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 subunit of different Gi-proteins (anti-Gi 1 , anti-Gi 2 , anti-Gi 3 , anti-Go 1 , anti-Go 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 g per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Gi 1 (12.5 g per mouse i.c.v.), anti-Gi 2 (12.5 g per mouse i.c.v.), anti-Gi 3 (6.25 g per mouse i.c.v.), and anti-Go 1 (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-Go 2 (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 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 antidepressantlike effect produced by amitriptyline and clomipramine.