Microinjection of sanguinarine into the ventrolateral orbital cortex inhibits Mkp-1 and exerts an antidepressant-like effect in rats

doi:10.1016/j.neulet.2011.11.038

Neuroscience Letters

Volume 506, Issue 2, 11 January 2012, Pages 327-331

https://doi.org/10.1016/j.neulet.2011.11.038 Get rights and content

Abstract

We investigated the antidepressant effects of bilateral intra-the ventrolateral orbital cortex (VLO) administration of sanguinarine (SA), a selective mitogen-activated protein kinase phosphatase-1 (Mkp-1) inhibitor, in rats that had been subjected to a forced swimming test (FST) which is a classic animal model of depression. The expression of Mkp-1 and activation of ERK (ratio of phosphor-ERK to ERK) were also examined by immunoblotting. A single bilateral intra-VLO infusion of SA (2.5, 5 or 10 μg/0.5 μl per side) significantly reduced immobility time in the FST in dose-dependent fashion, as compared to vehicle-treated controls. A similar antidepressant effect was also observed in rats systemically administered fluoxetine, a classic antidepressant. The effects observed in the FST could not be attributed to non-specific increases in activity as neither microinjection of SA into the VLO nor fluoxetine treatment altered the behavior of the rats during the locomotion test. In addition, a decrease in the expression of Mkp-1 and a correlative increase in ERK activation were involved in the antidepressant effects of the bilateral SA administration into the VLO. The results indicated that Mkp-1 within the VLO is involved in the process of depression and may be a potential target for therapeutic action of antidepressant treatment.

Highlights

► Intra-VLO infusion of SA dose-dependently reduced immobility time in the FST. ► Intra-VLO infusion of SA did not alter the locomotion behavior. ► Mkp-1 expression and the ERK activation showed a dose-dependent reduction. ► Mkp-1 within the VLO is involved in the process of depression.

Section snippets

Conflict of interest

None.

Acknowledgements

This work was supported by National Natural Science Foundation of China (30700259 to Yunchun Chen, 30870886 to Qingrong Tan) and the National Science and Technology Program of China (2009BAI77B06 to Qingrong Tan).

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Methamphetamine (METH) is an illicit psychostimulant that is widely abused. After producing extreme pleasure, METH abuse leads to negative emotional states during withdrawal in clinical survey. However, the mood behavioral consequences of withdrawal from chronic METH exposure in animal experiments and related mechanisms have not been clarified yet. The aim of this study was to investigate the anxiety and depression-like phenotype in mice induced by withdrawal from chronic METH treatment and the potential molecular mechanism. We found that withdrawal from chronic METH treatment increased the immobility time during the forced swimming test and decreased central activities in open field test, indicating increased anxiety and depression-like behavior. Additional experiments showed that expression of brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (p-TrkB), phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated cAMP-response element binding protein (p-CREB) were decreased in the hippocampus and prefrontal cortex of mice in METH group and the level of mitogen activated protein kinase phosphatase-1 (MKP-1) was increased. Combined, our data show that withdrawal from chronic METH exposure induces anxiety and depression-like behavior associated with aberrant changes of proteins in BDNF-ERK-CREB pathway, providing new evidence for the involvement of BDNF pathway in the negative emotional states induced by withdrawal from METH.
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Moreover, positive and negative emotional signals are differentially processed in distinct subregions of the OFC (Northoff et al., 2000). Among those subregions, the ventrolateral orbital cortex (VLO) is strongly implicated in the pathogenesis of mood disorders, such as depression (Chen et al., 2012; Lin et al., 2012), as well as in nociception (Dang et al., 2011) and stress-related memory (Zhao et al., 2013). Recent studies by our group and others have demonstrated that VLO is involved in regulating depressive-like behaviors in rodents.
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The behavioral phenotypes of the three phrases reflect the development of drug-seeking behavior, learning to extinguish drug-seeking, and the potential for relapse (i.e., the reinstatement of conditioned behavior), respectively (Itzhak et al., 2013). The ventrolateral orbital cortex (VLO) has been suggested to be part of the limbic–thalamic–cortical circuits that are strongly implicated in the pathogeneses of mood disorders, such as depression (Chen et al., 2012; Lin et al., 2012; Xing et al., 2011), as well as nociception (Dang et al., 2010; Dang et al., 2011) and stress-related memory (Zhao et al., 2013). Moreover, the VLO is one of the main divisions of the orbitofrontal cortex (OFC) that have been linked to learning deficits (Dalley et al., 2004; Feierstein et al., 2006).
The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval.

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Microinjection of sanguinarine into the ventrolateral orbital cortex inhibits Mkp-1 and exerts an antidepressant-like effect in rats

Abstract

Highlights

Section snippets

Conflict of interest

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Trends Pharmacol. Sci.

Neurosci. Biobehav. Rev.

J. Affect. Disord.

Biol. Psychiatry

Prog. Neuropsychopharmacol. Biol. Psychiatry

Med. Hypotheses

Behav. Brain Res.

Brain Cogn.

Behav. Brain Res.

Neurobiol. Dis.

Biol. Psychiatry

J. Biol. Chem.

Brain Res. Bull.