Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Abstract

Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine ␤-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh ؊/؊ mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh ؉/؊ mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh ؊/؊ mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh ؊/؊ mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh ؊/؊ mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs.A ntidepressant medications are thought to elicit their therapeutic effects by increasing synaptic concentrations of the monoamines serotonin (5-HT) and͞or norepinephrine (NE) (1). Most tricyclic antidepressants enhance NE and 5-HT transmission because they inhibit presynaptic reuptake, although most of these drugs have affinity for other neurotransmitter receptors that contribute to their side effect profile. More recently, selective 5-HT reuptake inhibitors (SSRIs) have become widely prescribed because of their improved safety profile from limited interaction with other neurotransmitter receptors (1). However, some investigators have recently challenged whether SSRIs produce effects selectively on the serotonergic system over the noradrenergic and dopaminergic systems (2, 3). Indeed, a number of in vivo microdialysis studies have shown that acute (4-6) and chronic (7-9) treatment with certain SSRIs can increase extracellular concentrations of NE in addition to that of 5-HT.Attempts to delineate the role of NE in the behavioral effects of antidepressants have used inhibition of synthetic enzymes to deplete the neurotransmitter or chemical lesion techniques to destroy NE terminals. However, many depletion agents, such as the tyrosine hydroxylase inhibitor ␣-methyl-p-tyrosine or the v...

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…Studies with knockout mice that are unable to synthesize norepinephrine and epinephrine show that these mice are unresponsive not only to the NRIs, desipramine and reboxetine, the monoamine oxidase inhibitor (MAOI) pargyline and the norepinephrine/dopamine reuptake inhibitor bupropion, but also to the SSRIs fluoxetine, sertraline and paroxetine [69]. These results demonstrate the important role norepinephrine plays in antidepressant therapy.…”

Effects of Acute and Long-Term Administration of Escitalopram and Citalopram on Serotonin Neurotransmission: an In Vivo Electrophysiological Study in Rat Brain

“…On the one hand, this discrepancy could stem from the fact that citalopram may be unique in that it exerts their antidepressant action differently from other SSRIs. In norepinephrine-deficient mice, unlike paroxetine, fluoxetine, and sertraline, citalopram has been shown to partially increase 5-HT levels in the hippocampus and reduce immobility, in tail suspension test in mice, independently of norepinephrine system integrity (Cryan et al, 2004). On the other, the regulation of postsynaptic 5-HT 1A receptor function in hippocampus may occur at a level distal to the receptor, such as regulation of G protein expression.…”

Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats

“…Hippocampal neurotransmission controls memory, learning, stress responses, and behavior in humans and animals (Bremner et al, 1996;Cryan et al, 2004;Dietmar et al, 1998;Galeotti et al, 2004). The NE neurons derived from the locus ceruleus target hippocampus and release NE to modulate brain functions in response to changes in the environment (Bremner et al, 1996).…”

“…It is expected that NE4DA in the hippocampus and DA4NE in the striatum (Xu et al, 2000, Cryan et al, 2004. The brain microdialysis study revealed that extracellular NE level in the hippocampus of SPORTS rats was significantly greater than that of control rats all day (Figure 2a).…”

“…Following exercise stimulation, a variety of changes in gene expression and NE metabolism occurred in the hippocampus (Bronikowski et al, 2004;Dunn et al, 1996;Rhodes et al, 2003). Whether hippocampal NE induces voluntary wheel running has not yet been clarified, although genetically or pharmacologically enhanced NE level in brain regions that include the hippocampus increases field locomotor activity in experimental animals (Xu et al, 2000;Cryan et al, 2004;Shishikina et al, 2004;Lahdesmaki et al, 2003;Cases et al, 1995). Given the fact that obese and diabetic animals with low physical activity have less NE in the hippocampus than normal controls (Gallego et al, 2003;Yamato et al, 2004;Lackovic et al, 1990), we hypothesized that hippocampal NE is involved in the initiation of voluntary exercise.…”