Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Abstract

One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

“…Interestingly, the a 2A -AR KOs express mGluR5-LTD after an application of DHPG, demonstrating that signaling via GPCRs, and more specifically those coupled to G aq , are still intact. Autoradiography data in the NET KOs shows a reduction in the cell surface expression of a 1 -ARs in several brain regions Xu et al, 2000;Dziedzicka-Wasylewska et al, 2006) but an upregulation of a 2A/C -AR within the BNST (Gilsbach et al, 2006). One possibility of our results, taken together with this data, suggest that within these mouse models a 1 -ARs and/or their signaling pathways are desensitized, preventing induction of a 1 -AR LTD. An intriguing observation was that a 1 -AR LTD can occlude mGluR5-LTD in the BNST.…”

“…Interestingly, both of these KO mice have altered anxiety/ depression phenotypes (Schramm et al, 2001;Lahdesmaki et al, 2002;Dziedzicka-Wasylewska et al, 2006;Keller et al, 2006) including increased anxiety-like behavior in the elevated plus maze (a 2A -AR KOs), increased response to injection stress (a 2A -AR KOs), decreased struggling/mobility in the forced swim and tail suspension tests (NET KOs) and bradycardia to stressful stimuli (NET KOs). In addition the NET KO animals have heightened sensitivity to psychostimulants, enhanced conditioned place preference to cocaine, and increased analgesia to opiates Xu et al, 2000;Hall et al, 2002).…”

Induction of c-Fos and ΔFosB Immunoreactivity in Rat Brain by Vagal Nerve Stimulation

“…Consistent with many other reports (Cryan et al, 2002b), when DMI, the noradrenergic reuptake inhibitor, was administered in this way it caused a decrease in immobility that was due to an increase in climbing, but not swimming, behavior. There are substantial data that antidepressants that act selectively through norepinephrine increase climbing but not swimming behavior (see Cryan et al, 2002b), whereas serotonergic antidepressants reduce immobility by increasing swimming activity rather than climbing activity (Dziedzicka-Wasylewska et al, 2006;Page et al, 1999;Xu et al, 2000). VNS, when administered for thee sessions of 2 h each between the two swim sessions, produced a comparable reduction in immobility to DMI.…”

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…The NET-KO mice also display marked behavioral alterations, including reduced locomotor activity upon exposure to a novel environment and elevated locomotor responses to psychostimulants (Xu et al, 2000). In addition, the NET-KO mice behave like antidepressant-treated wild-type animals in the tail suspension test with no additional effects of antidepressants such as desipramine, reboxetine, and imipramine (Gainetdinov et al, 2002; for review, see Gainetdinov and Caron, 2003;Dziedzicka-Wasylewska et al, 2006). Moreover, the NET-KO mice show characteristic hemodynamic changes, such as excessive tachycardia and increased blood pressure during sympathetic activation with wakefulness and activity, whereas resting mean arterial pressure and heart rate are maintained at nearly normal levels, most likely because of increased central sympathoinhibition (Keller et al, 2004a).…”