Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Abstract

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT 5-HTT Ϫ / Ϫ mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT Ϫ / Ϫ mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT Ϫ / Ϫ mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg Antidepressants are thought to normalize the disturbances in monoamine function that occur in affective disorders (Feighner and Boyer 1996;Frazer 1997; Montgomery and Den Boer 2001). While dysfunctions in noradrenergic and dopaminergic systems are putative etiological factors in depression, there is considerable evidence indicating that perturbation of central serotonergic activity is a major etiological component of depression (Willner 1985;Murphy 1990;Maes and Meltzer 1995;Charney 1998 NO . 6 Antidepressant Responses in 5-HTT KO Mice 915 (for reviews see Brown and Linnoila 1990;Owens and Nemeroff 1998;Mann 1999). The serotonin transporter (5-HTT) acts as a key regulator of serotonin signaling. By regulating reuptake of released serotonin, the 5-HTT controls the duration and intensity of serotoninergic activity at the synapse. The 5-HTT has been directly implicated in depression by the finding that brain 5-HTT binding density is reduced in brains and platelets of depressed patients (e.g., Nemeroff et al. 1994;Malison et al. 1998;Mann et al. 2000). Moreover, a number of studies have found an association between genetic variation in the regulatory region of the 5-HTT gene and depression (e.g., Battersby et al. 1996; Collier et al. 1996a,b;Furlong et al. 1998;Rees et al. 1997;Menza et al. 1999; but see Seretti et al. 1999). The 5-HTT is also a major target for many antidepressant drug treatments (Blakely et al. 1991;Ramamoorthy et al. 1993). It is well known that the serotonin reuptake inhibitor (SRI) class of antidepressants increase concentrations of serotonin in the synapse by blocking the serotonin transporter (5-HTT) (Blakely et al. 1991;Ramamoorthy et al. 1993). However, given the time lag between the initial inhibitory effects of antidepressants on the 5-HTT and an observable improvement in sympt...

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

“…These findings indicate serotonergic and adrenergic systems may have been modified in GAT1 mutant mice secondary to the modification in the GABAergic system. This hypothesis is weakly supported by the report that mice lacking the serotonin transporter exhibit similar pharmacological effects to fluoxetine (Holmes et al, 2002). Amitriptyline and imipramine are antidepressants with more mixed pharmacological profiles.…”

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

“…In fact, the drugs used in the abovementioned studies exerted rather expected effects. Antiimmobility effects of the 5-HT reuptake inhibitor fluoxetine were abolished in 5-HTT À/À mice, whereas these mice retained sensitivity to the anti-immobility effects of the NE reuptake inhibitor desipramine and the mixed 5-HT/NE reuptake inhibitor imipramine (Holmes et al, 2002). Similarly, Dbh À/À mice failed to respond to the behavioral effects of the NET inhibitors desipramine and reboxetine, but effects of SSRIs (fluoxetine, sertraline, and paroxetine, but not citalopram) were also absent or severely attenuated in these mice .…”

“…An example illustrating this notion are the data provided by Holmes et al (2002), who have studied antidepressant responses in 5-HTT knockout mice (5-HTT À/À ), and by , who have examined dopamine b-hydroxylase knockout (Dbh À/À ) mice, which are unable to synthesize NE and epinephrine. In these two animal models, no differences in baseline immobility were observed in the knockout mice with a C57BL/6 background.…”

“…Therefore, repeated administration of this drug mimics in some ways a situation observed in mice deficient in 5-HTT. Holmes et al (2002) have shown that 5-HTT À/À mice (on the 129S6 background, however) showed markedly increased immobility in the FST. These mice exhibited reduced neuromuscular strength and stamina on the wire hang test indicating neuromuscular impairment, and this might have seriously compromised swimming in the FST.…”

“…Therefore, it was interesting to use the recently generated (Xu et al, 2000), genetically modified mice lacking the NET (NET À/À mice) for studying the role of the NET and the noradrenergic system in the actions of ADs, and to compare the effects of ADs with those described in previous studies carried out with mice lacking the 5-HT transporter (Holmes et al, 2002).…”