulation after NSD I015, the rate of serotonin decline after ~-propyldopacetamide, and the rate of 5-hydroxyindoleacetic acid accumulation after probenecid. The elevation of serotonin was probably due to weak inhibition of monoamine oxidase. Quipazine reversibly inhibited the oxidation of serotonin by rat brain monoamine oxidase in v i t r o and protected against the irreversible inactivation of the enzyme in vivo. Quipazine also was a potent i n h i b i t o r of serotonin uptake into brain synaptosomes in v i t r o and attained concentrations in brain higher than the in v i t r o ICSO. However, quipazine did not prevent the ~ p ~ n of brain serotonin by p-chloroamphetamine in vivo. In addition to stimulating serotonin receptors i ~ b--r-a-l-n, quipazine may i n h i b i t monoamine oxidase and serotonin reuptake in vivo. Quipazine, 2-(l-piperazinyl)-quinoline, is a drug reported to act as an agonist on serotonin (SHT) receptors in brain ( I - 3 ) . Since we have previously studied the alteration of 5HT turnover ~roduced when 5HT receptors are stimulated by inhibiting 5HT reuptake (4,5), we undertook a series of studies with quipazine to determine i t s effect on brain 5MT metabolism. These studies extend the work of Grabowska et al (6), who reported that quipazine reduced 5-hydroxyindoleacet~ a-c-id (5HIAA) levels and the rate of 5MIAA decl}ne after pargyline administration in rats. An abstract by Jacoby et al (7) reporting quipazine effects on brain 5-hydrox~ indoles appeared after these studies were essentially complete.
925
926
Qulpazlne Effect on Serotonin Metabolism
Vol. 18, No. 9
Materials and Methods Male Wistar r a t s , 130-150 g, were obtained from Harlan I n d u s t r i e s , Cumberland, Indiana and were maintained on food and water ad l i b i t u m in a room with 12 hour l i g h t : d a r k cycles. After drug in--~ec-t-ion, the rats were k i l l e d by decapitation, and the brains were rapidly removed, frozen on dry ice, and stored at -15 ° p r i o r to analysis. The spectrofluorometric method of M i l l e r et al (8) was used to determine 5HT and 5HIAA l e v e l s . Quipazine levels were determined by reaction with methyl orange a f t e r extraction (9) Monoamine oxidase a c t i v i t y was determined with -4C-5HT (New England Nuclear) as substrate by e x t r a c t i n g deaminated metabolites into ethyl acetate (lO). Uptake of "~C-5HT into rat brain synaptosomes was measured as described previously ( l l ) . The sources of drugs used were as follows: probenecid from Merck Sharp & Dohme, m-hydroxybenzylhydrazine hydrochloride (NSD lOl5) from A l d r i c h , e-propyldopacetamide and p-chloroamphetamine hydrochloride from Regis, and chlorimipramine from Ciba/Geigy. Quipazine maleate, f l u o x e t i n e , and 3-amino-2-oxazolidinone were synthesized in the L i l l y Research Laboratories. Results The effec of quipazine given at three dose levels on 5HT and 5HIAA concentra ion in rat brain is shown in Fig. I . There was a
I -= E
] 5HT 5HIAA
0.8
I I
;[
06
,,, I,D
06 "
tl-
E
0.4
::::::::::::
,,,
" m~
.~:..
04
"~
3
,:.:+:.:,:
"N
0.2
i!i!i!!!~!~
0.2
t
.----.. :.:.:.:.:.:. '~'?i'~'l
~
0
0
3
10
0
-~"
32
Dose of quipazine, mE/k[ FIG. I. Dose-related elevation of 5HT level8 5HIAA levels in rat brain by quipazine.
and depression
of
Quipazine was injected i.p. 2 hrs before groups of 5 rats were killed. Mean values ~ standard errors are shown. Asterisks indicate significant differences from the control group (P
Pergamon Press
THE EFFECTS OF QUIPAZINE ON SEROTONIN METABOLISM IN RAT BRAIN Ray W. Fuller, Harold D. Snoddy, Kenneth W. Perry, Betty W. Roush, Bryan B. Molloy, Frank P. Bymaster, and David T. Wong The L i l l y Research Laboratories, Eli L i l l y and Company Indianapolis, Indiana 46206 (Received in final form March 15, 1976)
Summary Quipazine, 2-(l-piperazinyl)-quinoline, is a drug that has been reported to stimulate serotonin receptors in brain. We therefore studied the effect of quipazine on several parameters of serotonin metabolism in rat brain. Quipazine caused a s l i g h t , dose-related elevation of serotonin levels and decrease in 5-hydroxyindoleacetic acid levels for 2-4 hrs after i t was administered. The decrease in 5-hydroxyindoleacetic acid levels was probably due primarily to a depression of 5-hydroxyindole synthesis, since quipazine also decreased the rate of 5-hydroxytryptophan accumulation after NSD I015, the rate of serotonin decline after ~-propyldopacetamide, and the rate of 5-hydroxyindoleacetic acid accumulation after probenecid. The elevation of serotonin was probably due to weak inhibition of monoamine oxidase. Quipazine reversibly inhibited the oxidation of serotonin by rat brain monoamine oxidase in v i t r o and protected against the irreversible inactivation of the enzyme in vivo. Quipazine also was a potent i n h i b i t o r of serotonin uptake into brain synaptosomes in v i t r o and attained concentrations in brain higher than the in v i t r o ICSO. However, quipazine did not prevent the ~ p ~ n of brain serotonin by p-chloroamphetamine in vivo. In addition to stimulating serotonin receptors i ~ b--r-a-l-n, quipazine may i n h i b i t monoamine oxidase and serotonin reuptake in vivo. Quipazine, 2-(l-piperazinyl)-quinoline, is a drug reported to act as an agonist on serotonin (SHT) receptors in brain ( I - 3 ) . Since we have previously studied the alteration of 5HT turnover ~roduced when 5HT receptors are stimulated by inhibiting 5HT reuptake (4,5), we undertook a series of studies with quipazine to determine i t s effect on brain 5MT metabolism. These studies extend the work of Grabowska et al (6), who reported that quipazine reduced 5-hydroxyindoleacet~ a-c-id (5HIAA) levels and the rate of 5MIAA decl}ne after pargyline administration in rats. An abstract by Jacoby et al (7) reporting quipazine effects on brain 5-hydrox~ indoles appeared after these studies were essentially complete.
925
926
Qulpazlne Effect on Serotonin Metabolism
Vol. 18, No. 9
Materials and Methods Male Wistar r a t s , 130-150 g, were obtained from Harlan I n d u s t r i e s , Cumberland, Indiana and were maintained on food and water ad l i b i t u m in a room with 12 hour l i g h t : d a r k cycles. After drug in--~ec-t-ion, the rats were k i l l e d by decapitation, and the brains were rapidly removed, frozen on dry ice, and stored at -15 ° p r i o r to analysis. The spectrofluorometric method of M i l l e r et al (8) was used to determine 5HT and 5HIAA l e v e l s . Quipazine levels were determined by reaction with methyl orange a f t e r extraction (9) Monoamine oxidase a c t i v i t y was determined with -4C-5HT (New England Nuclear) as substrate by e x t r a c t i n g deaminated metabolites into ethyl acetate (lO). Uptake of "~C-5HT into rat brain synaptosomes was measured as described previously ( l l ) . The sources of drugs used were as follows: probenecid from Merck Sharp & Dohme, m-hydroxybenzylhydrazine hydrochloride (NSD lOl5) from A l d r i c h , e-propyldopacetamide and p-chloroamphetamine hydrochloride from Regis, and chlorimipramine from Ciba/Geigy. Quipazine maleate, f l u o x e t i n e , and 3-amino-2-oxazolidinone were synthesized in the L i l l y Research Laboratories. Results The effec of quipazine given at three dose levels on 5HT and 5HIAA concentra ion in rat brain is shown in Fig. I . There was a
I -= E
] 5HT 5HIAA
0.8
I I
;[
06
,,, I,D
06 "
tl-
E
0.4
::::::::::::
,,,
" m~
.~:..
04
"~
3
,:.:+:.:,:
"N
0.2
i!i!i!!!~!~
0.2
t
.----.. :.:.:.:.:.:. '~'?i'~'l
~
0
0
3
10
0
-~"
32
Dose of quipazine, mE/k[ FIG. I. Dose-related elevation of 5HT level8 5HIAA levels in rat brain by quipazine.
and depression
of
Quipazine was injected i.p. 2 hrs before groups of 5 rats were killed. Mean values ~ standard errors are shown. Asterisks indicate significant differences from the control group (P
