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Influence of four butyrophenone neuroleptics on rat brain noradrenaline depletory effect of reserpine
Life Sciences Vol . 3, pp. 759-782, 1984. Pergamon Press, Inc. Printed in the United States .
INFLUENCE OF FOUR BUTYROPHENONE NEUROLEPTICS ON RAT BRAIN NORADRENALINE DEPLETORY EFFECT OF RESERPINE Alb, Dresse and R, De Meyer Department of Neuropharm3codynamica
Research Laboratoria, Janssen Pharmaceutics - Beerse, Belgium (Received 8 June 1984) Extending the experiments of Erhinger et al (1), Pletecher et al (2) and others, we have recently investigated the action of 6 butyrophenone and 2 phenothiazine neuroleptica on the tranylcypromine-induced increase of rat brain noradrenaline (NA) (3), Four of the neuroleptica used were good inhibitors of the NA increase, For example, 0, 31 mg~kg spiroperidol or 1, 25 mg~kg haloperidol administered subcutaneously 2 hours before tranylcypromine were sufficient to counteract the NA increase produced by this monoamine oxidase inhibitor, The four others were weakly or not active . For various theoretical reasons it was interesting to check the specificity of this property and to determine whether the same substances were also able to counteract the rat brain NA .depletory effect of reserpine, Material and Methods
Four butyrophenonea were chosen for this purpose, The two first are good inhibitors of tranylcypromine-induced NA increase, The two last are weakly active in this respect despite the fact that they are pharmacologically very active, (4), The chemical structures of the substances used are as follow : 1, Haloperidol : 1 -~y -(4-fluorobenzoyl)-propyl~-4-(4-chlorophenyl)piperidine-4-ol,
2, Spiroperidol : 1-oxo-4-phenyl-8-~3-(4-fluorobenzoyl)-propyl~-2, 4, 8triazaspiro~4, 5~decane, 3, Droperidol : 1_{1-~y -(4-fluorobenzoyl)-propyl~-l, 2, 3, 6-tetrahydro4-pyridyl}-2-benzimidazoliaone hydrate . 4, Benperidol: 1 ~{ 1-~y -(4-fluorobenzoyl)-propy~-4-piperidyl~-2` benzimidazolinone hydr ochloride hydrate . These neuroleptica were dissolved in 2 ml 0, 1 M tartaric ac. , diluted 759
760
FOUR BUTYROPHENONE NEUROLEPTICS
Vol . 3, No . 7
NA lrg/g . 0.60~ 0.500.40Controls
Q30020 0.10-
Reserpine I .Y 2 h.
0~ .OB
.16
.31
.63
1.25
2.5
5mg/kg .
FIG . 1 Influence of various doses of reserpine intravenously administered 2 hours before decapitation on the noradrenaline content of rat brain. Ordinate : noradrenaline (base) concentration in }Lg per g tissue, Abcissa : dose levels of reserpine . The points represent the average values of 6 experiments - 12 for the controls with standard error . with water and injected subcutaneously 2 hours before reserpine administration (0, 31 mg~kg i, v. ) and 4 hours before the rats were killed by decapitation . Droperidol and benperidol were also injected thirty minutes before reserpine, Ascorbic ac, was used to dissolve reserpine just before use . The female Wietar rats weighed 200 + 10 grs and were maintained in individual cages at a temperature of 21-23° after the injections, Noradrenaline was measured, as previously described (3) by the m,~thod of Euler and Lishajko (5) . Each point of the figures represents the average of 6 dosages + S . E . When necessary the statistical significance of observed differences was calculated using the non-parametric Man Whitney U test (6) . Results 1, Reserpine only As expected, reserpine produces a decrease of rat brain noradrenaline content. In good agreem ,~nt with the results of Orlans and Brodie (7) as little as 0 . 08 mg~kg reserpine administered intravenously to rata two hours before decapitation is sufficient to produce a statistically significant difference (P< 0, O1) between treated and control rata (fig . 1), The dosage of 0, 31 m3~kg
Vol. 3, No. 7
FOUR BUTYROPHENONE NEUROLEPTICS
761
which gives a noradrenaline decrease of approximately 60°fo (12 control rata : 0. 373 + 0 . 007 }tg/g ; 6 reserpine rats : 0 . 154 + 0. 011 }~g/g) was chosen to study the eventual inhibitory effect of the butyrophenonee . 2 . Reserpine after neuroleptice As clearly demonstrated by table I, none of the 4 butyrophenone neuroleptice used is able to counteract the noradrenaline depletory effect of reserpine. With haloperidol for example, neither 0. 63, 2. 5 nor 5 m3/kg produce a tendency of the NA content to return to control values . TABLE I
Treatment
Reserpine Haloperidol + reserpine
Spiroperidol + reserpine Droperidol + reserpine Droperidol + reserpine Benperidol + reserpine Benperidol + reserpine
Dose levels
Time between butyrophenonee and reserpine
Noradrenaline
0. 31
-
0 .373 + 0 . 007 0. 154 + 0. O11
0. 63 2 . 50 5 . 00
2h 2 h 2 h
0. 160 + 0. 019 0. 141 + 0. 009 0. 126 + 0. 005
0 . 63
2h
0. 154 + 0. 013
10 .
30 min
0. 122 + 0. 008
10 .
2h
0. 123 + 0. 008
10 .
30 min
0. 125 + 0. O11
10 .
2h
0 . 132 + 0 . 012
Absence of influence of various neuroleptics on the rat brain noradrenaline depletory effect of reserpine . Reserpine (0 .31 mg/kg) was administered intravenously 30 min or 2 hours after the various butyrophenonee . Discussion Together with previous ones, these observations seem to indicate that a major neuroleptic such as haloperidol can be a good inhibitor of the action of tranylcypromine without modifying the reserpine depletory effect .
762
FOUR BUTYROPHENONE NEUROLEPTICS
Vol. 3, No . 7
Inhibition by neuroleptics of tranylcypromine activity seems to be a rather specific action (3), On the contrary, and as already pointed out by Brodie and co-workers, the inhibition of the reserpine depletory effect is not specific and is more related to hypothermy (8). These few observations also show the importance of using specific neuroleptics in an attempt to determ ne mire precisely the mechanism of action of these drugs, Like haloperidol and other chemically related compounds, they should be as mach as possible devoid of hypothermic and other undesirable side-effects . Summary Four potent butyrophenone neuroleptics, haloperidol, spiroperidol, droperidol and benperidol fail to counteract the rat brain noradrenaline depletory effect of reserpine, These observations lead to the conclusion that the inhibition of the action of reserpine by certain neuroleptics is a non specific property. References 1, H. Ehringer, O. Hornykiewicz and K. Lechner, Arch, exp . Path, Pharmak ., 239, 507 (1960), 2. A. Pletscher and K. Gey, Med . Exp, , 2 , 259 (1960), 3 . Alb . Dresse and R . De Meyer, Biochem . Pharmacol , , in press .
4, P. A, J. Janssen, C . I. N, P. Third International Meeting Munich , 1962, 5, U. S, von Euler and F. Lishajko, Acta Physiol, Scand . , 51 . 348 (1961) . 6. S, Siegel, Non param~tric statistics , p. 116, McGrawHillBookComp. N.Y . (19 . 7, F. B, Orlans and B. B. Brodie, Nature, 187, 1034 (1960), 8, E, Costa, G. L . Gessa and B . B . Brodie, Life Sciences , 1 , 315 (1862),
INFLUENCE OF FOUR BUTYROPHENONE NEUROLEPTICS ON RAT BRAIN NORADRENALINE DEPLETORY EFFECT OF RESERPINE Alb, Dresse and R, De Meyer Department of Neuropharm3codynamica
Research Laboratoria, Janssen Pharmaceutics - Beerse, Belgium (Received 8 June 1984) Extending the experiments of Erhinger et al (1), Pletecher et al (2) and others, we have recently investigated the action of 6 butyrophenone and 2 phenothiazine neuroleptica on the tranylcypromine-induced increase of rat brain noradrenaline (NA) (3), Four of the neuroleptica used were good inhibitors of the NA increase, For example, 0, 31 mg~kg spiroperidol or 1, 25 mg~kg haloperidol administered subcutaneously 2 hours before tranylcypromine were sufficient to counteract the NA increase produced by this monoamine oxidase inhibitor, The four others were weakly or not active . For various theoretical reasons it was interesting to check the specificity of this property and to determine whether the same substances were also able to counteract the rat brain NA .depletory effect of reserpine, Material and Methods
Four butyrophenonea were chosen for this purpose, The two first are good inhibitors of tranylcypromine-induced NA increase, The two last are weakly active in this respect despite the fact that they are pharmacologically very active, (4), The chemical structures of the substances used are as follow : 1, Haloperidol : 1 -~y -(4-fluorobenzoyl)-propyl~-4-(4-chlorophenyl)piperidine-4-ol,
2, Spiroperidol : 1-oxo-4-phenyl-8-~3-(4-fluorobenzoyl)-propyl~-2, 4, 8triazaspiro~4, 5~decane, 3, Droperidol : 1_{1-~y -(4-fluorobenzoyl)-propyl~-l, 2, 3, 6-tetrahydro4-pyridyl}-2-benzimidazoliaone hydrate . 4, Benperidol: 1 ~{ 1-~y -(4-fluorobenzoyl)-propy~-4-piperidyl~-2` benzimidazolinone hydr ochloride hydrate . These neuroleptica were dissolved in 2 ml 0, 1 M tartaric ac. , diluted 759
760
FOUR BUTYROPHENONE NEUROLEPTICS
Vol . 3, No . 7
NA lrg/g . 0.60~ 0.500.40Controls
Q30020 0.10-
Reserpine I .Y 2 h.
0~ .OB
.16
.31
.63
1.25
2.5
5mg/kg .
FIG . 1 Influence of various doses of reserpine intravenously administered 2 hours before decapitation on the noradrenaline content of rat brain. Ordinate : noradrenaline (base) concentration in }Lg per g tissue, Abcissa : dose levels of reserpine . The points represent the average values of 6 experiments - 12 for the controls with standard error . with water and injected subcutaneously 2 hours before reserpine administration (0, 31 mg~kg i, v. ) and 4 hours before the rats were killed by decapitation . Droperidol and benperidol were also injected thirty minutes before reserpine, Ascorbic ac, was used to dissolve reserpine just before use . The female Wietar rats weighed 200 + 10 grs and were maintained in individual cages at a temperature of 21-23° after the injections, Noradrenaline was measured, as previously described (3) by the m,~thod of Euler and Lishajko (5) . Each point of the figures represents the average of 6 dosages + S . E . When necessary the statistical significance of observed differences was calculated using the non-parametric Man Whitney U test (6) . Results 1, Reserpine only As expected, reserpine produces a decrease of rat brain noradrenaline content. In good agreem ,~nt with the results of Orlans and Brodie (7) as little as 0 . 08 mg~kg reserpine administered intravenously to rata two hours before decapitation is sufficient to produce a statistically significant difference (P< 0, O1) between treated and control rata (fig . 1), The dosage of 0, 31 m3~kg
Vol. 3, No. 7
FOUR BUTYROPHENONE NEUROLEPTICS
761
which gives a noradrenaline decrease of approximately 60°fo (12 control rata : 0. 373 + 0 . 007 }tg/g ; 6 reserpine rats : 0 . 154 + 0. 011 }~g/g) was chosen to study the eventual inhibitory effect of the butyrophenonee . 2 . Reserpine after neuroleptice As clearly demonstrated by table I, none of the 4 butyrophenone neuroleptice used is able to counteract the noradrenaline depletory effect of reserpine. With haloperidol for example, neither 0. 63, 2. 5 nor 5 m3/kg produce a tendency of the NA content to return to control values . TABLE I
Treatment
Reserpine Haloperidol + reserpine
Spiroperidol + reserpine Droperidol + reserpine Droperidol + reserpine Benperidol + reserpine Benperidol + reserpine
Dose levels
Time between butyrophenonee and reserpine
Noradrenaline
0. 31
-
0 .373 + 0 . 007 0. 154 + 0. O11
0. 63 2 . 50 5 . 00
2h 2 h 2 h
0. 160 + 0. 019 0. 141 + 0. 009 0. 126 + 0. 005
0 . 63
2h
0. 154 + 0. 013
10 .
30 min
0. 122 + 0. 008
10 .
2h
0. 123 + 0. 008
10 .
30 min
0. 125 + 0. O11
10 .
2h
0 . 132 + 0 . 012
Absence of influence of various neuroleptics on the rat brain noradrenaline depletory effect of reserpine . Reserpine (0 .31 mg/kg) was administered intravenously 30 min or 2 hours after the various butyrophenonee . Discussion Together with previous ones, these observations seem to indicate that a major neuroleptic such as haloperidol can be a good inhibitor of the action of tranylcypromine without modifying the reserpine depletory effect .
762
FOUR BUTYROPHENONE NEUROLEPTICS
Vol. 3, No . 7
Inhibition by neuroleptics of tranylcypromine activity seems to be a rather specific action (3), On the contrary, and as already pointed out by Brodie and co-workers, the inhibition of the reserpine depletory effect is not specific and is more related to hypothermy (8). These few observations also show the importance of using specific neuroleptics in an attempt to determ ne mire precisely the mechanism of action of these drugs, Like haloperidol and other chemically related compounds, they should be as mach as possible devoid of hypothermic and other undesirable side-effects . Summary Four potent butyrophenone neuroleptics, haloperidol, spiroperidol, droperidol and benperidol fail to counteract the rat brain noradrenaline depletory effect of reserpine, These observations lead to the conclusion that the inhibition of the action of reserpine by certain neuroleptics is a non specific property. References 1, H. Ehringer, O. Hornykiewicz and K. Lechner, Arch, exp . Path, Pharmak ., 239, 507 (1960), 2. A. Pletscher and K. Gey, Med . Exp, , 2 , 259 (1960), 3 . Alb . Dresse and R . De Meyer, Biochem . Pharmacol , , in press .
4, P. A, J. Janssen, C . I. N, P. Third International Meeting Munich , 1962, 5, U. S, von Euler and F. Lishajko, Acta Physiol, Scand . , 51 . 348 (1961) . 6. S, Siegel, Non param~tric statistics , p. 116, McGrawHillBookComp. N.Y . (19 . 7, F. B, Orlans and B. B. Brodie, Nature, 187, 1034 (1960), 8, E, Costa, G. L . Gessa and B . B . Brodie, Life Sciences , 1 , 315 (1862),