A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders.
Human studies have shown that a reduction of 5-HT transporter (SERT) increases the vulnerability for anxiety and depression. Moreover, women are more vulnerable to develop depression and anxiety disorders than men. For that reason we hypothesized that homozygous 5-HT transporter knockout rat (SERT(-/-)) models, especially female, are valuable and reliable animal models for humans with an increased vulnerability for anxiety- and depression-related disorders. As rats are extensively used in neuroscience research, we used the unique 5-HT transporter knockout rat, that was recently generated using N-ethyl-N-nitrosurea (ENU) -driven mutagenesis, to test this hypothesis. Behavioral testing revealed that male and female SERT(-/-) rats spent less time in the center of the open field and spent less time on the open arm of the elevated plus maze compared with wild-type 5-HT transporter knockout rats (SERT(+/+)). In the novelty suppressed feeding test, only male SERT(-/-) rats showed a higher latency before starting to eat in a bright novel arena compared with SERT(+/+) controls. Both male and female SERT(-/-) rats showed a higher escape latency from their home cage than SERT(+/+) littermates. Moreover, SERT(-/-) rats were less mobile in the forced swim test, and sucrose consumption was reduced in SERT(-/-) rats relative to SERT(+/+) rats. Both effects were sex-independent. Neurochemically, basal extracellular 5-HT levels were elevated to a similar extent in male and female SERT(-/-) rats, which was not influenced by the selective 5-HT reuptake inhibitor citalopram. 5-HT immunostaining revealed no difference between SERT(+/+) and SERT(-/-) rats in the dorsal raphe nuclei, in both males and females. These findings demonstrate that SERT(-/-) rats show anxiety and depression-related behavior, independent of sex. Genetic inactivation of the SERT has apparently such a great impact on behavior, that hardly any differences are found between male and female rats. This knockout rat model may provide a valuable model to study anxiety- and depression-related disorders in male and female rats.
Olivier
J D A
JD
Department of Cognitive Neuroscience: Psychoneuropharmacology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. j.olivier@cns.umcn.nl
Van Der Hart
M G C
MG
Van Swelm
R P L
RP
Dederen
P J
PJ
Homberg
J R
JR
Cremers
T
T
Deen
P M T
PM
Cuppen
E
E
Cools
A R
AR
Ellenbroek
B A
BA
D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001069:Appetite Regulation / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D008297:Male; D018782:Maze Learning / Q000502:physiology; D017551:Microdialysis; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D011930:Reaction Time / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012727:Sex Characteristics; D009435:Synaptic Transmission / Q000235:genetics
D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors