Inactivation of Gi proteins induces an antidepressant-like effect in the mouse forced-swimming test.

The effect of Gi protein inactivation was evaluated in an animal model of depression, the mouse forced swimming test. Animals were i.c.v. injected with pertussis toxin (PTX) or with antisense oligodeoxynucleotides directed against the α subunit of each Giprotein subtype (anti-Giα1, anti-Giα2, anti-Giα3, anti-Goα1, anti-Goα2). The administration of PTX (0.25 μg per mouse i.c.v.) produced an increase in the mobility time. Similarly, anti-Giα2 (25 μg per mouse i.c.v.), anti-Giα3 (25 μg per mouse i.c.v.), anti- Goα1 (12.5–25 μg per mouse i.c.v.) and anti-Goα2 (12.5–25 μg per mouse i.c.v.) increased the mobility time. The antidepressantlike effect obtained was similar to that produced by amitriptyline and clomipramine. By contrast, pretreatment with anti-Giα1 (3.12– 25 μg per mouse i.c.v.) never modified the mobility time in comparison with control animals. At the highest effective doses, none of the compounds used impaired motor coordination (rota rod test), nor modified spontaneous motility and inspection activity, (hole board test). These results indicate the involvement of Gi2, Gi3 , Go1, and Go2, but not Gi1, protein subtypes in the transduction mechanism responsible for the induction of an antidepressant-like effect in the mouse forced swimming test