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 ofthese 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 KO mice and wildtype littermates were studied in the forced swim test (FST), the tail suspension test (TST) and for sucrose consumption. In order to dissociate general activity from the potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing and swimming. In confirmation of previous reports, both DAT KO and NET KO mice exhibited less immobility than wildtype littermates while SERT KO mice did not. Effects of DAT deletion were not simply due to 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, while swimming was almost eliminated in DAT -/-mice, while 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 forced swim test results in antidepressant animal models, while 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 TST, 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 due to 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 knockout 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.

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Notwithstanding that the monoamine hypothesis may be an oversimplification unlikely to fully explain the complexity of human depression (68 -71), unbalance of monoaminergic systems is considered a key factor of the disease, and a prominent neurochemical feature of animal models (72,73). Here we found several distinctions in monoaminergic function between wild-type and PrP C -null mice.…”

Depression-related anhedonic behaviors caused by immobilization stress: a comparison with nicotine-induced depression-like behavioral alterations and effects of nicotine and/or "antidepressant" drugs

“…Although the contributions of more than a single monoamine-related mechanisms, including dopamine-related mechanisms, were suggested by previous studies (Miller et al, 1996;Perona et al, 2008), the selective serotonin reuptake inhibitor FL, as well as AT and CL, the drugs which inhibit the reuptake of serotonin and norepinephrine, caused -mental model, which is consistent with previous studies (Rygula et al, 2006;Strekalova et al, 2006). On the other hand, in the IM-NC group of mice co-treated with AT, -erence index were not caused by NC, which antagonized the IM-induced attenuated preference for sucrose in the IM-NC group without the co-treatment (Figs.…”

Assessment of Depression in a Rodent Model of Spinal Cord Injury

“…25 Further, supporting the validity of this approach, even with the small group sizes reported in these initial studies, we found reversal of depression diagnosed with the pilot equation in experiment 2 for the FST, a standard screen of antidepressant efficacy. 48,49 The depression identified with the equation, therefore, meets the criterion proposed by McKinney and Bunney.…”