HAB Mice Displayed Features of TRD
HAB mice display enhanced depression-like behavior as well as altered stress-induced neuronal activity in networks related to depression and anxiety in comparison with their normal depression/anxiety NAB counterparts (Sah et al, 2012; Sartori et al, 2011b). In this study, we demonstrate for the first time that male HABs are insensitive to at least three SSRIs differing in half-life, plasma-binding, active metabolites, and Ki values of 5-HT uptake (Hiemke and Hartter, 2000). Interestingly, we observed that treatment resistance seemed to be restricted to drugs targeting solely the serotonergic system, as both the selective noradrenaline re-uptake inhibitor reboxetine and the tricyclic antidepressant desipramine significantly reduced the depression-like behavior of HAB mice. This finding was surprising further suggesting that male HAB mice represent a valid model to study treatment resistance against SSRIs in humans. Indeed, at least 33% of patients do not respond to first-line pharmacotherapies such as the SSRI citalopram (Koenig and Thase, 2009; Trivedi et al, 2006). Changed responsiveness to SSRI treatment in humans has been linked to SNPs affecting 5-HT synthesis and polymorphism in the 5-HTT promoter region as well as functional polymorphisms in the 5-HT1A and 5-HT1B receptor genes (for a review see Kroeze et al, 2012). However, while an aberrant 5-HT neurotransmission has been reported in male HAB rats (Keck et al, 2005), pathophysiological correlates underlying the selective insensitivity to SSRIs in HAB mice remain to be elucidated in further experiments.
To date, there are only a few reports on TRD in animal models of depression. For example, the Flinders sensitive rat line has recently been described as being insensitive to citalopram and nortryptilin when subjected to repeated maternal separation (Borsini, 2012; Carboni et al, 2010). Furthermore, congenital learned-helplessness rats and about a quarter of rats subjected to unpredictable mild stress do not respond to chronic treatment with desipramine or fluoxetine, or to electroconvulsive therapy, respectively (Sartorius et al, 2007; Wang et al, 2011). It is possible that in the past insensitivities to certain drug classes were less likely to be reported. However, more recently the restriction of predictive validity of animal models for depression has been (partially) eased as a consequence of the need to model TRD (Borsini, 2012; Samuels and Hen, 2011) and to test new antidepressant approaches not primarily acting via monoaminergic systems.