title: Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.
abstract: Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.
authors.affiliation: Molecular Neurobiology Branch, NIDA-IRP, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Maria T G
authors.initials: MT
authors.lastname: Perona
authors.forename: Shonna
authors.initials: S
authors.lastname: Waters
authors.forename: Frank Scott
authors.initials: FS
authors.lastname: Hall
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Marc
authors.initials: M
authors.lastname: Caron
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D002872:Chromosome Deletion; D003866:Depressive Disorder / Q000235:genetics* / Q000503:physiopathology; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005473:Fluoxetine / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D006380:Helplessness, Learned; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation; D009043:Motor Activity / Q000235:genetics; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D010641:Phenotype; D010879:Piperazines; D013395:Sucrose; D013550:Swimming; D013649:Taste / Q000235:genetics
chemical_list: C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D050485:GABA Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; C493414:Slc6a1 protein, mouse; C493228:Slc6a2 protein, mouse; C493215:Slc6a3 protein, mouse; D005473:Fluoxetine; D013395:Sucrose; D003891:Desipramine