Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration.
Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.
Center of Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
T M
TM
Eriksson
P
P
Delagrange
M
M
Spedding
M
M
Popoli
A A
AA
Mathé
S O
SO
Ögren
P
P
Svenningsson
D000386:AIDS-Related Complex / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015283:Citalopram / Q000627:therapeutic use; D003863:Depression / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004644:Emotions / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013550:Swimming / Q000523:psychology
D001578:Benzopyrans; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D016291:Dizocilpine Maleate; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C108607:robalzotan
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