[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats].
The effects of two antidepressant drugs, amoxapine and amitriptyline, that belong to distinct chemical classes, have been examined on various biochemical parameters related to serotoninergic and opioidergic neurotransmission in the rat brain and spinal cord. In vitro binding studies showed that both amoxapine and amitriptyline interact in the nanomolar range with 5-HT2 receptors labelled by [3H]ketanserin in cortical membranes. By contrast, neither amoxapine nor amitriptyline can be considered as possible ligands of 5-HT1A and 5-HT1B receptors because their affinities for these sites are in the micromolar range (or even worse). Interestingly, amoxapine binds with a good affinity (IC50 = 0.30 microM) to 5-HT3 receptors labelled by [3H]zacopride in cortical membranes. Complementary experiments using the 5-HT3-dependent Bezold-Jarisch reflex confirmed that amoxapine really acts in vivo as a 5-HT3 antagonist (IC50 = 50 micrograms/kg i.v.), whereas amitriptyline is essentially inactive on 5-HT3 receptors. The second part of this study consisted of looking for possible changes in central 5-HT receptors 24 h after either a single or a repeated (for 14 days) treatment with amoxapine (10 mg/kg i.p. each day) or amitriptyline (10 mg/kg i.p.). A marked decrease in the density of 5-HT2 receptors was found in the cerebral cortex in both treatment groups. By contrast, neither 5-HT1A nor 5-HT1B receptors were significantly affected in any brain region studied. Finally we explored whether acute and/or chronic administration of amoxapine or amitriptyline affected the levels of opioid peptides and the mu and delta classes of opioid receptors in various regions of the brain and the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)
Gozlan
H
H
INSERM U 288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris.
Saddiki-Traki
F
F
Merahi
N
N
Laguzzi
R
R
Hamon
M
M
D000639:Amitriptyline / Q000008:administration & dosage / Q000494:pharmacology*; D000657:Amoxapine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D002490:Central Nervous System / Q000187:drug effects; D008297:Male; D009479:Neuropeptides / Q000032:analysis; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*
D009479:Neuropeptides; D011957:Receptors, Opioid; D011985:Receptors, Serotonin; D000639:Amitriptyline; D000657:Amoxapine
Pharmacologie préclinique de l'amoxapine et de l'amitriptyline. Implications des systèmes sérotoninergiques et opioïdergiques dans leurs effets centraux chez le rat.