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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2017 Jan 26;174(4):314–327. doi: 10.1111/bph.13692

Anti‐anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma‐1 receptors in picrotoxin‐treated mice

S Hasebe 1,†, Y Ago 2,†, Y Watabe 2, S Oka 2, N Hiramatsu 3, T Tanaka 2, C Umehara 2, H Hashimoto 2,4,5, K Takuma 1,4, T Matsuda 3,✉
PMCID: PMC5289945  PMID: 27987210

Abstract

Background and Purpose

Prefrontal dopamine release by the combined activation of 5‐HT1A and sigma‐1 (σ1) receptors is enhanced by the GABAA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.

Experimental Approach

Male mice were treated with picrotoxin to decrease GABAA receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c‐Fos was determined immunohistochemically.

Key Results

Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter‐induced increase in c‐Fos expression in the nucleus accumbens. Picrotoxin‐induced anhedonia was ameliorated by fluvoxamine and S‐(+)‐fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ1 receptor. The effect of fluvoxamine was blocked by a 5‐HT1A or a σ1 receptor antagonist, and co‐administration of the σ1 receptor agonist (+)‐SKF‐10047 and the 5‐HT1A receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ1 receptor, did not affect picrotoxin‐induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D2/3 receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin‐induced anhedonia.

Conclusion and Implications

Picrotoxin‐treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5‐HT1A and σ1 receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti‐anhedonic effect observed in picrotoxin‐treated mice.

Abbreviations

SSRI

selective serotonin reuptake inhibitor

Tables of Links

TARGETS
Ligand‐gated ion channels a Other protein targets c
GABAA receptors Sigma non‐opioid intracellular receptor 1
GPCRs b Transporters d
5‐HT1A receptor DAT
Dopamine D1 receptor NET
Dopamine D2 receptor SERT
LIGANDS
BD1047 Methylphenidate
Bicuculline Paroxetine
Desipramine Picrotoxin
Duloxetine Raclopride
Fluoxetine SCH39166, ecopipam
Fluvoxamine WAY100635
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,b,c,dAlexander et al., 2015a,b,c,d).

Introduction

Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Among the SSRIs, fluvoxamine and fluoxetine, but not paroxetine, also act as agonists of the sigma intracellular (σ1) receptor (Hashimoto et al., 2007; Hayashi and Su, 2008). The σ1 receptor plays a key role in psychiatric disorders: the σ1 receptor antagonists can attenuate the acquisition, expression and reactivation of cocaine‐induced conditioned place preference, an animal model of reward (Romieu et al., 2002; Martin‐Fardon et al., 2007), and the σ1 receptor agonists produce antidepressant‐like effects (Ukai et al., 1998; Lucas et al., 2008). Furthermore, a clinical study using positron emission tomography suggests that the σ1 receptor is involved in the clinical effects of fluvoxamine (Ishikawa et al., 2007). It is likely, then, that fluvoxamine has a pharmacological profile different from that of other antidepressants, which lack affinity for the σ1 receptor, but this is currently unknown.

We have previously observed that fluvoxamine increases extracellular levels of 5‐HT and dopamine in the prefrontal cortex of normal rodents (Ago et al., 2005a) and that fluvoxamine‐induced prefrontal dopamine release is enhanced by adrenalectomy+castration through a σ1 receptor‐mediated mechanism (Ago et al., 2011). Our subsequent studies have shown that the effect of fluvoxamine on prefrontal dopamine release is mediated by an interaction between the presynaptic 5‐HT1A autoreceptor and the σ1 receptor in the prefrontal cortex (Hiramatsu et al., 2013; Hasebe et al., 2015b) and that the GABAA receptor is involved in the adrenalectomy+castration‐induced enhancement of the fluvoxamine‐induced increase in prefrontal dopamine levels (Ago et al., 2016). These findings provide a novel regulation mechanism for prefrontal dopamine release that is associated with the interactions among the σ1, 5‐HT1A and GABAA receptors. However, it is unknown whether these neurochemical events are accompanied by behavioural changes.

The GABAA receptors are targets of clinically useful drugs, including anxiolytics, sedatives, anaesthetics, anti‐amnesics, muscle relaxants and anticonvulsants (Reynolds, 2008; Brickley and Mody, 2012). The GABAA receptor antagonist picrotoxin causes an anxiogenic effect on the social interaction (File and Lister, 1984), elevated plus‐maze (Dalvi and Rodgers, 1996) and light/dark transition (Shimada et al., 1995) tests in mice, but a depression‐like effect has not been reported. We have developed the female encounter test, a novel method to assess anhedonia, a marker of motivation (Ago et al., 2015). Then, the present study aimed to clarify whether SSRIs with an affinity for the σ1 receptor have anti‐anhedonic effects in picrotoxin‐treated mice. The present study demonstrates that picrotoxin treatment causes anhedonia and that this abnormal behaviour is ameliorated by SSRIs with an affinity for the σ1 receptor or by methylphenidate, an activator of the prefrontal dopamine system (Koda et al., 2010).

Methods

Animals and experimental schedule

All animal care and experimental protocols for this study were approved by the Animal Care and Use Committee of the Graduate School of Pharmaceutical Sciences, Osaka University. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al., 2010; McGrath and Lilley, 2015). Every effort was made to minimize animal suffering and to reduce the number of animals used. Five‐week‐old male and female CD‐1 mice were obtained from SHIMIZU Laboratory Supplies Co., Ltd. (Kyoto, Japan) and housed in cages (28 × 17 × 12 cm) in groups of five or six animals under controlled environmental conditions (22 ± 1°C; 12 h light–dark cycle, lights on at 0800 h; food and water ad libitum) for at least 1 week before being used in the experiments. Each mouse was used only once. The experimental schedule is shown in Figure 1.

Figure 1.

Figure 1

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Schedules for drug administration and behavioural and immunohistochemical analyses.

c‐Fos immunohistochemistry

Brain expression of the neuronal activity marker c‐Fos was determined 2 h after a 10 min encounter with a female intruder, as described previously (Ago et al., 2015). Mice that were not exposed to an intruder were used as controls. Each male mouse was deeply anesthetized with pentobarbital and then perfused transcardially with saline, followed by a solution of 4% paraformaldehyde in PBS. Serial 20‐μm‐thick coronal sections of brain were cut using a cryostat microtome at −20°C. The brain sections were heated in a microwave oven in 0.01 M sodium citrate buffer (pH 6.0) for 10 min and then washed in PBS containing 0.03% Triton X‐100 (PBST). The sections were preincubated for 5 min in 0.3% hydrogen peroxide in PBST and then blocked in 5% goat serum in PBST for 60 min at room temperature. Thereafter, the sections were incubated with an anti‐c‐Fos rabbit polyclonal primary antibody (1:3000; sc‐253, Santa Cruz Biotechnology, Santa Cruz, CA, USA) overnight at 4°C. Subsequently, the sections were washed in PBST and incubated with a secondary antibody solution containing biotinylated anti‐rabbit IgG for 60 min at room temperature. Biotinylated secondary antibodies were detected using an immunoperoxidase technique with an avidin‐biotin‐peroxidase complex (Vector Laboratories, Burlingame, CA, USA). Brown cytosolic products were obtained by reacting the sections with 3,3′‐diaminobenzidine. Four independent sections per animal containing the nucleus accumbens shell were selected. The c‐Fos‐positive nuclei were counted manually by experienced observers blinded to treatment conditions under bright‐field illumination using an Axio Imager M2 microscope (Carl Zeiss, Jena, Germany). The number of c‐Fos‐positive nuclei in each section was determined in a 500 × 500 μm area in the left and right hemispheres and averaged using the ImageJ 1.41 software package (NIH, Bethesda, MD, USA). The mean value of the averages from four sections was then calculated for each subject.

Forced swim test

The forced swim test was performed as previously described (Kawasaki et al., 2011; Ago et al., 2013b). A male mouse was placed in a cylinder made from acrylic material (height, 25 cm; diameter, 19 cm) containing 13 cm of water (25 ± 1°C) for 6 min. After a test session, the mouse was removed from the cylinder, dried with a towel and returned to its home cage. The behaviour of each mouse was video recorded for analysis. The duration of immobility during the last 4 min of the test period and the full 6 min period was measured manually by an observer blinded to the treatment conditions.

Reciprocal social interaction test

The reciprocal social interaction test was performed as described previously (Kataoka et al., 2013; Hara et al., 2016). Male mice were placed individually as a resident in an observation cage (38 × 22 × 20 cm) under bright‐light conditions (350 lx) for 60 min. A novel male CD‐1 mouse of the same age that had been housed in a different cage was then introduced into the resident mouse cage. The interaction between the two mice was recorded for 20 min using a digital camera. Sniffing behaviours (face and anogenital sniffs) of the resident (test) mouse were assessed manually by an experienced observer blinded to the drug treatment.

Light/dark test

The apparatus consists of a cage (20 × 40 × 30 cm) divided into two sections of equal size by a partition with door (8 × 5 cm). One chamber is brightly illuminated (380 lx), whereas the other chamber is completely dark. A male mouse was placed in the centre of the dark chamber with its head facing the door and was allowed to explore freely both chambers for 10 min. The behaviour was recorded using a digital camera, and the time spent in the light chamber and the number of transitions between chambers were measured manually by an experienced observer blinded to the drug treatment. Chamber entry was defined as all four paws entering a chamber.

Elevated plus‐maze test

The elevated plus‐maze test was performed as described previously (Ago et al., 2014; Ota et al., 2015). The apparatus – consisting of two open arms (25 × 8 cm) and two enclosed arms (25 × 8 cm, surrounded by a 20‐cm‐high opaque wall) – was elevated 50 cm from the ground (BrainScience·Idea Co., Ltd., Osaka, Japan). A male mouse was placed on the central platform with its head facing an open arm and was allowed to explore freely for 5 min under dim light conditions (15 lx). The performance of the mouse over a 5 min period was videotaped using a digital camera and then subsequently scored manually by an experienced observer blinded to the drug treatment. Arm entry was defined as all four paws entering an arm. The time spent in various sections of the maze (open arms, closed arms, central platform) and the numbers of open and closed arm entries were measured. The following parameters were calculated: (i) ratio of time spent in the open arms (time spent in the open arms/time spent in the open and closed arms); (ii) ratio of open arm entries (open arm entries/total entries); and (iii) total arm entries (entries into open and closed arms).

Female encounter test

To assess reward‐seeking behaviour in mice, we developed a new test for sexual motivation using a three‐chambered apparatus, which we termed the female encounter test (Figure 4A) (Ago et al., 2015). This test is based on our recent finding that social encounter through a mesh partition is a form of psychological stress and provides information on the communication between two animals (Ago et al., 2013a). A sexually naïve 9‐week‐old male CD‐1 mouse was placed in the central chamber of an opaque acrylic‐modified polyvinyl chloride box (42 × 50 × 30 cm) divided into three interconnected chambers under illumination of 400 lx (measured in the centre zone). The clear partitions have openings that allow the animal to move freely from one chamber to another. After a 90 min habituation period, unfamiliar sexually naïve age‐ and strain‐matched male and female mice were introduced into the intruder boxes (10 × 6.5 × 20 cm). The resident (test) and intruder mice were allowed to interact through the wire‐mesh walls for 10 min, and then the intruder mice were removed. To eliminate all odours from the previous trial, the intruder boxes were washed with 0.1% chlorhexidine gluconate solution, and the apparatus was wiped with 70% ethanol solution before the start of each experiment. The behaviours of the test mouse were videotaped, and its occupancy in the box and locomotor path were automatically analysed off‐line using the ANY‐maze video‐tracking software (Stoelting Co., Wood Dale, IL, USA). The amount of time spent in each of the three chambers was measured to evaluate the behavioural reactivity of mice to an intruder. Preference for a female encounter was then calculated as a percentage score for each intruder: Preference (%) = (time spent in female zone/total time spent in male and female zones) × 100.

Measurement of spontaneous locomotor activity

Locomotor activity was measured using a digital counter system with an infrared sensor (Supermex®, Muromachi Kikai Co., Ltd., Japan) as described previously (Koda et al., 2010; Ota et al., 2015). Male mice were placed individually in a novel clear polycarbonate cage (28 × 17 × 12 cm), and then locomotor activity was recorded for 20 min.

Data and statistical analysis

The data and statistical analyses comply with the recommendations on experimental design and analysis in pharmacology (Curtis et al., 2015). Each animal was randomly assigned to an experimental group. The researchers treating the animals were not aware of the pharmacological treatments of each group by numbering during the scoring and thereafter accessed to the administration sheet during the data analysis. The minimum number of animals per experiment was based on previous data (Ago et al., 2013b, 2015) and a corresponding power analysis. An a priori power analysis was performed using G*Power 3.1.9.2 for Windows (Faul et al., 2007). The α error probability was set at 0.05, and Power (1–β error probability) was set at 0.8. Effect size is large. The exact group size for the individual experiments is shown in the corresponding figure legends. A group size of 10 or 12 animals was used for behavioural tests. The variability is due to the requirement of the additional experiments. For c‐Fos immunohistochemistry, the group size was eight animals. There were no omitted animals for the analysis. All data are expressed as mean ± SEM. Data were analysed with one‐ or two‐way ANOVA and, when significant, with post hoc Dunnett's test (Figures 2B left, 3, 4 and 6) or Bonferroni/Dunn test (Figures 2B right, 5 and 7–9). Significance is set at P < 0.05. Statistical analyses were performed using the software package Statview 5.0 J for Apple Macintosh (SAS Institute Inc., Cary, NC, USA).

Figure 2.

Figure 2

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Effects of picrotoxin on behaviour in the forced swim (A) and social interaction (B) tests. (A) Mice were i.p. injected with picrotoxin or vehicle and tested for 6 min. The duration of immobility during the last 4 min and the full 6 min period is shown. The data are expressed as the mean ± SEM of 12 mice per group. (B) The duration of sniffing was measured during a 20 min test period. The data are expressed as the mean ± SEM of 12 (dose–response effect of picrotoxin, left) and 10 (effect of fluvoxamine, right) mice per group. * P < 0.05, significantly different from the vehicle or saline‐treated group; † P < 0.05, significantly different from the picrotoxin or saline‐treated group.

Figure 3.

Figure 3

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Effects of picrotoxin on behaviour in the light/dark (A) and elevated plus‐maze (B) tests. (A) The time spent in the light chamber and the total number of transitions between chambers were measured during a 10 min test period. The data are expressed as the mean ± SEM of 12 mice per group. (B) The time spent in the open arms, open arm entries and total arm entries were measured during a 5 min test period. The data are expressed as the mean ± SEM of 12 mice per group. * P < 0.05, compared with the vehicle‐treated group.

Figure 4.

Figure 4

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Effects of GABAA receptor antagonists on preference for a female encounter. (A) Schematic diagram of the three‐chambered test apparatus, and representative occupancy and locomotor path profiles of the resident mice during a 10 min encounter, analysed by the ANY‐maze video tracking system. (B) A 9‐week‐old male naïve mouse (resident) was placed in the central chamber of the apparatus. After a 90 min habituation period, picrotoxin, (+)‐bicuculline or vehicle was injected i.p. Unfamiliar age‐ and strain‐matched male and female mice were placed in their respective intruder boxes for a 10 min period. Time spent in each zone and preference for a female encounter by the resident test mouse are shown. (C) The total distance travelled by the mice during a 10 min encounter was analysed as locomotor activity. The data are expressed as the mean ± SEM of 10 mice per group. * P < 0.05, significantly different from the vehicle‐treated group.

Figure 6.

Figure 6

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Effects of antidepressants on the picrotoxin‐induced decrease in female preference. A 9‐week‐old male naïve mouse (resident) was placed in the central chamber of the apparatus. After a 90 min habituation period, picrotoxin (1 mg·kg−1) was injected i.p. Fluvoxamine (A), S‐(+)‐fluoxetine (B), paroxetine (C), duloxetine (D), desipramine (E) or saline was injected i.p., 20 min after picrotoxin treatment. Eighty minutes later, unfamiliar male and female mice were placed in their respective intruder boxes for a 10 min period. Time spent in each zone and preference for a female encounter by the resident test mouse are shown. The data are expressed as the mean ± SEM of 10 (fluvoxamine) and 12 (other antidepressants) mice per group. * P < 0.05, significantly different from the saline‐treated group.

Figure 5.

Figure 5

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Effects of picrotoxin on the female encounter‐induced increase in c‐Fos expression in the nucleus accumbens shell of mice. Picrotoxin or vehicle was injected i.p., 100 min before the encounter. (Left panel) Representative photomicrographs showing c‐Fos‐immunoreactive cells in the brains of resident male test mice after an encounter with a female intruder. Mice that were not exposed to an intruder were used as controls (Control). Scale bar, 100 μm. (Right panel) The number of c‐Fos‐positive cells was counted. The data are expressed as the mean ± SEM of eight mice pergroup. * P < 0.05, significantly different from the vehicle‐treated control group; † P < 0.05, significantly different from the picrotoxin‐treated female‐encountered group.

Materials

Fluvoxamine maleate (Abbott Japan Co., Ltd., Tokyo, Japan), BD1047 dihydrobromide, SCH39166 hydrobromide, (+)‐SKF‐10047 hydrochloride, raclopride (Tocris Cookson, Bristol, UK), osemozotan, WAY100635 (Mitsubishi Tanabe Pharma Corp., Yokohama, Japan), (+)‐bicuculline, desipramine hydrochloride, S‐(+)‐fluoxetine hydrochloride, methylphenidate hydrochloride, paroxetine maleate, picrotoxin (Sigma, St Louis, MO, USA) and duloxetine hydrochloride (AvaChem Scientific LLC, San Antonio, TX, USA) were used. Osemozotan was suspended in 0.5% w/v carboxymethylcellulose. Picrotoxin, raclopride and SCH39166 were dissolved in sterile distilled water containing DMSO at a final concentration of 0.01%. (+)‐Bicuculline (0.03, 0.1 mg·kg−1) was dissolved in saline (0.9% NaCl solution) containing 0.01% DMSO and 0.37% hydrochloric acid. All other drugs were dissolved in saline. All drugs were administered in a volume of 10 mL·kg−1 body weight. Picrotoxin was used at doses of 1 mg·kg−1 or less, a subconvulsive dose, to inhibit GABAA receptors (Girish et al., 2013; Ago et al., 2016). The doses of the other drugs were those used in previous studies (Koda et al., 2010; Ago et al., 2011, 2013a,b, 2015; Hiramatsu et al., 2013; Hasebe et al., 2015a,b). In the present study, picrotoxin at 1 mg·kg−1 decreased locomotor activity 30–60 min after the injection, but did not affect the locomotor activity on the behavioural assay (100 min after the injection). Anhedonic behaviour was not observed 3 h after the injection of picrotoxin. Drugs under the conditions used here did not affect behaviour in the female preference test in normal mice.

Results

Behaviours of picrotoxin‐treated mice

Picrotoxin (0.3 and 1 mg·kg−1) did not affect the immobility time during either the last 4 min of the test period (F (2,33) = 1.7, P > 0.05) or the full 6 min period (F (2,33) = 1.5, P > 0.05) in the forced swim test, although it at the higher dose showed a tendency to increase the immobility time (Figure 2A). In contrast, these mice showed anxiety‐like behaviour in the social interaction test (F (2,33) = 17.1, P < 0.05) (Figure 2B left). Picrotoxin at 0.3 mg·kg−1 and 1 mg·kg−1 caused a significant (P < 0.05) reduction in sniff duration. The anxiety‐like behaviour was ameliorated by fluvoxamine (Figure 2B right). Two‐way ANOVA revealed a significant interaction effect between the picrotoxin and fluvoxamine treatments (F (1,36) = 4.9, P < 0.05). Post hoc tests revealed that picrotoxin (1 mg·kg−1) caused a reduction in sniff duration and this was significantly ameliorated by fluvoxamine (30 mg·kg−1). Picrotoxin‐induced anxiety‐like behaviours were also observed in the light/dark test (Figure 3A) and elevated plus‐maze test (Figure 3B). For the light/dark test, picrotoxin dose‐dependently decreased the time spent in the light chamber (F (2,33) = 3.8, P < 0.05), whereas it did not affect the number of transitions between chambers (F (2,33) = 1.0, P > 0.05). Post hoc tests revealed that picrotoxin at 1 mg·kg−1, but not 0.3 mg·kg−1, significantly decreased the time spent in the light chamber. For the elevated plus‐maze test, picrotoxin dose‐dependently decreased the per cent time spent in the open arms (F (2,33) = 6.5, P < 0.05) and number of entries into the open arms (F (2,33) = 6.4, P < 0.05), whereas it did not affect the number of total arm entries (F (2,33) = 0.5, P > 0.05). Post hoc tests revealed that picrotoxin at 1 mg·kg−1, but not 0.3 mg·kg−1, decreased the per cent time spent in the open arms and number of entries into the open arms. Figure 4A shows a representative occupancy profile and the locomotor path of the test male mouse during the 10 min female encounter test. Sexually naïve male control (vehicle‐treated) mice spent more time in the female zone than in the male or centre zone, indicating a preference for a female encounter. This preference for a female encounter was not observed in picrotoxin‐treated mice (F (2, 27) = 4.9, P < 0.05; Figure 4B). Post hoc tests revealed that picrotoxin at 1 mg·kg−1, but not 0.3 mg·kg−1, decreased the preference for female encounter. (+)‐Bicuculline, another GABAA receptor antagonist, also decreased female preference in the female encounter test (F (2, 27) = 3.4) (Figure 4B). Post hoc tests revealed that (+)‐bicuculline at 0.1 mg·kg−1, but not 0.03 mg·kg−1, decreased the preference for female encounter. Neither drug affected the locomotor activity of the mice (Figure 4C). In addition, picrotoxin treatment inhibited the female encounter‐induced increase in c‐Fos expression in the nucleus accumbens shell, a marker of the reward system (Figure 5). Two‐way ANOVA revealed a significant interaction effect between the female encounter and picrotoxin treatment (F (1, 28) = 4.7). Post hoc tests revealed that the female encounter caused an increase in c‐Fos expression and that this increase was significantly attenuated by picrotoxin (1 mg·kg−1).

Effects of various antidepressants on picrotoxin‐induced decrease in female preference

Picrotoxin‐induced decrease in female preference was ameliorated by fluvoxamine (F (2, 27) = 4.5) and S‐(+)‐fluoxetine (F (2, 33) = 4.3), but not by paroxetine (F (2, 33) = 0.02), duloxetine (F (2, 33) = 0.50) or desipramine (F (2, 33) = 0.15), anti‐depressants which have little affinity for σ1 receptors (Figure 6). Post hoc tests revealed that picrotoxin (1 mg·kg−1)‐induced reduction in female preference was significantly ameliorated by fluvoxamine (30 mg·kg−1) and S‐(+)‐fluoxetine (3 mg·kg−1). Fluvoxamine (30 mg·kg−1), S‐(+)‐fluoxetine (3 mg·kg−1), paroxetine (30 mg·kg−1), duloxetine (30 mg·kg−1) and desipramine (10 mg·kg−1) did not affect the spontaneous locomotor activity (Table 1).

Table 1.

Effects of various drugs used here on spontaneous locomotor activity of mice

Treatment Locomotor activity (counts)
Saline 4951 ± 219
Fluvoxamine (30 mg·kg−1) 4857 ± 318
S‐(+)‐Fluoxetine (3 mg·kg−1) 4795 ± 267
Paroxetine (30 mg·kg−1) 5085 ± 412
Duloxetine (30 mg·kg−1) 5094 ± 283
Desipramine (10 mg·kg−1) 5461 ± 130
Saline 4786 ± 337
WAY100635 (1 mg·kg−1) 3927 ± 406
BD1047 (3 mg·kg−1) 4678 ± 357
Vehicle 4449 ± 256
(+)‐SKF‐10047 (5 mg·kg−1) 4221 ± 372
Osemozotan (1 mg·kg−1) 4563 ± 253
Vehicle 4483 ± 321
SCH39166 (0.2 mg·kg−1) 4193 ± 461
Raclopride (0.1 mg·kg−1) 4964 ± 387
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Drugs were injected 80 min (antidepressants, (+)‐SKF‐10047, osemozotan) or 100 min (WAY100635, BD1047, SCH39166, raclopride) before the experiments, and the locomotor activity was recorded for 20 min. Antidepressants (F (5,42) = 0.7), WAY100635 and BD1047 (F (2,21) = 1.6), (+)‐SKF‐10047 and osemozotan (F (2,21) = 0.34), raclopride and SCH39166 (F (2, 21) = 0.98, all P > 0.05) did not affect the spontaneous locomotor activity. The data are expressed as the mean ± SEM of eight mice per group.

Role of the interaction between σ1 and 5‐HT1A receptors

The amelioration of the picrotoxin‐induced decrease in female preference by fluvoxamine (30 mg·kg−1) was blocked by the 5‐HT1A receptor antagonist WAY100635 (1 mg·kg−1) or the σ1 receptor antagonist BD1047 (3 mg·kg−1) in the female encounter test (Figure 7). One‐way ANOVA revealed a significant main effect of the treatment (F (3, 36) = 5.6, P < 0.05). WAY100635 and BD1047 alone did not affect the spontaneous locomotor activity (Table 1). Furthermore, the picrotoxin‐induced decrease in the female preference was ameliorated by co‐administration of the σ1 receptor agonist (+)‐SKF‐10047 (5 mg·kg−1) + the 5‐HT1A receptor agonist osemozotan (1 mg·kg−1; F (3, 36) = 4.9, P < 0.05; Figure 8A) or + (+)‐SKF‐10047 paroxetine (10 mg·kg−1; F (3, 36) = 4.8, P < 0.05; Figure 8B). Post hoc tests revealed that osemozotan (1 mg·kg−1), paroxetine (10 mg·kg−) and (+)‐SKF‐10047 (5 mg·kg−1) alone did not affect the picrotoxin‐induced decrease in the female preference, but the combination of (+)‐SKF‐10047 with osemozotan or with paroxetine did modify the effects of picrotoxin. (+)‐SKF‐10047 and osemozotan alone did not affect the spontaneous locomotor activity (Table 1).

Figure 7.

Figure 7

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Effects of either a 5‐HT1A or σ1 receptor antagonist on fluvoxamine‐induced amelioration of the picrotoxin‐induced decrease in female preference. A 9‐week‐old male naïve mouse (resident) was placed in the central chamber of the apparatus. After a 90 min habituation period, picrotoxin was injected i.p. WAY100635, BD1047 or vehicle was injected i.p., immediately after picrotoxin treatment. Fluvoxamine or saline was injected i.p., 20 min after picrotoxin treatment. Eighty minutes later, unfamiliar male and female mice were placed in their respective intruder boxes for a 10 min period. Time spent in each zone and preference for a female encounter by the resident test mouse are shown. The data are expressed as the mean ± SEM of 10 mice per group. * P < 0.05, significantly different from the picrotoxin alone‐treated group; † P < 0.05, significantly different from the picrotoxin+fluvoxamine‐treated group.

Figure 8.

Figure 8

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Combined activation of σ1 and 5‐HT1A receptors ameliorates the picrotoxin‐induced decrease in female preference. A 9‐week‐old male naïve mouse (resident) was placed in the central chamber of the apparatus. After a 90 min habituation period, picrotoxin was injected i.p. (+)‐SKF‐10047 and osemozotan (A) or paroxetine (B) was simultaneously injected 20 min after picrotoxin treatment. Eighty minutes later, unfamiliar male and female mice were placed in their respective intruder boxes for a 10 min period. Time spent in each zone and preference for a female encounter by the resident test mouse are shown. The data are expressed as the mean ± SEM of 10 mice per group. * P < 0.05, significantly different from the picrotoxin alone‐treated group.

Role of the dopaminergic system in the effect of fluvoxamine

Finally, we investigated the involvement of dopaminergic system in the amelioration of the picrotoxin‐induced decrease in female preference (Figure 9). The amelioration of the picrotoxin‐induced decrease in female preference by fluvoxamine (30 mg·kg−1) was antagonized by the dopamine D2/3 receptor antagonist raclopride (0.1 mg·kg−1), but not by the dopamine D1/5 receptor antagonist SCH39166 (0.2 mg·kg−1; Figure 9A). One‐way ANOVA revealed a significant main effect of the treatment (F (3, 36) = 6.0, P < 0.05). Methylphenidate at 3 mg·kg−1 also ameliorated the picrotoxin‐induced decrease in female preference and this effect was blocked by raclopride, but not by SCH39166 (Figure 9B). One‐way ANOVA revealed a significant main effect of the treatment (F (3, 36) = 4.3, P < 0.05). Raclopride and SCH39166 alone did not affect the spontaneous locomotor activity (Table 1).

Figure 9.

Figure 9

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Involvement of the dopaminergic system in ameliorating the picrotoxin‐induced decrease in female preference. A 9‐week‐old male naïve mouse (resident) was placed in the central chamber of the apparatus. After a 90 min habituation period, picrotoxin was injected i.p. SCH39166, raclopride or vehicle was injected i.p., immediately after picrotoxin treatment. Fluvoxamine (A), methylphenidate (B) or saline was injected i.p., 20 min after picrotoxin treatment. Eighty minutes later, unfamiliar male and female mice were placed in their respective intruder boxes for a 10 min period. Time spent in each zone and preference for a female encounter by the resident test mouse are shown. The data are expressed as the mean ± SEM of 10 mice per group. * P < 0.05, significantly different from the picrotoxin alone‐treated group; † P < 0.05, significantly different from the picrotoxin+fluvoxamine‐ or the picrotoxin+methylphenidate‐treated group.

Discussion

Our previous neurochemical studies examining the effects of fluvoxamine have shown that the increase in prefrontal dopamine release by the functional interaction between 5‐HT1A and σ1 receptors is enhanced by adrenalectomy + castration (Ago et al., 2011; Hiramatsu et al., 2013). Adrenalectomy + castration decreases circulating neurosteroids, which affect brain GABAA receptors (Belelli and Lambert, 2005; Luscher et al., 2011; Carver and Reddy, 2013). Our subsequent study showed that the GABAA receptor antagonist picrotoxin mimicked the effect of adrenalectomy + castration on the fluvoxamine‐induced increase in prefrontal dopamine levels, and conversely, that the benzodiazepine receptor agonist diazepam attenuated the effect of adrenalectomy/castration (Ago et al., 2016). These findings suggest that the functional interaction between brain 5‐HT1A and σ1 receptors plays a critical role in the regulation of prefrontal dopamine release under the conditions of decreased GABAA receptor function. The present study was performed to clarify the functional significance of enhanced prefrontal dopaminergic activity in picrotoxin‐treated mice, a model of decreased GABAA receptor function.

GABAergic deficits cause behavioural and endocrine abnormalities that are associated with psychiatric disorders, such as anxiety and depression (Earnheart et al., 2007; Reynolds, 2008; Shen et al., 2010; Luscher et al., 2011). Mice with a heterozygous mutation in the γ2 subunit of the GABAA receptor exhibit anxiety‐related behaviours (Crestani et al., 1999) and increased immobility time in the forced swim test, but not in the tail suspension test (Shen et al., 2010). Furthermore, the GABAA receptor antagonist picrotoxin has an anxiogenic effect on the social interaction (File and Lister, 1984), elevated plus‐maze (Dalvi and Rodgers, 1996) and light/dark transition (Shimada et al., 1995) tests in mice. However, it was not known whether picrotoxin caused a depressive‐like state in rodents. The current study showed that picrotoxin treatment did not affect immobility time in the forced swim test in mice, although it caused anxiety‐like behaviour in the social interaction test. We recently developed the novel female encounter test to assess anhedonia, a marker of motivation (Ago et al., 2015). Using this test, the present study showed that picrotoxin and bicuculline impaired the preference for a female encounter. Therefore, it is likely that the decreased GABAA receptor function induces anhedonia, a depressive‐like state.

In the present study, we found that picrotoxin caused a deficit in sexual reward‐seeking behaviour. Picrotoxin treatment did not affect the immobility time, but it showed a tendency to increase the immobility time in the forced swim test. This implies that this model has a potential to induce a prototypical pro‐depressive phenotype. The present study shows that picrotoxin attenuates encounter‐induced increase in c‐Fos expression in the nucleus accumbens. This result is in agreement with the behavioural observation that picrotoxin reduces the preference for a female encounter. Picrotoxin‐treated mice also showed anxiety‐like behaviour in the social interaction, light/dark and elevated plus‐maze tests. These findings suggest that the picrotoxin‐treated mouse is a novel anxiety/anhedonia model that is sensitive to the female encounter test, but not to the forced swim test as it is generally conducted. Furthermore, picrotoxin‐treated mice appear to be a unique model, since the impaired preference in the female encounter test is not improved by desipramine, duloxetine or paroxetine. Therefore, the picrotoxin model and the female encounter test may contribute to studies on the pathophysiology and treatment of anxiety and anhedonia‐related psychiatric disorders.

The present study showed that the picrotoxin‐induced anhedonia was ameliorated by fluvoxamine and S‐(+)‐fluoxetine, both of which have an affinity for the σ1 receptor, but not by other antidepressants. The anti‐anhedonic effect of fluvoxamine was blocked by an antagonist of the 5‐HT1A or of σ1 receptors, and simultaneous activation of 5‐HT1A and σ1 receptors ameliorated the impaired preference in the female encounter test. Furthermore, we found that paroxetine, an SSRI with little affinity for the σ1 receptor, had no effect on the impaired preference, but co‐administration of paroxetine and the σ1 receptor agonist (+)‐SKF‐10047 alleviated the behavioural impairment. These observations suggest that the interaction between brain 5‐HT1A and σ1 receptors is involved in the amelioration of the depressive‐like state observed in picrotoxin‐treated mice. The effectiveness of SSRIs with an affinity for the σ1 receptor has also been shown in a number of clinical studies (Carrasco and Sandner, 2005; Kishimoto et al., 2010). Taken together with the recent finding that fluvoxamine increases prefrontal dopamine release in picrotoxin‐treated mice and that the effect is mediated by co‐activation of the 5‐HT1A and σ1 receptors (Ago et al., 2016), it is likely that the increased prefrontal dopamine release results in an anti‐anhedonic effect. Concerning the mechanism, we observed that the anti‐anhedonic effect of fluvoxamine was blocked by a dopamine D2/3 receptor antagonist. Additionally, methylphenidate mimicked the effect of fluvoxamine. We previously found that acute methylphenidate at 3 mg·kg−1 increased prefrontal dopamine and noradrenaline, but not 5‐HT, release without any effect on the spontaneous locomotor activity in mice (Koda et al., 2010). Furthermore, we showed that methylphenidate selectively activates the prefrontal cortex: it increased the expression of c‐Fos in the prefrontal cortex, but not in the striatum, (Koda et al., 2010). These results suggest that the increased dopamine release induces an anti‐anhedonic effect via activation of dopamine D2/3 receptors.

The primary reward circuit includes dopaminergic projections from the ventral tegmental area to the nucleus accumbens, which release dopamine in response to reward‐related stimuli (Russo and Nestler, 2013). In drug addiction, the prefrontal cortex also plays a key role in reward‐related behaviour, although the exact mechanism is not known (Goldstein and Volkow, 2011). In the female encounter test, we showed that sexual motivation was accompanied by an increase in c‐Fos expression in the nucleus accumbens, in a dopaminergic mechanism, suggesting a role for the mesolimbic dopaminergic system (Ago et al., 2015). On the other hand, we found that simultaneous activation of the 5‐HT1A and σ1 receptors increased c‐Fos expression in the prefrontal cortex and ventral tegmental area, but not in the nucleus accumbens, in adrenalectomized+castrated mice (Hiramatsu et al., 2013) and picrotoxin‐treated mice (Ago et al., 2016). This does not appear to support the role of the mesolimbic dopamine system in the effect of fluvoxamine on picrotoxin‐treated mice. There is a glutamatergic projection from the prefrontal cortex to the nucleus accumbens, which is activated by dopamine (Russo and Nestler, 2013), and there is increasing evidence supporting the role of glutamate in mediating the rewarding effects of drugs of abuse (Kalivas and Volkow, 2011). It is thus likely that the prefrontal dopamine release plays a key role in the anti‐anhedonic effect of fluvoxamine, but it is not known how the increased dopamine release is linked to the behavioural effect.

The dopaminergic system may be a target for treatment of psychiatric disorders, including depression, because it plays a key role in many physiological and pathological processes. Potentiation of the dopamine system induced by antidepressant drugs may contribute to their therapeutic effect (Tanda et al., 1994, 1996; D'Aquila et al., 2000). We have also shown that a combination of sulpiride and fluvoxamine increases dopamine release in the prefrontal cortex and decreases immobility time in the tail suspension test (Ago et al., 2005a,b). These observations suggest that the enhanced activity of prefrontal dopaminergic neurons may result in an antidepressant‐like effect. Compatible with this finding, earlier studies have shown that a drug inhibiting the uptake of 5‐HT, noradrenaline and dopamine could produce a more rapid onset of action and possess greater efficacy than traditional antidepressants (Chen and Skolnick, 2007). Furthermore, recent studies have suggested that brain dopamine systems are involved in the pathophysiology of several psychiatric disorders, including schizophrenia and depression (Grace, 2016). Our previous study demonstrated that simultaneous activation of the 5‐HT1A and σ1 receptors increased prefrontal dopamine release (Ago et al., 2016). Furthermore, the present study shows that SSRIs with an affinity for the σ1 receptor have an anti‐anhedonic effect, when GABAA receptors are blocked. It should be noted that the enhancement of the dopamine system is not observed in normal conditions. It is likely that the enhancement of prefrontal dopamine system is beneficial for treatment of impaired GABAA receptor function‐related disorders.

In conclusion, the present findings showed that picrotoxin impaired the preference for a female encounter. This impairment was ameliorated by SSRIs that have an affinity for the σ1 receptor, but not by antidepressants that have little affinity for the σ1 receptor. Thus, picrotoxin‐treated mice can be used to characterize the pharmacological profiles of antidepressants with an affinity for the σ1 receptor. Although the exact mechanisms through which picrotoxin causes anhedonia are not known, the picrotoxin‐treated mouse appears to be a useful model for studying the role of the prefrontal dopaminergic system in the effects of SSRIs with an affinity for the σ1 receptor.

Author contributions

S.H., Y.W., S.O., N.H., T.T. and C.U. performed the research. S.H., Y.A., H.H., K.T. and T.M. designed the research study. S.H., Y.A., Y.W., S.O. and N.H. analysed the data. S.H., Y.A. and T.M. wrote the paper.

Conflict of interest

The authors declare no conflicts of interest.

Declaration of transparency and scientific rigour

This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research recommended by funding agencies, publishers and other organisations engaged with supporting research.

Acknowledgements

This study was supported in part by JSPS KAKENHI (25460099 [Y.A.], 16K08268 [Y.A.], 16K19183 [S.H.], 16K15126 [K.T.], 26293020 [H.H.], 26670122 [H.H.] and 15H01288 [H.H.]), the Neuropsychiatry Drug Discovery Consortium established by Dainippon Sumitomo Pharma Co., Ltd. (Japan) with Osaka University (T.M. and H.H.), Takeda Science Foundation (Japan) (Y.A.), Research Foundation for Pharmaceutical Sciences (Japan) (Y.A.), and the Programme for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (grant no. S2603; H.H.).

Hasebe, S. , Ago, Y. , Watabe, Y. , Oka, S. , Hiramatsu, N. , Tanaka, T. , Umehara, C. , Hashimoto, H. , Takuma, K. , and Matsuda, T. (2017) Anti‐anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma‐1 receptors in picrotoxin‐treated mice. British Journal of Pharmacology, 174: 314–327. doi: 10.1111/bph.13692.

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