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Lack of Effect of Repeated Administration of Milnacipran, a Double Noradrenaline and Serotonin Reuptake Inhibitor, on the β-adrenoceptor-linked Adenylate Cyclase System in the Rat Cerebral Cortex
Neuropharmaco[ogy, Vol. 35, No. 5, pp. 58%593, 1996 Copyright@ 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028-3908/96$15.00 + 0.00
Pergamon @ PII:SO028-3908(%)00038-X
Lack of Effect of Repeated Administration of Milnacipran, a Double Noradrenaline and Serotonin Reuptake Inhibitor, on the ~-adrenoceptor-linked Adenylate Cyclase System in the Rat Cerebral Cortex E B
and M. BRILEY3* 2eentre
1
de Devejoppement
d
1
2
Summary-The effects of subacute administrationof the double noradrenalineand serotoninuptake inhibitor antidepressant, milnacipran, and the tricyclic antidepressant, imipramine, on radioligand binding to /3adrenergic receptors and on /?-adrenergicagonist-stimulated adenylate cyclase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with mihtacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mgkgjday). The treatment with milnacipran up to 30 mg/kg/day did not modify either the maximum number of [3H]CGP-12177binding sites or the equilibrium dissociation constant (Q. On the other hand, treatment of the rats with 10mgikg/dayimipramineinduceda decrease (27%) in [3H]CGP-12177binding sites without affecting the K value. Furthermore,milnacipran did not affect the stimulation of cAMP productioninduced by either 30 PM isoprenaline, 10pl$lGTPySor 10PM forskolin. Under similar conditions, treatment with imipramine reduced by 70% the isoprenaline-inducedstimulation of cAMP productionwithout affecting that inducedby either GTPySor forskolin.These results demonstratethat, unlike imipramine, subacute administration of milnacipran does not produce any change in /?-adrenoceptor sensitivity in the rat brain cortex. Copyright 01996 Elsevier Science Ltd. Keywords-Milnacipran, imipramine, /?-adrenoceptor binding, /?-adrenoceptor-linkedadenylate cyclase, antidepressants,adenylate cyclase.
t
antidepressants take
s o
t
et al.
e al., o i e e al., e al.,
t i t
*To whom correspondenceshould be addressed. Tel. (33) 63 714231, Fax (33) 63714209 589
W
e al., b a t e al.,
F et al.,
e al., et al.,
590
G. Neliat e
e
p 2m
al.,
2m
i t
p
a
o
a o
a
o
i i i
a [\
I
e
b 1m o
t o i a
t
p m
o
p o
al.,
a
o 3
t
a i
o 2 o
o
i a a
3
o 5m
a i
o a
METHODS
Adenylate cyclase assays
b o
a b
e
p m
i a 1m m
3m p
2 o 2 a
5 o
o
2(ZO
40
m
m t
6 t
a b [x a a
o t 1m
1 2 3 4 5
5m
A 2 x 1m
3m m
M
t a 1 m o
i a i a
g b
a Drugs used [3H](–)CGP-12177
Membrane preparation
b b a
( 2
2m
Data analysis
b
Effect of repeated milnacipran
a
o
1
591 o o
o i Kd
a
* i A + ~
(
+
o
f * * t f *p c
t
o o o
b
i
o
a a
t
I a i b o
1
~
@
b
RESULTS
DISCUSSION
Animal body weight variations
o n
M
2 o
e
t
Binding assays In all cases Scatchard plots were linear indicating a single population of binding
a
3t 3 t
o
o i
o
o 1 o
K~
a a
i
I
o b
b
Bm.x
b
K,
o
o
t et al.,
Adenylate cyclase assays
a
a
e
a
a
o 3 3t
o i
3 t 4
o
o
o i
~
~ * + + &
* ~ + ~ k
(
*p
o b
t o
* + + + ~
G Neliat et o
o o
3
o 2 2 1 3 2 4 4 4 1 1 2 2 2
2
2 2 2 2
1 1 1 2 B=
C=
e e e e e e
B B B B s B B
al.,
et al., et al., et al.,
B
et al.,
B
S=
o a a
e al.,
et al.,
a
b
a
t ( h i
i o
n
t
o a
o
t i
o
d
a
i
o a
o a
al.,
e
a
i REFERENCES
D
Ansseau M.,
J M., Evrard J. L., De Nayer A., Darimont P.,
o 6
e
o 6 i i o o vivo a measured by microdialysis (Moret and Briley, 1996), it is rather surprising that there is no influence on ~-adrenoceptor sensitivity. For the moment we have no clear explanation but the very low lipophilicity of milnacipran compared to tricyclic and many other antidepressants may be important. It is possible that the very high local concentration of the lipophilic antidepressants in the membranes surrounding fl-adrenoceptors have effects that are not directly related to their activation of the receptor by increased noradrenaline levels. Since milnacipran is a clinically effective antidepressant, /?-adrenoceptor down-regulation would thus not appear to be implicated in its antidepressant activity. The initially proposed universality of &adrenoceptor downregulation by antidepressants has already been shown not to apply to all selective serotonin reuptake inhibitors
Dejaiffe G., Mirel J., Meurice E., Parent M., Couzinier J. P., DemarezJ. P. and Serre C. (1989) Controlledcomparisonof two doses of milnacipran(F 2207) and amitriptylinein major depressive inpatients. Assi6 M. B., Le Lann A. -D., Stenger A. and Briley M. (1990) Repeated administration of milnacipran, a new antidepressant, has no effect on a functional /Ladrenergic response in J the rat brain. M B., Charv6ronM., Palmier C., Puozzo C., Moret C. and Briley M. (1992) Effects of prolongedadministrationof milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat. M L and Costa E. (1986) Maprotiline: an antidepressantwith an unusualpharmacologicalprofile.J.
BenfieldP. and Ward A. (1986) Fluvoxamine.A review of its pharrnacodynamic and pharrnacokinetic properties, and therapeuticefticacy in depressiveillness. D A K J (1979) Adrenergic and serotonergic receptor binding in rat brain after chronic desmethylimipramine treatment. J
J
J
N
Y
o DuncanG. E., KnappD. J., Little K. Y. and Breese G. R. (1994)
Effect of repeated milnacipran Neuroanatomicalspecificityand dose dependencein the time course of imipramine-induced beta adrenergic receptor down-regulation in rat brain. J. Ferris R. M. and Beaman O. J. (1983) Bupropion: a new antidepressant drug, the mechanism of action of which is not associatedwith down-regulationof postsynaptic fl-adrenergic, serotonergic (5-HT2), uz-adrenergic, imipramine or dopaminergic receptors in the brain.
593
stimulated adenylate cyclase activity in cerebral cortex, striatum,and hippocampusfrom rats treated chronicallywith lithium. Nelson D. R., Thomas D. R. and Johnson A. M. (1989) Pharmacologicaleffects of paroxetine after repeated administration to animals. (suppl):21– 23. OlpeH. -R. and SchellenbergA. (1980) Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressantdregs. J Redmond A. M., Kelly J. P. and Leonard B. E. (1995) The behavioral effects of milnacipran in the olfactory bulbectomised rat model of depression. I (1989)Reevaluationof the regulation Riva M A of /3-adrenergicreceptor binding by desipramine treatment.
Gandolfi O., Barbaccia M. L., Chuang M. D. and Costa E. (1983) Daily bupropion injections for three weeks attenuate the NE-stimulationof adenylatecyclase and the numberof /?adrenergic recognition sites in rat frontal cortex. Neuropharmacology22: 927–929. Hyttel J., Overo F. K. and Arnt J. (1984) Biochemical effects and dmg levels in rats after long-term treatment with the Sarai K., Frazer A., Brunswick D. and Mendels J. (1978) specific 5-HT-uptake inhibitor, citalopram. Desmethylimipramine-induced decrease in /1-adrenergic COIO~ receptor binding in rat cerebral cortex. MatsubaraR., KoyamaT., OdagakiY., NakayamaM., InoueT. and Yamashita I. (1988) Pharmacological properties of Salomon Y., Londos C. and Rodbell M. (1974) A highly midalcipran (F 2207), a novel antidepressant. sensitive adenylatecyclase assay. Matsubara R., Koyama T., Muraki A., Matsubara S., Odagaki o Y., Nakayama M., Yamashita I. (1990) (F o i
SchoffelmeerA. N. M., Hoomeman E. M. D., Siminia P. and Mulder A. H. (1984) Presynaptic and postsynaptic beta-adrenoceptorsensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs.
Abstract, 17th CINP meeting, Kyoto, p. 70. Moret C., Charv6ronM., Finberg J. P. M., Couzinier J. P. and Briley M. (1985) Biochemical profile of midalcipran (F Stenger A., Couzinier J. P. and Briley M. (1987) Psychopharmacology of midalcipran, I-phenyl-l-diethyl-aminocarbo2207), l-phenyl-l-diethyl-aminocarbonyl-2-aminomethylnyl-2-amino-methyl-cyclopropane hydrochloride(F 2207), a cyclopropane (Z) hydrochloride, a potential fourth generanew potential antidepressant. tion antidepressant drug. Moret C. and Briley M. (1996) In Vivo
o
a
Abstract Brain Research Association meeting Newcastle, U.K., p. 35. Mork A. and Geisler A. (1989) Effects of GTP on hormone-
A D H Mobley P. L. (1983)Regulationof recognitionand action functionof the norepinephrine(NE) receptor-coupledadenylate cyclase system in the brain. Implications for the therapy of depression.
Pergamon @ PII:SO028-3908(%)00038-X
Lack of Effect of Repeated Administration of Milnacipran, a Double Noradrenaline and Serotonin Reuptake Inhibitor, on the ~-adrenoceptor-linked Adenylate Cyclase System in the Rat Cerebral Cortex E B
and M. BRILEY3* 2eentre
1
de Devejoppement
d
1
2
Summary-The effects of subacute administrationof the double noradrenalineand serotoninuptake inhibitor antidepressant, milnacipran, and the tricyclic antidepressant, imipramine, on radioligand binding to /3adrenergic receptors and on /?-adrenergicagonist-stimulated adenylate cyclase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with mihtacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mgkgjday). The treatment with milnacipran up to 30 mg/kg/day did not modify either the maximum number of [3H]CGP-12177binding sites or the equilibrium dissociation constant (Q. On the other hand, treatment of the rats with 10mgikg/dayimipramineinduceda decrease (27%) in [3H]CGP-12177binding sites without affecting the K value. Furthermore,milnacipran did not affect the stimulation of cAMP productioninduced by either 30 PM isoprenaline, 10pl$lGTPySor 10PM forskolin. Under similar conditions, treatment with imipramine reduced by 70% the isoprenaline-inducedstimulation of cAMP productionwithout affecting that inducedby either GTPySor forskolin.These results demonstratethat, unlike imipramine, subacute administration of milnacipran does not produce any change in /?-adrenoceptor sensitivity in the rat brain cortex. Copyright 01996 Elsevier Science Ltd. Keywords-Milnacipran, imipramine, /?-adrenoceptor binding, /?-adrenoceptor-linkedadenylate cyclase, antidepressants,adenylate cyclase.
t
antidepressants take
s o
t
et al.
e al., o i e e al., e al.,
t i t
*To whom correspondenceshould be addressed. Tel. (33) 63 714231, Fax (33) 63714209 589
W
e al., b a t e al.,
F et al.,
e al., et al.,
590
G. Neliat e
e
p 2m
al.,
2m
i t
p
a
o
a o
a
o
i i i
a [\
I
e
b 1m o
t o i a
t
p m
o
p o
al.,
a
o 3
t
a i
o 2 o
o
i a a
3
o 5m
a i
o a
METHODS
Adenylate cyclase assays
b o
a b
e
p m
i a 1m m
3m p
2 o 2 a
5 o
o
2(ZO
40
m
m t
6 t
a b [x a a
o t 1m
1 2 3 4 5
5m
A 2 x 1m
3m m
M
t a 1 m o
i a i a
g b
a Drugs used [3H](–)CGP-12177
Membrane preparation
b b a
( 2
2m
Data analysis
b
Effect of repeated milnacipran
a
o
1
591 o o
o i Kd
a
* i A + ~
(
+
o
f * * t f *p c
t
o o o
b
i
o
a a
t
I a i b o
1
~
@
b
RESULTS
DISCUSSION
Animal body weight variations
o n
M
2 o
e
t
Binding assays In all cases Scatchard plots were linear indicating a single population of binding
a
3t 3 t
o
o i
o
o 1 o
K~
a a
i
I
o b
b
Bm.x
b
K,
o
o
t et al.,
Adenylate cyclase assays
a
a
e
a
a
o 3 3t
o i
3 t 4
o
o
o i
~
~ * + + &
* ~ + ~ k
(
*p
o b
t o
* + + + ~
G Neliat et o
o o
3
o 2 2 1 3 2 4 4 4 1 1 2 2 2
2
2 2 2 2
1 1 1 2 B=
C=
e e e e e e
B B B B s B B
al.,
et al., et al., et al.,
B
et al.,
B
S=
o a a
e al.,
et al.,
a
b
a
t ( h i
i o
n
t
o a
o
t i
o
d
a
i
o a
o a
al.,
e
a
i REFERENCES
D
Ansseau M.,
J M., Evrard J. L., De Nayer A., Darimont P.,
o 6
e
o 6 i i o o vivo a measured by microdialysis (Moret and Briley, 1996), it is rather surprising that there is no influence on ~-adrenoceptor sensitivity. For the moment we have no clear explanation but the very low lipophilicity of milnacipran compared to tricyclic and many other antidepressants may be important. It is possible that the very high local concentration of the lipophilic antidepressants in the membranes surrounding fl-adrenoceptors have effects that are not directly related to their activation of the receptor by increased noradrenaline levels. Since milnacipran is a clinically effective antidepressant, /?-adrenoceptor down-regulation would thus not appear to be implicated in its antidepressant activity. The initially proposed universality of &adrenoceptor downregulation by antidepressants has already been shown not to apply to all selective serotonin reuptake inhibitors
Dejaiffe G., Mirel J., Meurice E., Parent M., Couzinier J. P., DemarezJ. P. and Serre C. (1989) Controlledcomparisonof two doses of milnacipran(F 2207) and amitriptylinein major depressive inpatients. Assi6 M. B., Le Lann A. -D., Stenger A. and Briley M. (1990) Repeated administration of milnacipran, a new antidepressant, has no effect on a functional /Ladrenergic response in J the rat brain. M B., Charv6ronM., Palmier C., Puozzo C., Moret C. and Briley M. (1992) Effects of prolongedadministrationof milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat. M L and Costa E. (1986) Maprotiline: an antidepressantwith an unusualpharmacologicalprofile.J.
BenfieldP. and Ward A. (1986) Fluvoxamine.A review of its pharrnacodynamic and pharrnacokinetic properties, and therapeuticefticacy in depressiveillness. D A K J (1979) Adrenergic and serotonergic receptor binding in rat brain after chronic desmethylimipramine treatment. J
J
J
N
Y
o DuncanG. E., KnappD. J., Little K. Y. and Breese G. R. (1994)
Effect of repeated milnacipran Neuroanatomicalspecificityand dose dependencein the time course of imipramine-induced beta adrenergic receptor down-regulation in rat brain. J. Ferris R. M. and Beaman O. J. (1983) Bupropion: a new antidepressant drug, the mechanism of action of which is not associatedwith down-regulationof postsynaptic fl-adrenergic, serotonergic (5-HT2), uz-adrenergic, imipramine or dopaminergic receptors in the brain.
593
stimulated adenylate cyclase activity in cerebral cortex, striatum,and hippocampusfrom rats treated chronicallywith lithium. Nelson D. R., Thomas D. R. and Johnson A. M. (1989) Pharmacologicaleffects of paroxetine after repeated administration to animals. (suppl):21– 23. OlpeH. -R. and SchellenbergA. (1980) Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressantdregs. J Redmond A. M., Kelly J. P. and Leonard B. E. (1995) The behavioral effects of milnacipran in the olfactory bulbectomised rat model of depression. I (1989)Reevaluationof the regulation Riva M A of /3-adrenergicreceptor binding by desipramine treatment.
Gandolfi O., Barbaccia M. L., Chuang M. D. and Costa E. (1983) Daily bupropion injections for three weeks attenuate the NE-stimulationof adenylatecyclase and the numberof /?adrenergic recognition sites in rat frontal cortex. Neuropharmacology22: 927–929. Hyttel J., Overo F. K. and Arnt J. (1984) Biochemical effects and dmg levels in rats after long-term treatment with the Sarai K., Frazer A., Brunswick D. and Mendels J. (1978) specific 5-HT-uptake inhibitor, citalopram. Desmethylimipramine-induced decrease in /1-adrenergic COIO~ receptor binding in rat cerebral cortex. MatsubaraR., KoyamaT., OdagakiY., NakayamaM., InoueT. and Yamashita I. (1988) Pharmacological properties of Salomon Y., Londos C. and Rodbell M. (1974) A highly midalcipran (F 2207), a novel antidepressant. sensitive adenylatecyclase assay. Matsubara R., Koyama T., Muraki A., Matsubara S., Odagaki o Y., Nakayama M., Yamashita I. (1990) (F o i
SchoffelmeerA. N. M., Hoomeman E. M. D., Siminia P. and Mulder A. H. (1984) Presynaptic and postsynaptic beta-adrenoceptorsensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs.
Abstract, 17th CINP meeting, Kyoto, p. 70. Moret C., Charv6ronM., Finberg J. P. M., Couzinier J. P. and Briley M. (1985) Biochemical profile of midalcipran (F Stenger A., Couzinier J. P. and Briley M. (1987) Psychopharmacology of midalcipran, I-phenyl-l-diethyl-aminocarbo2207), l-phenyl-l-diethyl-aminocarbonyl-2-aminomethylnyl-2-amino-methyl-cyclopropane hydrochloride(F 2207), a cyclopropane (Z) hydrochloride, a potential fourth generanew potential antidepressant. tion antidepressant drug. Moret C. and Briley M. (1996) In Vivo
o
a
Abstract Brain Research Association meeting Newcastle, U.K., p. 35. Mork A. and Geisler A. (1989) Effects of GTP on hormone-
A D H Mobley P. L. (1983)Regulationof recognitionand action functionof the norepinephrine(NE) receptor-coupledadenylate cyclase system in the brain. Implications for the therapy of depression.