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International Journal of Neuropsychopharmacology logoLink to International Journal of Neuropsychopharmacology
. 2014 Dec 19;18(1):pyu005. doi: 10.1093/ijnp/pyu005

Lipopolysaccharide-Induced Depressive-Like Behavior is Associated with α1-Adrenoceptor Dependent Downregulation of the Membrane GluR1 Subunit in the Mouse Medial Prefrontal Cortex and Ventral Tegmental Area

Miyu Sekio 1, Kenjiro Seki 1,✉
PMCID: PMC4368860  PMID: 25539502

Abstract

Background:

Chronic stress-induced depressive-like behavior is relevant to inflammatory immune activation. However, the neurobiological alterations in the brain following the central inflammatory immune activation remain elusive.

Methods:

Therefore, we investigated the neurobiological alterations during depressive-like behavior induced in mice by systemic administration of lipopolysaccharide (LPS; 1.2mg/kg administered twice at a 30-min interval via intraperitoneal injection).

Results:

At 24h after the second administration of LPS, an increased immobility time in the tail suspension test and the forced swimming test were observed, as well as reduced sucrose preference. Protein levels of the AMPA receptor GluR1 were significantly decreased at the plasma membrane in the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA), while levels of the GluR2 were increased at the plasma membrane in the nucleus accumbens (NAc) at 24h after LPS. However, total GluR1 and GluR2 protein levels in the mPFC, VTA, and NAc were not affected by LPS. Moreover, LPS facilitated release of noradrenaline in the mPFC and VTA, but not in the NAc. Consistently, systemic administration of prazosin, an α1-adrenoceptor antagonist, blocked the LPS-induced downregulation of the membrane GluR1 subunit in both the mPFC and VTA and also blocked the upregulation of the membrane GluR2 subunit in the NAc. Intracerebroventricular administration of prazosin 30min before LPS injection abrogated the LPS-induced depressive-like behaviors. In opposition, administration of propranolol, a β-adrenoceptor antagonist, did not affect the LPS-induced downregulation of GluR1, the upregulation of GluR2, or the depressive-like behavior.

Conclusions:

These results suggest that LPS-activated α1-adrenoceptor-induced downregulation of membrane GluR1 in the mPFC and VTA is associated with inflammation-induced depressive-like behavior.

Keywords: α, 1-adrenoceptor, depressive-like behavior, immune system, neuronal plasticity, reward system

Introduction

Since the initial proposal of the cytokine hypothesis of depression (Maes et al., 1991; Smith, 1991), many clinical studies have provided the evidence to support this hypothesis (Maes et al., 1997; Maes, 1999; Kim et al., 2007; Simon et al., 2008). In particular, meta-analyses have revealed that elevations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in peripheral blood are reliable biomarkers of depression (Zorrilla et al., 2001; Dowlati et al., 2010). It has been demonstrated that long-term administration of interferon (IFN)-α in patients with hepatitis C increases depressive symptoms compared with control patients not given this therapy over the same duration (Majer et al., 2008; Raison et al., 2010; Felger et al., 2012). Furthermore, it has been suggested that there is considerable overlap in symptom expression between cytokine-induced depression and idiopathic depression in medically healthy subjects (Capuron et al., 2009). Recent studies have also demonstrated that administration either of the bacterial endotoxin lipopolysaccharide (LPS) or of proinflammatory cytokines can cause depressive symptoms in rodents (Frenois et al., 2007; Koo and Duman, 2008; O’Connor et al., 2009; Bay-Richter et al., 2011) and humans (Reichenberg et al., 2001). Consistent with these results, IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors (Chourbaji et al., 2006), and TNF-α receptor knockout mice exhibit an antidepressant phenotype (Simen et al., 2006).

Because monoamine reuptake inhibitors and monoamine oxidase inhibitors have been shown to be effective against major depression, depletion of monoamines has been suggested as a central mechanism of major depression (Ressler and Nemeroff, 2000; Morilak and Frazer, 2004). However, because the currently available antidepressants have a therapeutic lag time before they become effective, more complicated neurobiological alterations must be involved in the development of depression. Recently, dopamine-related neuroanatomical alterations in the reward system in major depression have also been suggested (Tremblay et al., 2005; Nestler and Carlezon, 2006). Bidirectional neural encoding of action in dopamine neurons of the nucleus accumbens (NAc) affects depressive-like behavior (Tye et al., 2013). Phasic activation of ventral tegmental area (VTA) neurons projecting to the NAc induces susceptibility to social-defeat stress. Furthermore, inhibition of the VTA-NAc projection induces resilience, whereas inhibition of the VTA projecting to the medial prefrontal cortex (mPFC) promotes susceptibility (Chaudhury et al., 2013). Therefore, the contribution of the reward system is important for understanding the development of major depression.

Peripheral administration of LPS increases the extracellular concentration of noradrenaline, serotonin (Linthorst et al., 1996), and dopamine in the brain (Lavicky and Dunn, 1995). However, the role of these elevated monoamine system components in the induction of depressive-like behavior remains unclear. A recent study suggested that LPS-induced depressive-like behavior is mediated by activation of the N-methyl-D-aspartate (NMDA) receptor (Walker et al., 2013). Furthermore, LPS impairs the induction of long-term potentiation (LTP) in the hippocampus (Kelly et al., 2003; Kavanagh et al., 2004). In addition, it has been reported that the NMDA receptor–independent LTP was also impaired by chronic administration of LPS in rats (Min et al., 2009). Therefore, it is possible that the alteration of synaptic strengthening induced by neuromodulators in the brain is involved in the mechanism of depressive symptoms.

In the present study, we found that downregulation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit at the plasma membrane in the mPFC and VTA was induced at 24h after LPS administration. Conversely, upregulation of the membrane GluR2 subunit was observed in the NAc at 24h after LPS administration. Because LPS induced both depressive-like behaviors and downregulation of the membrane GluR1 subunit in the mPFC and VTA, and because upregulation of the membrane GluR2 subunit in the NAc was abrogated by the administration of prazosin, an α1-adrenoceptor antagonist, we suggest that locus coeruleus activity-dependent neuroplasticity is part of the mechanism of inflammation-induced depressive-like behavior.

Methods

Chemicals and Antibodies

Rabbit polyclonal antibodies against AMPA-GluR1 (1:1000) were purchased from Abcam. A mouse monoclonal antibody against AMPA-GluR2 (1:1000) and Anti-NMDAR1 (clone 1.17.2.6) were purchased from Millipore. A mouse monoclonal antibody against Na+/K+ ATPase α-1 was purchased from Novus Biologicals LLC. A rabbit polyclonal antibody against the postsynaptic density protein-95 (PSD-95; 1:200) was purchased from Santa Cruz Biotechnology, Inc. A rabbit monoclonal antibody against β-actin (D6A8) was purchased from Cell Signaling Technology. Lipopolysaccharides (L3129, serotype 0127:B8), Prazosin hydrochloride (P7791), and Propranolol hydrochloride (P0884) were purchased from Sigma-Aldrich.

Ethics Statement, Animal Care, and LPS Administration

This study was approved by the Animal Care Committee of Ohu University. All animal procedures were performed in accordance with the guidelines of the Animal Care Committee of Ohu University (see Supplementary Materials for additional information). Special care was taken to reduce animal distress, and to use the minimum number of animals needed for all studies. Adult CD1 mice (male; aged 7 weeks) were supplied by Charles River Laboratories Japan, Inc. All mice were housed at 25±2 °C on a 12-hour light (07:00-19:00) to 12-hour dark (19:00-07:00) schedule with ad libitum access to food and water. Mice were handled individually every day for the 10 days before the behavioral test. The mice that were to have a guide cannula implanted into the skull were handled individually once daily for the 4 days before surgery, and then twice daily during the 6 days after recovery from anesthesia until the behavioral tests were performed. LPS was dissolved in sterile endotoxin-free isotonic saline and administered intraperitoneally (at a dose of 2.4mg/kg, given as two injections of 1.2mg/kg each, with 19:00 [first injection] and 19:30 [second injection]) on the first day. The guide cannula–implanted mice used for studying intracerebroventricular drug administration had a higher activity level than the naïve mice, even though they were handled before performing the behavioral tests. Therefore, we believe that higher doses of LPS than those used in the present study are required for the induction of depressive-like behaviors. Additionally, we ascertained that our dose of LPS is within the appropriate range for the evaluation of depressive-like behavior in naïve mice.

Behavioral Tests

All behavioral tests were performed during the first 4h of the dark phase of the light-dark schedule (23:00 on the first day for the locomotor activity test, corresponding to 4h post-LPS, and 19:00 on the second day for the locomotor activity test, tail suspension test [TST], and forced swimming test [FST]). Brain tissues were harvested at 23:00 on the first day (corresponding to 4h post-LPS) and 19:00 on the second day (corresponding to 24h post-LPS) from mice that performed the behavioral tests.

Measurement of Locomotor Activity

Mobility time was measured as locomotor activity for 5min in an acrylic plastic box (294×294×297mm) lit with 40 lux. The box was covered by non-reflective paper on the bottom and the four inside walls. Each individual mouse was placed in the center of the open field, and was recorded by digital video camera in the absence of the investigator. Moving time was measured, except for periods of rearing and excreting, and was analyzed after the test.

Tail Suspension Test

For the TST, each mouse was individually suspended by the tail from a horizontal bar located 42cm above the bench top using adhesive tape placed approximately 2cm from the tip of the tail. Each mouse was suspended for 6min via a hanging hook connected from the horizontal bar, and was recorded with a digital video camera in the absence of the investigator. The immobility time during TST was measured after the experiments. All vertical movements over 1cm and movements consisting of twisting of the body were not counted, but the encompass immobility was included as the immobility time in this paradigm.

Forced Swimming Test

For the FST, each mouse was placed for 6min in a 3000mL glass beaker (15.3 x 22.5cm) containing 2250mL of water at 24±1° C. The water was changed between test sessions. Test sessions were recorded from the front of the beaker by digital video that was set at the same vertical height as the surface of the testing water, and were analyzed and scored by an investigator blinded to the allocated group. Immobility duration and latency were measured for the last 5min of the FST. All vertical movement over 1cm were excluded from the measurements of immobility.

Sucrose Preference Test

Sucrose preference was evaluated using a two-bottle free choice paradigm. Each mouse was habituated to a solution of 2% sucrose in tap water for 24h in its home cage. To assess individual sucrose intake, the mouse was deprived of water for 15h in its home cage before LPS injection. Immediately following saline or LPS injection, each tested mouse was placed in its home cage for 48h with access to two identical drinking bottles, containing either the 2% sucrose solution or normal sterilized water. To avoid any side bias during the test, the locations of the two drinking bottles were switched after 12h. In order to exclude any bias of the activity phase according to the light-dark cycle, three mice of each group were started at 07:00, and the other three mice of the same group were started at 19:00. In order to evaluate the extent of anhedonia-like symptoms, we considered the sucrose preference of mice during the first 24h post-LPS to be the effect of sickness, and during the second 24h period (24–48h post-LPS) to be the effect of depression.

Tissue Harvesting and the Plasma Membrane Extraction

At 4h and 24h after LPS, mice were euthanized for preparation of the samples from the mPFC, NAc, and VTA for western blotting. The regions of interest in both hemispheres were adapted from the digital Paxinos mouse brain atlas (Paxinos, 2004; Supplementary Figure S1A). The method for extraction of the plasma membrane fraction was performed as described previously (Ohtake et al., 2014). The plasma membrane fraction of each sample of interest was extracted using a commercially-available plasma membrane extraction kit (BioVision, Inc.).

The fidelity of these fractions was validated by the near-absence of the plasma membrane proteins (Na+/K+ ATPase) in the cytosolic fraction and the absence of the cytosolic protein (β-actin) in the plasma membrane fraction. To confirm whether the postsynaptic proteins were collected with the plasma membrane, the existence of postsynaptic density protein (PSD)-95 in the plasma membrane fraction and the near absence of PSD-95 in the cytosolic fractions were verified by immunoblotting with anti-PSD-95 antibody (Supplementary Figure S1B).

Western Blotting

Western blotting analysis was performed as described previously (Ohtake et al., 2014). Briefly, the protein extracts were mixed with sample buffer containing 50mM Tris-HCl (pH 7.6), 2% SDS, 10% glycerol, 10mM dithiothreitol, and 0.2% bromophenol blue and boiled at 94 °C for 5min. The samples were separated by electrophoresis by Sodium Dodecyl Sulfate Poly-Acrylamide Gel Electrophoresis (SDS-PAGE) in 8–10% gels, and transferred onto polyvinylidene fluoride (PVDF) membranes. The blots were detected (PerkinElmer, Inc., Waltham, Massachusetts) and were visualized using the Versadoc imaging system (Model 5000, BioRad). The protein bands were analyzed using ImageJ software (Version 1.48a, Wayne Rasband).

In Vivo Microdialysis

Anesthetized animals were placed in a stereotaxic frame (Narishige Group, SR-6M). Three holes were made through the skull using a dentist drill. One hole was made for implantation of a steel guide cannula (AG-4, Eicom), and the other two holes were made in order to anchor the stabilizing screws. The stereotaxic coordinates (in mm) were as follows: for the mPFC, anteroposterior (AP): +1.6, lateral (L): -0.6, depth (DV): -1.0; for the NAc, AP: +1.3, L: -0.6, DV: -4.6; and for the VTA, AP: -3.05, L: -0.4, DV: -4.4. Coordinates refer to bregma and the dura surface. The cannula was held in position by dental cement (GC Unifast II, Tokyo, Japan) attached to the stabilizing screw. The dummy cannula (AD-4, Eicom) was inserted into the guide cannula and fixed with cap nuts (AC-1, Eicom) until the behavioral experiments. After the mice awoke from the anesthesia, they were each caged individually until the experiments. A dialysis probe (A-I-8-02, Eicom) was carefully inserted into the pre-implanted guide cannula without anesthesia, fixed by a cap-nut, and perfused at a constant rate of 1 μl/min with artificial cerebrospinal fluid containing 150mM NaCl, 3mM KCl, 1.4mM CaCl2, 0.8mM MgCl2, and 1.0mM NaHPO4, which was adjusted to pH 7.4 with 0.1% endotoxin-free bovine serum albumin containing 0.1mM EDTA and 4mM sodium metabisulfite to protect against oxidation. Dialysates were collected using an Eicom cannula swivel unit (SSU-20) attached to an injector and a 25 µl Hamilton syringe, every 30min after the 90min stabilization period allowed to achieve a steady state in the freely moving mouse. A polytetrafluoroethylene coiling tube (CT-20, Eicom) was used to infuse the drug, and the mouse was allowed to move freely in the test cage during sampling.

Measurement of Noradrenaline

Dialysate samples (30μL) were assayed by a competitive enzyme-linked immunosorbent assay (ELISA; LDN Noradrenaline ELISA kit, BA E-5200, Labor Diagnostika Nord in triplicate against standard curves of known dilution and positive and negative controls as appropriate. According to the manufacturer’s instructions, the detection limits of this ELISA kit is 4 pg/ml. The minimum concentration of noradrenaline standard solution we measured was 0.15 pg/30ml and the coefficient of variation was 9.5% (n=3). The coefficient of variations of the ELISA measured in this study from all concentrations of standard solutions, as a measure of intra-assay variation, were 4.4–9.5% (n=5).

Intracerebroventricular Administration

The intracerebroventricular administration was performed as described previously (Ohtake et al., 2014). The guide cannula (AG-4, Eicom) was implanted projecting to the lateral ventricle using stereotactic coordinates (bregma, AP: −0.25mm, L: 1mm, DV: 2.25mm). A drug infusion probe was used as a dialysis probe, and the tip (the dialysis membrane part) was cut. The mice were administered a 5 μl intracerebroventricular infusion of either saline, 70mM prazosin, or 400mM propranolol 30min before LPS injection under freely moving conditions in the test cage.

Statistical Analysis

Unpaired t-tests, a two-way (time × treatment) analysis of variance (ANOVA), and a one-way (treatment) ANOVA were performed as appropriate. After ANOVA was performed, Bonferroni post-hoc test was used for comparisons between two independent groups. The Wilcoxon signed ranks test was used for analyzing the data for noradrenaline release. All statistical analyses were performed with StatView (Version 5.0, SAS Institute Inc.) or ystat2013.xls (Igaku-Tosho) as appropriate. All data in the bar and line graphs indicate the mean ± SEM. The levels of significance for all analyses were set at p < 0.01 or p < 0.05.

Results

Assessment of Mouse Depressive-Like Behavior

Before the investigation of LPS-induced neurobiological alterations in the mouse brain, we confirmed the effects of LPS on sickness behavior and depressive-like behavior to determine if the concentration of LPS was adequate. We measured the locomotor activity at 4 and 24h after LPS injection. A two-way ANOVA (time × treatment) on the mobility time in the open field test demonstrated a significant interaction (Figure 1A; F (1,20) = 72.8, p < 0.001). Bonferroni post-hoc tests revealed a significant difference between 4h post-LPS versus 4h post-saline (p < 0.001), but the decreased locomotor activity had recovered by 24h post-LPS (p = 0.429, 24h post-LPS vs. 24h post-saline). Furthermore, a significant decrease in body weight was observed at 24h post-LPS (Figure 1B; unpaired t-test, p = 0.0053). We next examined the mice at 24h post-saline or post-LPS for the assessment of LPS-induced depressive-like behavior in the TST and FST. The immobility time during the TST for the mice in the LPS group was significantly longer than for the mice in the control group (Figure 1C; unpaired t-test, p = 0.023). The immobility time during the FST for mice in the LPS group was also significantly longer than for the mice in the control group (Figure 1D, unpaired t-test, p = 0.013). In addition, LPS-injected mice showed a significantly lower preference for sucrose compared with the saline-injected mice at both 0–24h (Figure 1E; unpaired t-test, p = 0.004) and 24–48h post-LPS (Figure 1F; unpaired t-test, p = 0.047). These results indicate that the concentration of LPS used in the present study is an appropriate range for the assessment of depressive-like behavior.

Figure 1.

Figure 1.

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Mice were injected with LPS (1.2mg/kg) twice with a 30min interval. The locomotor activity was measured at either 4 or 24h after LPS injection. The mobility time of mice in the open field was recorded over each 6min period, and results are presented as mouse locomotor activity (A; control, n=6; LPS, n=6). Change in body weight at 24h post-LPS was measured. The body weight of each mouse was measured at 5min before and 24h after LPS injection (B; control, n=6; LPS, n=6). The duration of immobility during the TST at 24h post-LPS was recorded for 6min (C; control, n=6; LPS, n=6). The duration of immobility during the FST at 24h post-LPS was recorded each for 6min (D; control, n=6; LPS, n=6). Sucrose preference was measured at 24h post-LPS (E; control, n=6; LPS, n=6) and 24–48h post-LPS (F; control, n=6; LPS, n=6) and the percentage of sucrose intake against total intake was calculated. All data are presented as means ± SEM. Statistically significant effects of LPS injection (**p < 0.01) are noted.

LPS-Induced Downregulation and Upregulation

It has previously been suggested that the mesolimbic dopamine system has reward-related (Schultz et al., 1997), hedonic (Chaudhury et al., 2013), and motivational components (Ikemoto and Panksepp, 1999; Wise, 2004). In addition to these components, the VTA dopaminergic neurons modulate the neural representation in the NAc of escape behavior from aversive stimuli (Roitman et al., 2008; Tye et al., 2013). Because our LPS-injected mice showed lower sucrose preferences and increased immobility times in the TST and FST, we investigated whether LPS modulates neuronal activity in the reward system. To investigate the effects of LPS at 4 and 24h on neuronal network activity in the reward system, we measured the protein levels of the AMPA receptor GluR1, the GluR2 subunit, and the NMDA receptor NR1 subunit at the plasma membrane in the mPFC, NAc, and VTA regions. One-way ANOVA (with the factor treatment) revealed that LPS affected the protein level of the GluR1 subunit at the plasma membrane in the mPFC (Figure 2A and B, F (2,9) = 102.044, p < 0.0001) and VTA (Figure 2O and P, F (2,9) = 13.338, p = 0.0020). Bonferroni post hoc tests between individual groups in the mPFC and VTA indicated that there were significant differences between saline and 4h post-LPS in the mPFC (p < 0.0001), between control and 24h post-LPS in the mPFC (p < 0.0001), between saline and 4h post-LPS in the VTA (p = 0.0007), and between saline and 24h post-LPS in the VTA (p = 0.0059). The protein level of the NR1 subunit at the plasma membrane in the mPFC was also affected by LPS (Figure 2A and D, F (2,9) = 37.733, p < 0.0001). Bonferroni post hoc tests revealed a significant reduction in NR1 subunits at the plasma membrane at 4h post-LPS in the mPFC (p < 0.0001), but recovery to the control level by 24h post-LPS (p = 0.1378 for saline vs. 24 h-post LPS). However, the effects of LPS on the protein level of NR1 at the plasma membrane in the VTA were not significant (Figure 2O and R, F (2,9) = 1.778, p = 0.2235 for VTA). Contrary to the results for GluR1 and NR1, the protein level of the GluR2 subunit was affected only in the NAc (Figure 2A, C, H, J, O and Q; F (2,9) = 22.027, p = 0.0003). Bonferroni tests revealed that, compared with the control, the protein level of the GluR2 subunit at the plasma membrane was significantly increased in the NAc at both 4h and 24 h-post LPS (p = 0.0001 for 4 h-post LPS vs. control and p = 0.010 for 24 h-post LPS vs. control). The total protein levels of the GluR1 and NR1 subunits in the mPFC (and VTA (Figure 2A, E and G for mPFC and Figure 2O, S and U) were not affected by LPS. Moreover, the total GluR2 protein level in the NAc was also unaffected by LPS (Figure 2H and M). From these data, we believe that long-term downregulation of the protein level of the GluR1 subunit at the plasma membrane in the mPFC and VTA is induced by LPS. Moreover, long-term upregulation of the membrane GluR2 subunit in the NAc is induced by LPS.

Figure 2.

Figure 2.

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Representative western blot of the protein level of membrane and total GluR1, GluR2, and NR1 in mouse mPFC (A), NAc (H), and VTA (O) with at 4h and 24h post-LPS injection (1.2mg/kg, twice at 30min interval). Representative graphs of the protein levels of membrane GluR1 (B; control, n=4; LPS, n=4), GluR2 (C; control, n=4; LPS, n=4), and NR1 (D; control, n=4; LPS, n=4) in the mPFC; of the total protein level of GluR1 (E; control, n=4; LPS, n=4), GluR2 (F; control, n=4; LPS, n=4), and NR1 (G; control, n=4; LPS, n=4) in the mPFC; of the protein levels of membrane GluR1 (I; control, n=4; LPS, n=4), GluR2 (J; control, n=4; LPS, n=4), and NR1 (K; control, n=4; LPS, n=4) in the NAc; of the total protein levels of GluR1 (L; control, n=4; LPS, n=4), GluR2 (M; control, n=4; LPS, n=4), and NR1 (N; control, n=4; LPS, n=4) in the NAc; of the protein levels of membrane GluR1 (P; control, n=4; LPS, n=4), GluR2 (Q; control, n=4; LPS, n=4), and NR1 (R; control, n=4; LPS, n=4) in the VTA; and of the total protein levels of GluR1 (S; control, n=4; LPS, n=4), GluR2 (T; control, n=4; LPS, n=4), and NR1 (U; control, n=4; LPS, n=4) in the VTA. The graph indicates the percentage of control (saline) levels. All data are presented as mean ± SEM. Statistically significant effects of LPS injection (*p < 0.05, **p < 0.01) are noted.

LPS Facilitation of Noradrenaline Release

Because the neurobiological effects of LPS in the NAc were different from those in the mPFC and VTA, we hypothesized that the origin of neurotransmission to the mPFC and VTA after LPS are different from that of the NAc. The activity of the monoamine system in the brain is very important for regulating mood and motivation (Ressler and Nemeroff, 2000; Morilak and Frazer, 2004). Dopamine neurons in the VTA project to neurons in the NAc and mPFC, and serotonergic neurons in the raphe nucleus project to the mPFC, NAc. and VTA. However, the primary source of adrenergic innervations to the NAc is the A2 region of the NTS, while the primary source of adrenergic innervations to the mPFC and the VTA is the locus coeruleus (LC; Mitrano et al., 2012). Therefore, we tested whether the effect of LPS on noradrenaline release in the mPFC, NAc, and VTA is different. Dialysates were discarded if the probe location was not in the correct area (mPFC, NAc, or VTA), and we verified the probe location histologically after each experiment (Figure 3A, C, and E). We injected LPS in freely moving mice 1.5h after the insertion of the dialysis probe. As shown in Figure 3B and F, the amounts of dialysate noradrenaline in the mPFC and VTA were significantly increased at 30–60min after LPS injection (Wilcoxon signed rank test; mPFC: p = 0.0216 for 30min and p = 0.0047 for 60min; VTA: p = 0.0012 for 30min and p = 0.0061 for 60min). However, the content of noradrenaline in the NAc was not affected by LPS (Figure 3D). These results indicate that LPS activates adrenergic neurons in the LC.

Figure 3.

Figure 3.

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Schematic drawing of the histological reconstruction of coronal sections from the mPFC (A), the NAc (C), and the VTA (E) in the microdialysis studies. Each symbol represents the approximate microdialysis probe placement for the sampling of the artificial cerebrospinal fluid containing the noradrenaline. LPS-induced facilitation of noradrenaline release in the mPFC (B, n=5), the NAc (D, n=5) and the VTA (F, n=5). Drawings were adapted from the digital Paxinos and Franklin Mouse Brain Atlas; the numbers on the left upper side of the drawings indicate the distance (in millimeters) anterior (+) and posterior (-) to bregma. Mice were injected with LPS (1.2mg/kg, twice at a 30min interval) and microdialysate effluents were collected from the mPFC (B), NAc (D), and VTA (F) at 30min intervals, starting at 30min before LPS injection (i.e., at the end of the preceding 90min stabilization period) and ending 90min after the LPS injection. Values are the mean ± SEM. *p < 0.01 relative to content of noradrenaline (pg/30 μl) at 0min are noted.

Effects of α1- and β-Adrenoceptor Antagonists on LPS-Induced Downregulation and Upregulation

To investigate whether LPS-induced facilitation of noradrenaline release is involved in either the downregulation of the membrane GluR1 subunit in the mPFC and VTA or the upregulation of the membrane GluR2 subunit in the NAc at 24h post-LPS, we administered prazosin (3.0mg/kg), an α1-adrenoceptor antagonist, or propranolol (2.0mg/kg), a β-adrenergic antagonist, 30min before the LPS injection. Neither prazosin nor propranolol affected the total protein levels of GluR1 and GluR2 in either the mPFC or the VTA (Figure 4A, D, and E for mPFC; Figure 4K, N, and O for VTA). However, one-way ANOVA of the protein level of GluR1 at the plasma membrane in the mPFC and the VTA showed a significant interaction (Figure 4A and B for mPFC, F (3,16) = 19.944, p < 0.0001; Figure 4K and L for VTA, F (3,16) = 22.234, p < 0.0001). The protein level of GluR1 at the plasma membrane at 24h post-LPS in the mPFC and the VTA was abrogated by intracerebroventricular infusion of prazosin, but not propranolol (Bonferroni tests; in the mPFC, p < 0.0001 for LPS vs. control, p = 0.1401 for prazosin + LPS vs. control, and p < 0.0001 for LPS vs. prazosin + LPS; in the VTA, p < 0.0001 for LPS vs. control, p = 0.0689 for prazosin + LPS vs. control, and p < 0.0001 for LPS vs. prazosin + LPS). Propranolol did not affect LPS-induced downregulation of the membrane GluR1 in either the mPFC or VTA at 24h post-LPS (Bonferroni tests; in the mPFC, p < 0.0001 for LPS vs. control, p = 0.0017 for propranolol + LPS vs. control, and p < 0.1630 for LPS vs. propranolol + LPS; in the VTA, p < 0.0001 for LPS vs. control, p = 0.0007 for propranolol + LPS vs. control, and p < 0.4475 for LPS vs. propranolol + LPS). In addition, although the total GluR2 protein level in the NAc was also not affected by either prazosin or propranolol (Figure 4F and J), one-way ANOVA of the GluR2 protein level at the plasma membrane after LPS, prazosin, or propranolol showed a significant interaction (Figure 4F and H; F (3,16) = 7.638, p = 0.0022). Bonferroni tests revealed that prazosin blocked the LPS-induced upregulation of the membrane GluR2 in the NAc at 24h post-LPS (p = 0.0031 for LPS vs. control, p = 0.8600 for prazosin + LPS vs. control, and p = 0.0021 for prazosin + LPS vs. LPS). However, propranolol did not affect the LPS-induced upregulation of the membrane GluR2 in the NAc. These results indicate that both downregulation of the membrane GluR1 in the mPFC and VTA and LPS-induced upregulation of membrane GluR2 in the NAc are mediated by α1-adrenoceptor activation.

Figure 4.

Figure 4.

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Effects of pretreatment with prazosin (Prazo) or propranolol (Proprano) on LPS-induced alterations of the GluR1 and GluR2 subunits protein levels at the plasma membrane fraction and total extracts of the mouse mPFC (A-E), NAc (F-J), and VTA (K-O) at 4 and 24h post-LPS injection. Prazosin and propranolol were injected intracerebroventricularly at 30min before LPS injection (1.2mg/kg, twice at 30min interval). The graph indicates the percentage of control (saline) levels. Representative graph for the protein level of membrane GluR1 (B; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (C; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the mPFC; of the total protein levels of GluR1 (D; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (E; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the mPFC; of the protein levels of membrane GluR1 (G; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (H; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the NAc; of the total protein levels of GluR1 (I; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (J; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the NAc; of the protein levels of membrane GluR1 (L; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (M; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the VTA; and of the total protein level of GluR1 (N; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) and GluR2 (O; control, n=5; LPS, n=5; prazosin + LPS, n=5; propranolol + LPS, n=5) in the VTA. All data are presented as mean ± SEM. Statistically significant effects of LPS injection (*p < 0.01) are noted.

Effects of Intracerebroventricular Infusion of α1- or β-Adrenoceptor Antagonists on LPS-Induced Depressive-Like Behavior

We next investigated whether the LPS-induced depressive-like behavior was dependent on α1-adrenoceptor stimulation. To avoid any direct effect of prazosin-induced or propranolol-induced changes in blood pressure or heart rate on depressive-like behavior, we infused 5 μl intracerebroventricularly with 70mM prazosin or 400mM propranolol at 30min before LPS injection. Pretreatment with prazosin did not attenuate the LPS-induced reduction in locomotor activity at 4h or the changes in body weight at 24h after LPS (Figure 5A and B). However, a one-way ANOVA of the effect of antagonist pretreatment on the LPS-induced increase in immobility time during the TST and FST showed significant interactions (Figure 5C and D; for TST, F (3,20) = 7.078, p = 0.0020; for FST, F (3,20) = 8.281, p = 0.0009). Bonferroni tests revealed that the LPS-induced increase in immobility time during the TST was attenuated by pretreatment with prazosin, but not propranolol, as measured at 24h post-LPS (p = 0.5797 for prazosin + LPS vs. control and p = 0.0010 for prazosin + LPS vs. LPS; p = 0.0191 for propranolol + LPS vs. control and p = 0.4775 for propranolol + LPS vs. LPS). LPS-induced increase in immobility time during the FST was also attenuated by pretreatment with prazosin, but not propranolol (p = 0.1514 for prazosin + LPS vs. control and p = 0.0259 for prazosin + LPS vs. LPS; p = 0.0004 for propranolol + LPS vs. control and p = 0.6954 for propranolol + LPS vs. LPS). Moreover, one-way ANOVA showed a significant effect of these antagonists on the LPS-induced decrease in sucrose preference during both the first 24h post-LPS and 24–48h post-LPS periods (Figure 5E and F; for 0–24h, F (3,20) = 19.199, p < 0.0001; for 24–48h, F (3,20) = 3.965, p = 0.0228). Bonferroni tests revealed that pretreatment with prazosin significantly increased sucrose preference at 24h post-LPS (p = 0.0738 for prazosin + LPS vs. control; p = 0.0015 for prazosin + 24h post LPS vs. LPS:) and at 48h (p = 0.5706 for prazosin + LPS vs. control; p = 0.0328 for prazosin + LPS vs. LPS) post LPS. However, propranolol did not affect the LPS-induced decease in sucrose preference at 24h (p < 0.0001 for propranolol + LPS vs. control; p = 0.2987 for propranolol + LPS vs. LPS) and at 48h (p = 0.0220 for propranolol + LPS vs. control; p = 0.7028 for propranolol + LPS vs. LPS). These results suggest that LPS-induced depressive-like behavior is associated with α1-adrenoceptor activation.

Figure 5.

Figure 5.

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Prazosin or propranolol were injected intracerebroventricularly 30min before the LPS injections (1.2mg/kg, twice at a 30min interval). (A) The locomotor activity was measured at either 4 or 24h following the relevant injection. The mobility time in the open field was recorded every 6min, and results are presented as mouse locomotor activity (control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6). (B) Changing body weight at 24h post LPS was measured. The body weight of each mouse was measured at 5min before and 24h after LPS or saline injection (control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6). (C) The duration of immobility during the tail suspension test at 24h post LPS was recorded for each 6min test (control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6). (D) The duration of immobility during the forced swim test at 24h post LPS or saline was recorded for each 6min test (control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6). Sucrose preference was measured at the first 24h post LPS (E; control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6) and at 24–48h post LPS or saline (F; control, n=6; LPS, n=6; prazosin + LPS, n=6; propranolol + LPS, n=6), and the percentage of sucrose intake against total intake was presented. All data are presented as the mean ± SEM. Statistically significant effects of LPS injection (*p < 0.01) are noted.

Discussion

In the present study, we found that LPS facilitates noradrenaline release, which stimulates the α1-adrenoceptor and induces GluR1 internalization in the mPFC and VTA. To our knowledge, this is the first demonstration that downregulation of the AMPA receptor GluR1 subunit at the plasma membrane in the reward system is associated with induction of depressive-like behaviors. Chronic unpredictable stress in animals can elicit symptoms similar to those in depressed human patients, such as anhedonia and decreased social interaction (Willner et al., 1987; Berton and Nestler, 2006). It has been demonstrated that chronic social stress decreases the amount of mRNA for GluA1 AMPAR subunits in the CA1 region (Schmidt et al., 2010) and also decreases the number and function of AMPA receptors in specific synapses. In addition, stress-induced impairment of excitatory synapses has been described in the mPFC (Yuen et al., 2012) and NAc (Lim et al., 2012). From these reports, it has been suggested that decreased synaptic input in neuron is an underlying cause of depression (Kallarackal et al., 2013). By contrast, AMPA receptor potentiation has an antidepressant effect in mice with chronic mild stress (Farley et al., 2010). Therefore, from the results of our study, we suggest that LPS-induced downregulation of GluR1 protein levels at the plasma membrane results in a decrease in the strengthening of excitatory synapses, which might contribute to the pathogenesis of depression.

Peripheral administration of LPS produces cognitive impairment with decreased hippocampal expression of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase-B (Wu et al., 2007), which sustains the GluR1 subunit distribution within the synapses (Jourdi and Kabbaj, 2013). Internalization of the AMPA receptor GluR1 subunit is a central mechanism of long-term synaptic depression (Brown et al., 2005). Consistently, reduced BDNF content in platelets and decreased BDNF mRNA expression in peripheral blood lymphocytes and mononuclear cells have also been reported in patients with depression (Lee and Kim, 2009; Pandey et al., 2010). Conversely, intracerebroventricular BDNF infusion induced sustained antidepressant-like effects (Hoshaw et al., 2005). In addition, enhanced long-term synaptic depression (LTD) in an animal model of depression has been reported (Holderbach et al., 2007). A recent study suggested that a receptor coupled to the Gq/11 protein promotes LTD, but suppresses LTP; conversely, a Gs-coupled receptor promotes LTP, but suppresses LTD (Huang et al., 2012). The α1-adrenoceptor is coupled to a Gq/11 protein, whereas all subtypes of β-adrenoceptors are coupled to Gs proteins. In the present study, prazosin, an α1-adrenoceptor antagonist, blocked the downregulation of the membrane GluR1 subunit in the mPFC and VTA, whereas propranolol, a non-selective β-adrenoceptor antagonist, did not affect this downregulation of the membrane GluR1 subunit. Therefore, we suggest that α1-adrenoceptor stimulation following LPS-induced facilitation of noradrenaline release induces downregulation of membrane GluR1 in the mPFC and VTA. Furthermore, these neuroplastic properties of the reward system are part of the mechanism of LPS-induced depressive-like behaviors.

Acute stress inhibits LTP at synapses from the hippocampus to the PFC in the rat (Dupin et al., 2006). Antidepressants can reverse the impairment in LTP induced by LPS treatment (Rocher et al., 2004). Moreover, nicotine exposure-induced depressive-like behavior is accompanied by dephosphorylation of serine residues at position 845 (Ser845) of the GluR1 in the hippocampus (Parameshwaran et al., 2012). These results imply that the LTD is involved in depressive-like behavior.

In the present study, upregulation of membrane GluR2 in the NAc was also accompanied by LPS-induced depressive-like behavior, and prazosin blocked membrane GluR2 upregulation in the NAc. However, adrenergic neurons in the LC have fewer innervations to the NAc. Because LPS did not facilitate noradrenaline release in the NAc in the present study, there is the possibility that LPS-induced upregulation of membrane GluR2 in the NAc is independent of α1-adrenoceptor stimulation. It has been reported that activation of the dopamine D2 receptor induces internalization of GluR2 (Zou et al., 2005). From our results, it seems possible that LPS-induced downregulation of the membrane GluR1 subunit in the VTA neurons might also reduce excitatory input to the dopaminergic neurons in the VTA, resulting in a reduction of dopamine release in the NAc. It has been reported that activation of the dopamine D2 receptor induces internalization of GluR2 (Zou et al., 2005), and from the present study, it appears the internalization of the GluR2 subunit is relatively decreased because of the reduction in dopamine release, resulting in reduction of D2 receptor stimulation in the NAc. However, the mechanisms and roles of GluR2 upregulation in the NAc in depressive symptoms remain unclear from our present work. Therefore, elucidating these observations in future studies might support our understanding of the mechanisms behind inflammation-induced depressive-like behavior.

The role of α-adrenoceptor activation in depression is controversial. One study suggested that prazosin does not affect the efficacy of antidepressants (Souza et al., 2013). Moreover, postsynaptic α2-adrenoceptor stimulations amplify the effect of antidepressants, but antagonism of presynaptic α2-adrenoceptor facilitates noradrenaline release, which potentiates the effects of antidepressants (Zhang et al., 2009). By contrast, some studies have suggested that chronic treatment with antidepressants leads to desensitization of α1-adrenoceptors in the brain, indicating that insensitivity of α1-adrenoceptors is involved in improvement of major depression (Subhash et al., 2003; Ramakrishna and Subhash, 2010). Recently, 6-fluoronorepinephrine, a fully selective α-adrenoceptor agonist, has been shown to produce antidepressant effects by acting primarily as an α2-adrenoceptor agonist; this antidepressant effect of 6-fluoronorepinephrine is mediated though inhibition of LC neuronal activity and the enhancement of NAc activity (Stone et al., 2011). Although the mechanism behind the development of major depression is not entirely the same as the antagonism of their antidepressant effects, our results serve as an important reference for developing a novel treatment for preventing the progression of depressive disorders.

Supplementary Material

For supplementary material accompanying this paper, visit http://www.ijnp.oxfordjournals.org/

Statement of Interest

None.

Acknowledgments

This work was supported partly by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (Grant Number 25430070) and Grants for Research in the School of Pharmaceutical Science, Ohu University to K. Seki.

References

  1. Bay-Richter C, Janelidze S, Hallberg L, Brundin L. (2011). Changes in behaviour and cytokine expression upon a peripheral immune challenge. Behav Brain Res 222:193–199. [DOI] [PubMed] [Google Scholar]
  2. Berton O, Nestler EJ. (2006). New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151. [DOI] [PubMed] [Google Scholar]
  3. Brown TC, Tran IC, Backos DS, Esteban JA. (2005). NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45:81–94. [DOI] [PubMed] [Google Scholar]
  4. Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH. (2009). Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord 119:181–185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chaudhury D, et al. (2013). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532–536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chourbaji S, Urani A, Inta I, Sanchis-Segura C, Brandwein C, Zink M, Schwaninger M, Gass P. (2006). IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol Dis 23:587–594. [DOI] [PubMed] [Google Scholar]
  7. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. (2010). A meta-analysis of cytokines in major depression. Biol Psychiat 67:446–457. [DOI] [PubMed] [Google Scholar]
  8. Dupin N, Mailliet F, Rocher C, Kessal K, Spedding M, Jay TM. (2006). Common efficacy of psychotropic drugs in restoring stress-induced impairment of prefrontal plasticity. Neurotox Res 10:193–198. [DOI] [PubMed] [Google Scholar]
  9. Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET. (2010). Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychop 13:1207–1218. [DOI] [PubMed] [Google Scholar]
  10. Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller AH. (2012). Molecular signatures of peripheral blood mononuclear cells during chronic interferon-alpha treatment: relationship with depression and fatigue. Psychol Med 42:1591–1603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frenois F, Moreau M, O’Connor J, Lawson M, Micon C, Lestage J, Kelley KW, Dantzer R, Castanon N. (2007). Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Holderbach R, Clark K, Moreau JL, Bischofberger J, Normann C. (2007). Enhanced long-term synaptic depression in an animal model of depression. Biol Psychiat 62:92–100. [DOI] [PubMed] [Google Scholar]
  13. Hoshaw BA, Malberg JE, Lucki I. (2005). Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 1037:204–208. [DOI] [PubMed] [Google Scholar]
  14. Huang S, Trevino M, He K, Ardiles A, Pasquale R, Guo Y, Palacios A, Huganir R, Kirkwood A. (2012). Pull-push neuromodulation of LTP and LTD enables bidirectional experience-induced synaptic scaling in visual cortex. Neuron 73:497–510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ikemoto S, Panksepp J. (1999). The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Rev 31:6–41. [DOI] [PubMed] [Google Scholar]
  16. Jourdi H, Kabbaj M. (2013). Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression. Plos One 8:e57124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, Thompson SM. (2013). Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci 33:15669–15674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kavanagh T, Lonergan PE, Lynch MA. (2004). Eicosapentaenoic acid and gamma-linolenic acid increase hippocampal concentrations of IL-4 and IL-10 and abrogate lipopolysaccharide-induced inhibition of long-term potentiation. Prostag Leukot Ess 70:391–397. [DOI] [PubMed] [Google Scholar]
  19. Kelly A, Vereker E, Nolan Y, Brady M, Barry C, Loscher CE, Mills KH, Lynch MA. (2003). Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1 beta on long term potentiation in rat dentate gyrus. J Biol Chem 278:19453–19462. [DOI] [PubMed] [Google Scholar]
  20. Kim YK, Na KS, Shin KH, Jung HY, Choi SH, Kim JB. (2007). Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiat 31:1044–1053. [DOI] [PubMed] [Google Scholar]
  21. Koo JW, Duman RS. (2008). IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751–756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lavicky J, Dunn AJ. (1995). Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis. J Neurosci Res 40:407–413. [DOI] [PubMed] [Google Scholar]
  23. Lee BH, Kim YK. (2009). Reduced platelet BDNF level in patients with major depression. Prog Neuropsychopharmacol Biol Psychiat 33:849–853. [DOI] [PubMed] [Google Scholar]
  24. Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. (2012). Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183–189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Linthorst AC, Flachskamm C, Holsboer F, Reul JM. (1996). Activation of serotonergic and noradrenergic neurotransmission in the rat hippocampus after peripheral administration of bacterial endotoxin: involvement of the cyclo-oxygenase pathway. Neuroscience 72:989–997. [DOI] [PubMed] [Google Scholar]
  26. Maes M. (1999). Major depression and activation of the inflammatory response system. Adv Exp Med Biol 461:25–46. [DOI] [PubMed] [Google Scholar]
  27. Maes M, Bosmans E, Suy E, Vandervorst C, DeJonckheere C, Raus J. (1991). Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand 84:379–386. [DOI] [PubMed] [Google Scholar]
  28. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. (1997). Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9:853–858. [DOI] [PubMed] [Google Scholar]
  29. Majer M, Welberg LA, Capuron L, Pagnoni G, Raison CL, Miller AH. (2008). IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun 22:870–880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Min SS, Quan HY, Ma J, Han JS, Jeon BH, Seol GH. (2009). Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area. Neurosci Lett 456:20–24. [DOI] [PubMed] [Google Scholar]
  31. Mitrano DA, Schroeder JP, Smith Y, Cortright JJ, Bubula N, Vezina P, Weinshenker D. (2012). alpha-1 Adrenergic receptors are localized on presynaptic elements in the nucleus accumbens and regulate mesolimbic dopamine transmission. Neuropsychopharmacol 37:2161–2172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Morilak DA, Frazer A. (2004). Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychop 7:193–218. [DOI] [PubMed] [Google Scholar]
  33. Nestler EJ, Carlezon WA., Jr. (2006). The mesolimbic dopamine reward circuit in depression. Biol Psychiat 59:1151–1159. [DOI] [PubMed] [Google Scholar]
  34. O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatr 14:511–522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ohtake N, Saito M, Eto M, Seki K. (2014). Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex. Regul Pept 190–191:1–11. [DOI] [PubMed] [Google Scholar]
  36. Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Zhang H, Pavuluri MN. (2010). Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog Neuropsychopharmacol Biol Psychiat 34:645–651. [DOI] [PubMed] [Google Scholar]
  37. Parameshwaran K, Buabeid MA, Karuppagounder SS, Uthayathas S, Thiruchelvam K, Shonesy B, Dityatev A, Escobar MC, Dhanasekaran M, Suppiramaniam V. (2012). Developmental nicotine exposure induced alterations in behavior and glutamate receptor function in hippocampus. Cell Mol Life Sci 69:829–841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Paxinos GFK. (2004). The mouse brain in stereotaxic coordinates. Amsterdam, Netherlands: Elsevier Academic Press. [Google Scholar]
  39. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K, Miller AH. (2010). CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatr 15:393–403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ramakrishna D, Subhash MN. (2010). Differential modulation of alpha-1 adrenoceptor subtypes by antidepressants in the rat brain. J Neural Transm 117:1423–1430. [DOI] [PubMed] [Google Scholar]
  41. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmacher T. (2001). Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatr 58:445–452. [DOI] [PubMed] [Google Scholar]
  42. Ressler KJ, Nemeroff CB. (2000). Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(S1):2–19. [DOI] [PubMed] [Google Scholar]
  43. Rocher C, Spedding M, Munoz C, Jay TM. (2004). Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 14:224–229. [DOI] [PubMed] [Google Scholar]
  44. Roitman MF, Wheeler RA, Wightman RM, Carelli RM. (2008). Real-time chemical responses in the nucleus accumbens differentiate rewarding and aversive stimuli. Nat Neurosci 11:1376–1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schmidt MV, Trumbach D, Weber P, Wagner K, Scharf SH, Liebl C, Datson N, Namendorf C, Gerlach T, Kuhne C, Uhr M, Deussing JM, Wurst W, Binder EB, Holsboer F, Muller MB. (2010). Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J Neurosci 30:16949–16958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schultz W, Dayan P, Montague PR. (1997). A neural substrate of prediction and reward. Science 275:1593–1599. [DOI] [PubMed] [Google Scholar]
  47. Simen BB, Duman CH, Simen AA, Duman RS. (2006). TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiat 59:775–785. [DOI] [PubMed] [Google Scholar]
  48. Simon NM, McNamara K, Chow CW, Maser RS, Papakostas GI, Pollack MH, Nierenberg AA, Fava M, Wong KK. (2008). A detailed examination of cytokine abnormalities in major depressive disorder. Eur Neuropsychopharmacol 18:230–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Smith RS. (1991). The macrophage theory of depression. Med Hypotheses 35:298–306. [DOI] [PubMed] [Google Scholar]
  50. Souza LC, de Gomes MG, Goes AT, Del Fabbro L, Filho CB, Boeira SP, Jesse CR. (2013). Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice. Prog Neuropsychopharmacol Biol Psychiat 40:103–109. [DOI] [PubMed] [Google Scholar]
  51. Stone EA, Lin Y, Sarfraz Y, Quartermain D. (2011). Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full alpha-adrenoceptor agonist. Int J Neuropsychop 14:319–331. [DOI] [PubMed] [Google Scholar]
  52. Subhash MN, Nagaraja MR, Sharada S, Vinod KY. (2003). Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain. Neurochem Int 43:603–609. [DOI] [PubMed] [Google Scholar]
  53. Tremblay LK, Naranjo CA, Graham SJ, Herrmann N, Mayberg HS, Hevenor S, Busto UE. (2005). Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatr 62:1228–1236. [DOI] [PubMed] [Google Scholar]
  54. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K. (2013). Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537–541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R. (2013). NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacol 38:1609–1616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. (1987). Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358–364. [DOI] [PubMed] [Google Scholar]
  57. Wise RA. (2004). Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494. [DOI] [PubMed] [Google Scholar]
  58. Wu CW, Chen YC, Yu L, Chen HI, Jen CJ, Huang AM, Tsai HJ, Chang YT, Kuo YM. (2007). Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory. J Neurochem 103:2471–2481. [DOI] [PubMed] [Google Scholar]
  59. Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. (2012). Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 73:962–977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Zhang HT, Whisler LR, Huang Y, Xiang Y, O’Donnell JM. (2009). Postsynaptic alpha-2 adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior. Neuropsychopharmacol 34:1067–1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, McCorkle R, Seligman DA, Schmidt K. (2001). The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 15:199–226. [DOI] [PubMed] [Google Scholar]
  62. Zou S, Li L, Pei L, Vukusic B, Van Tol HH, Lee FJ, Wan Q, Liu F. (2005). Protein-protein coupling/uncoupling enables dopamine D2 receptor regulation of AMPA receptor-mediated excitotoxicity. J Neurosci 25:4385–4395. [DOI] [PMC free article] [PubMed] [Google Scholar]

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