Enhanced Cocaine-Associated Contextual Learning in Female H/Rouen Mice Selectively Bred for Depressive-Like Behaviors: Molecular and Neuronal Correlates.
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.
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy).
Virginie
V
Rappeneau
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy).
Anne-Laure
AL
Morel
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy).
Malika
M
El Yacoubi
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy).
Jean-Marie
JM
Vaugeois
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy).
Luc
L
Denoroy
INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team Physiopathology of the neuronal network responsible for the sleep-wake cycle, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, and Bérod); University Claude Bernard Lyon 1, Lyon, France (Ms Morel, Drs Rappeneau, El Yacoubi, Denoroy, and Bérod); 2EA 4651-ABTE /ToxEMAC Rouen, France (Dr Vaugeois); University of Rouen, Rouen, France (Dr Vaugeois); INSERM U1028/CNRS UMR5292, Lyon Neuroscience Research Center, Team BioRaN, Lyon, France (Dr Denoroy). anne.berod@univ-lyon1.fr.
Anne
A
Bérod
D017109:Akathisia, Drug-Induced / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D003866:Depressive Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012727:Sex Characteristics; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine
BDNF; H/Rouen mice; cocaine; depression; sex differences