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Original Article |
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Neuropsychopharmacology (2002) 27 554-564.10.1038/S0893-133X(02)00340-8
Role of Gi Proteins in the Antidepressant-like Effect of Amitriptyline and Clomipramine
Nicoletta Galeotti Ph.D, Alessandro Bartolini MD and Carla Ghelardini Ph.D |
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Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy
Correspondence: Dr Carla Ghelardini, Dept. of Pharmacology, Viale G. Pieraccini 6, 6I-50139 Florence, Italy. Tel.: +39 055 4271312; Fax: +39 055 4271280; E-mail: ghelard@pharm.unifi.it
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ABSTRACT
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The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the  subunit of different Gi-proteins (anti-Gi1, anti-Gi2, anti-Gi3, anti-Go1, anti-Go2) 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  g per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Gi1 (12.5 g per mouse i.c.v.), anti-Gi2 (12.5 g per mouse i.c.v.), anti-Gi3 (6.25 g per mouse i.c.v.), and anti-Go1 (6.25 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-Go2 (1.56-12.5 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 Gi1, Gi2, Gi3, and Go1 protein subtypes and the lack of involvement by Go2 protein subtype in the transduction mechanism responsible for the antidepressant-like effect produced by amitriptyline and clomipramine.
Keywords: Amitriptyline; Clomipramine; Tricyclic antidepressants; Pertussis toxin; Gi-proteins; Antisense oligodeoxyribonucleotides |
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