Enhanced Cocaine-Associated Contextual Learning in Female H/Rouen Mice Selectively Bred for Depressive-Like Behaviors Molecular and Neuronal Correlates

Virginie Rappeneau (1) , Anne-Laure Morel (1) , Malika El Yacoubi (1) , Jean-Marie Vaugeois (1) , Luc Denoroy (1) , Anne Bérod (1)

1 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center

BACKGROUND: Major depression has multiple comorbidities, in particular drug use disorders, which often lead to more severe and difficult-to-treat illnesses. However, the mechanisms linking these comorbidities remain largely unknown. METHODS: We investigated how a depressive-like phenotype modulates cocaine-related behaviors using a genetic model of depression: the Helpless H/Rouen (H) mouse. We selected the H mouse line for its long immobility duration in the tail suspension test when compared to non-helpless (NH) and intermediate (I) mice. Since numerous studies revealed important sex differences in drug addiction and depression, we conducted behavioral experiments in both sexes. RESULTS: All mice, regardless of phenotype or sex, developed a similar behavioral sensitization after 5 daily cocaine injections (10 mg/kg). Male H and NH mice exhibited similar cocaine-induced conditioned place preference scores that were only slightly higher than in I mice, whereas female H mice strikingly accrued much higher preferences for the cocaine-associated context than those of I and NH mice. Moreover, female H mice acquired cocaine-associated context learning much faster than I and NH mice, a facilitating effect that was associated to a rapid increase in striatal and accumbal brain-derived neurotrophic factor levels (BDNF; up to 35% 24 h after cocaine conditioning). Finally, when re-exposed to the previously cocaine-associated context, female H mice displayed greater Fos activation in the cingulate cortex, nucleus accumbens, and basolateral amygdala. CONCLUSIONS: Our data indicate that neurobiological mechanisms such as alterations in associative learning, striato-accumbal BDNF expression, and limbic-cortico-striatal circuit reactivity could mediate enhanced cocaine vulnerability in female depressive-like mice.

Mots clés: BDNF; H/Rouen mice; cocaine; depression; sex differences

Domaines: Médecine humaine et pathologie

Virginie Rappeneau, Anne-Laure Morel, Malika El Yacoubi, Jean-Marie Vaugeois, Luc Denoroy, et al.. Enhanced Cocaine-Associated Contextual Learning in Female H/Rouen Mice Selectively Bred for Depressive-Like Behaviors Molecular and Neuronal Correlates. International Journal of Neuropsychopharmacology, 2015, 18 (8), pp.1 - 12. ⟨10.1093/ijnp/pyv022⟩. ⟨hal-02185476⟩