title: Protein kinase C inhibition rescues manic-like behaviors and hippocampal cell proliferation deficits in the sleep deprivation model of mania.
abstract: BACKGROUND
  Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania.
  
  
  METHODS
  Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72 h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control.
  
  
  RESULTS
  We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD.
  
  
  CONCLUSIONS
  Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties.
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Erika
authors.initials: E
authors.lastname: Abrial
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bétourné
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Adeline
authors.initials: A
authors.lastname: Etiévant
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lucas
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Hélène
authors.initials: H
authors.lastname: Scarna
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné).
authors.forename: Laura
authors.initials: L
authors.lastname: Lambás-Señas
authors.affiliation: INSERM U846, Stem Cell and Brain Research Institute, F-69500 Bron, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Université de Lyon, Université Lyon 1, F-69373 Lyon, France (Drs Abrial, Etiévant, Lucas, Scarna, Lambás-Señas, and Haddjeri); Centre de Physiopathologie de Toulouse Purpan, INSERM UMR1043/CNRS UMR 5282, Université Toulouse III, CHU Purpan, BP 3028, F-31024 Toulouse, France (Dr Bétourné). nasser.haddjeri@inserm.fr.
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000627:therapeutic use; D000068180:Aripiprazole; D053119:Benzophenanthridines / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012892:Sleep Deprivation; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D053119:Benzophenanthridines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D005473:Fluoxetine; D013629:Tamoxifen; D000068180:Aripiprazole; C016299:chelerythrine; D011493:Protein Kinase C; D018021:Lithium Chloride
keywords: bipolar disorder; hippocampal cell proliferation; manic-like behaviors; protein kinase C; sleep deprivation