Down-regulation of norepinephrine transporter expression on membrane surface induced by chronic administration of desipramine and the antagonism by co-administration of local anesthetics in mice

Song, Liqiu; Kitayama, Tomoya; Morita, Kenichi; Morioka, Norimitsu; Dohi, Toshihiro

doi:10.1016/j.neuint.2007.09.013

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…In addition, chronic antidepressant treatment in both mice and humans results in enhanced levels of phosphorylated Akt (Krishnan et al, 2008) which our studies correlate with decreased surface NET. Interestingly, chronic antidepressant treatment has also been shown to result in a down regulation of NET (Kitayama et al, 2006; Song et al, 2008; Jeannotte et al, 2009b; Jeannotte et al, 2009a). Whether this antidepressant-stimulated decrease in surface NET is Akt dependent, however remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Insulin Reveals Akt Signaling as a Novel Regulator of Norepinephrine Transporter Trafficking and Norepinephrine Homeostasis

Robertson¹,

Matthies²,

Owens³

et al. 2010

J. Neurosci.

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Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicate that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high comorbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia, we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin, a drug that induces a type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis.

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Section: Discussionmentioning

confidence: 99%

Insulin Reveals Akt Signaling as a Novel Regulator of Norepinephrine Transporter Trafficking and Norepinephrine Homeostasis

Robertson¹,

Matthies²,

Owens³

et al. 2010

J. Neurosci.

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“…Jeannotte and colleagues (Jeannotte et al, 2009) reported that the proportion of total NET associated with the membrane compartment in frontal cortex was similar in DMI and vehicle treated animals. In contrast, Song et al (Song et al, 2008) reported a decrease of more than 50% in the amount of NET protein contained in cell surface fractions from the hippocampus after DMI treatment. Our present findings agree with the former study in frontal cortex, and suggest that chronic DMI did not induce substantial amounts of NET to traffic away from the plasmalemma in the PFC.…”

Section: Discussionmentioning

confidence: 87%

“…Several studies have shown that chronic DMI treatment resulted in no effect on measures of NET expression in the cortex (Bauer and Tejani-Butt 1992; Hebert et al, 2001; Song et al, 2008), while others reported reductions of NET expression ranging from 22-50% (Benmansour et al, 2004; Zhao et al, 2008). Differences in experimental design (drug dose, delivery route, treatment duration and NET assay method) may explain some of these disparities.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to consistent findings showing reduced transmitter synthesis, the effect of antidepressant treatment on the NET protein itself has produced variable results for measures of ligand binding, transmitter uptake and transporter detectability by immunoblot (Bauer and Tejani-Butt 1992; Benmansour et al, 2004; Galli et al, 1995; Hebert et al, 2001; Jeannotte et al, 2009; Ordway et al, 2005; Song et al, 2008; Weinshenker et al, 2002; Zhao et al, 2008; Zhu et al, 1998; Zhu et al, 2002; Zhu and Ordway 1997). Moreover, no study to date has examined NET protein within individual axon terminals or its localization to the plasma membrane in intact animals exposed to chronic NET blockade.…”

Section: Introductionmentioning

confidence: 99%

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Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

Erickson

Gandhi

Asafu‐Adjei

et al. 2011

International Journal of Neuropsychopharmacology

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Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.

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“…The region of L5 and L6 vertebrae, into which siRNAs were injected, was homogenized at 3 days postinjection with a homogenization buffer, and whole-cell fractions (for PRIPs, K + -Cl - -cotransporter-2 [KCC2], Na + -K + -Cl - -cotransporter-1 [NKCC1], glycine receptor [GlyR] α1, and tubulin) or cell membrane fractions (for GABA A receptor subunits) were obtained [12]. The homogenates were subjected to SDS-PAGE followed by immunoblotting using specific primary antibodies of interest.…”

Section: Methodsmentioning

confidence: 99%

Phospholipase C-Related but Catalytically Inactive Protein Modulates Pain Behavior in a Neuropathic Pain Model in Mice

et al. 2013

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BackgroundAn inositol 1,4,5-trisphosphate binding protein, comprising 2 isoforms termed PRIP-1 and PRIP-2, was identified as a novel modulator for GABAA receptor trafficking. It has been reported that naive PRIP-1 knockout mice have hyperalgesic responses.FindingsTo determine the involvement of PRIP in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIP-1 and PRIP-2 double knockout (DKO) mice. We found that naive DKO mice exhibited normal pain sensitivity. However, DKO mice that underwent PSNL surgery showed increased ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in PRIP-1 KO and DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIP-1 knockdown mice showed allodynia, while PRIP double knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. GABAA receptor subunit expression pattern was similar between PRIP-1 KO and DKO spinal cord, while expression of K+-Cl--cotransporter-2 (KCC2), which controls the balance of neuronal excitation and inhibition, was significantly upregulated in DKO mice. Furthermore, in the DKD PSNL model, an inhibitor-induced KCC2 inhibition exhibited an altered phenotype from painless to painful sensations.ConclusionsSuppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice.

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Down-regulation of norepinephrine transporter expression on membrane surface induced by chronic administration of desipramine and the antagonism by co-administration of local anesthetics in mice

Cited by 7 publications

References 29 publications

Insulin Reveals Akt Signaling as a Novel Regulator of Norepinephrine Transporter Trafficking and Norepinephrine Homeostasis

Insulin Reveals Akt Signaling as a Novel Regulator of Norepinephrine Transporter Trafficking and Norepinephrine Homeostasis

Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

Phospholipase C-Related but Catalytically Inactive Protein Modulates Pain Behavior in a Neuropathic Pain Model in Mice

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