Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression.
Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its physiopathology relies on the availability of experimental models potentially mimicking the disease. Here we describe a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increased pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal seric corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin(1A) autoreceptor stimulation induces larger hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.
El Yacoubi
Malika
M
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6036, Neuropsychopharmacologie Expérimentale, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, 76183 Rouen Cedex, France.
Bouali
Saoussen
S
Popa
Daniela
D
Naudon
Laurent
L
Leroux-Nicollet
Isabelle
I
Hamon
Michel
M
Costentin
Jean
J
Adrien
Joëlle
J
Vaugeois
Jean-Marie
JM
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000223:Adaptation, Psychological; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001345:Autoradiography; D002352:Carrier Proteins / Q000378:metabolism; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D005247:Feeding Behavior; D005260:Female; D007036:Hypothermia, Induced; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008960:Models, Psychological; D009419:Nerve Tissue Proteins; D011903:Raphe Nuclei / Q000503:physiopathology; D050486:Serotonin Plasma Membrane Transport Proteins; D012890:Sleep / Q000502:physiology; D013395:Sucrose; D014851:Wakefulness / Q000502:physiology
D000928:Antidepressive Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013395:Sucrose; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone