J.M. Vaugeois

Chronic agomelatine and fluoxetine induce antidepressant-like effects in H/Rouen mice, a genetic mouse model of depression.

The novel antidepressant agomelatine behaves as an agonist at melatonergic MT(1) and MT(2) receptors and as an antagonist at serotonin 5-HT(2C) receptors. This study investigated the effects of agomelatine and fluoxetine in a genetic model of depression called H/Rouen mice Male and female H/Rouen (helpless line) and NH/Rouen (nonhelpless line) mice, received once daily for 3 weeks agomelatine (10 and 50 mg/kgi.p.), fluoxetine (10 mg/kgi.p.) or vehicle. Immobility duration in the tail suspension test (TST) was assessed on day 1 (D1), day 8 (D8), day 15 (D15) and day 22 (D22). Locomotor activity in a novel environment was assessed on day 18 (D18) and anhedonia (2-bottle sucrose preference test) was considered after the end of chronic treatment, from days 22 to 25. Agomelatine (50 mg/kg) significantly reduced immobility at D15 (p<0.01), and D22 (p<0.001) in treated H/Rouen mice whereas agomelatine at 10 mg/kg did not induce a statistically significant change. Fluoxetine reduced immobility at D8 (p<0.01), D15 (p<0.001) and D22 (p<0.001). Locomotor activity was unchanged in all treated groups as compared to vehicle groups. In the sucrose test, there was a significant decrease in sucrose preference in H/Rouen mice compared with NH/Rouen mice receiving vehicle. Both agomelatine doses (10 mg/kg (p=0.05) and 50 mg/kg (p<0.001) as well as fluoxetine (p<0.001) significantly increased the sucrose preference in H/Rouen mice as compared with H/Rouen mice that had received vehicle. These data indicate that the novel antidepressant agomelatine has antidepressant-like properties in H/Rouen mice, a genetic model of depression.

The H/Rouen mouse model displays depression-like and anxiety-like behaviors

Cardinal symptoms of depression include helplessness and anhedonia. In addition, depression and anxiety are often comorbid disorders. H/Rouen mice, a genetic mouse model of depression, display helpless behavior in the tail suspension test, whereas non-helpless NH/Rouen mice show the opposite behavior. It is unknown whether H/Rouen mice display an anxious behavior as compared to NH/Rouen mice, and is unclear whether they display anhedonia. Time spent in the periphery of an open-field, an index of anxiety, was found to be higher in male and female H/Rouen mice as compared to NH/Rouen mice. In the elevated plus-maze, a decrease in the number of entries and in the time spent in the open arms was observed in both male and female H/Rouen. In the light/dark box, the number of entries and the time spent in the anxiogenic bright compartment was significantly reduced in male and female H/Rouen mice. In addition, the preference of consumption of a 2% sucrose solution was significantly reduced in male and female H/Rouen mice as compared to NH/Rouen and I/Rouen mice in a two-bottle choice paradigm but was restored by a chronic (3 weeks) fluoxetine treatment. H/Rouen mice thus display both anxiety and anhedonia making them a potent animal model in the treatment of forms depression comorbidly expressed with anxiety.

À propos d’un modèle animal de la dépression

Resume La depression est une maladie multifactorielle et des facteurs genetiques jouent un role dans son etiologie. La comprehension de sa physiopathologie requiert des modeles experimentaux qui miment la pathologie. Dans cette revue nous decrivons un modele elabore par une reproduction dirigee de souris presentant des reponses remarquablement differentes dans l’epreuve de la suspension par la queue, un paradigme de stress utilise pour cribler des antidepresseurs potentiels. Ainsi, les souris « resignees » sont essentiellement immobiles dans l’epreuve de la suspension par la queue, ainsi que dans l’epreuve de la nage forcee pratiquee selon Porsolt ; elles presentent une consommation reduite d’une solution de saccharose (2 %) agreable au gout. De plus, les souris « resignees » presentent des modifications du cycle veille-sommeil ressemblant a celles communement observees chez les malades deprimes, notamment un sommeil plus leger et plus fragmente, avec une augmentation de la duree du sommeil paradoxal. Comparees aux souris « non resignees », elles ont des taux basaux de corticosterone serique plus eleves et une vitesse de renouvellement de la serotonine plus faible dans l’hippocampe. De facon remarquable, la stimulation de l’autorecepteur serotoninergique 5-HT 1A induit une hypothermie plus grande et une inhibition de plus forte de l’activite electrique du neurone serotoninergique du noyau du raphe dorsal chez les souris « resignees » que chez les souris « non resignees ». Ainsi, les souris « resignees » presentent une diminution du tonus serotoninergique, qui evoque celui associe a la depression endogene humaine. Finalement, tant les alterations comportementales que le dysfonctionnement serotoninergique peuvent etre ameliores par l’administration chronique de l’antidepresseur fluoxetine. La lignee des « Souris depressives Rouen » peut constituer une opportunite pour approcher les genes influencant la susceptibilite a la depression et pour rechercher les substrats neurophysiologiques et neurochimiques sous-tendant les effets antidepresseurs.

P.2.028 Enhanced vulnerability to cocaine reinforcing effects in female H/Rouen mice selectively bred for depressive-like behaviour

leads to good memory performance of rats (1 h interval ORT, repeated measures ANOVA; MLA (F3,51 = 7.33; P< 0.001). This indicates that MLA could act both as a cognition enhancer and as a deficit model in this paradigm. Among other possibilities, one explanation for these findings could be that a7 nAChR antagonists promote a7 nAChR resensitisation. Since a7 nAChRs desensitise fast, by occupying a subset of a7 nAChRs with selective antagonists without intrinsic value, these receptors could have an opportunity to recover or resensitise. This hypothesis is currently investigated. In summary, while the main focus of the a7nAChR as a target for cognition enhancement lies on agonists and positive modulators, the antagonists of these receptors might prove to be a valuable tool for cognition enhancement in AD or schizophrenia.