Role of Gi proteins in the antidepressant-like effect of amitriptyline and clomipramine.
The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3), anti-Go alpha(1), anti-Go alpha(2)) on the antidepressant-like effect induced by amitriptyline and clomipramine, was evaluated in the mouse forced swimming test, an animal model of depression. The administration of amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.) produced an increase in the mobility time that was prevented by PTX (0.25 micro g per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Gi alpha(1) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(2) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(3) (6.25 micro g per mouse i.c.v.), and anti-Go alpha(1) (6.25 micro g per mouse i.c.v.), administered 24 and 18 h before the training session, prevented the amitriptyline and clomipramine increase of the mobility time. By contrast, pretreatment with anti-Go alpha(2) (1.56-12.5 micro g per mouse i.c.v.) never modified the antidepressant-like effect induced by the two investigated compounds. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota-rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole-board test. These results suggest the important role played by Gi(1), Gi(2), Gi(3), and Go(1) protein subtypes and the lack of involvement by Go(2) protein subtype in the transduction mechanism responsible for the antidepressant-like effect produced by amitriptyline and clomipramine.
Galeotti
Nicoletta
N
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Bartolini
Alessandro
A
Ghelardini
Carla
C
D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002997:Clomipramine / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D016376:Oligonucleotides, Antisense; D037342:Pertussis Toxin / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D000639:Amitriptyline; D037342:Pertussis Toxin; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse; D020962:Heterotrimeric GTP-Binding Proteins; D002997:Clomipramine