Antidepressant-like effect of ethanol in mice forced swimming test is mediated via inhibition of NMDA/nitric oxide/cGMP signaling pathway

Muhammad Imran Khan a, b, *, Vahid Nikoui c, Aamir Naveed d, Faiza Mumtaz e,Hamid Zaman b, Adnan Haider f, Waqar Aman g, Abdul Wahab b, Shahid Niaz Khan h, Najeeb Ullah i, Ahmad Reza Dehpour e, j, **

Abstract

NMDA There is evidence for a dramatic relationship between depression and alcohol consumption. Depressed patients may abuse ethanol because this agent reduces the symptoms of depression. In the current study, we aimed to investigate the NMDA/nitric oxide/cGMP pathway in the antidepressant-like effect of ethanol in an animal model of behavioral despair. Animals were subjected to locomotor activity in an open-field test separately, followed by a forced swimming test. During the forced swimming test (FST), ethanol (2 and 2.5 g/kg) significantly decreased the immobility time without altering the locomotor activity of animals. The antidepressant-like effect of ethanol (2.5 g/kg) was reversed by co-administration of N-methyl-D-aspartate (NMDA, 75 mg/kg), L-arginine (750 mg/kg), or sildenafil (5 mg/kg). In contrast, co-administration of MK-801 (0.05 mg/kg), ketamine (1 mg/kg), and ifenprodil (0.5 mg/kg) as antagonists of NMDAR, and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), 7-nitroindazole (7-NI, 30 mg/kg), and methylene blue (10 mg/kg) as inhibitors of nitric oxide synthase (NOS), or 1H-[1,2,4]oxadiazole[4,3a]quinoxalin-1-one (ODQ) (20 mg/kg), a nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) inhibitor, with a subeffective dose of ethanol (1.5 g/kg), significantly decreased the immobility time in the FST. Furthermore, injection of ethanol 2.5 g/kg alone or 1.5 g/kg with a 7-NI subeffective dose, significantly decreased the nitrite levels in the hippocampus and prefrontal cortex. Hence, it is concluded that blockade of NMDA receptors and the nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) pathway might be involved in the antidepressant-like effect of ethanol in mice.

Keywords: depression ethanol forced swimming test (FST) mice nitric oxide cyclic-guanosine monophosphate (NO-cGMP)

Introduction

Ethanol is a two-carbon-containing molecule that does not bind to a specific brain receptor and has neuropsychiatric effects mediated via modulation of various neurotransmitters. Numerous experimental studies have shown that ethanol has an antidepressant-like effect in various animal models of depression (Ciccocioppo et al., 1999; Fernandez-Pardal & Hilakivi, 1989; Jain, Kannamwar, & Verma, 2017; Kampov-Polevoy, Dubtchenko, Crosby, & Halikas, 1993). Some of these experimental reports suggest that an antidepressant-like effect of ethanol might be one of the possible reasons for high ethanol consumption in Sardinian alcohol-preferring rats (Ciccocioppo et al., 1999). In contrast, some studies have shown the relationship between prolonged alcohol consumption and the rat’s susceptibility to “behavioral despair” (Godfrey, Froehlich, Stewart, & Murphy, 1997). It is also declared that animals given more alcohol have shown more immobility in the FST (Ciccocioppo et al., 1999). However, acute injection of ethanol has been reported to increase the immobility time both in mice (Hirani, Khisti, & Chopde, 2002) and alcohol-preferring rats during the FST (Ciccocioppo et al., 1999), thus indicating the antidepressant-like properties of ethanol and possibly be the reason for its high levels of continuation and consumption(Ciccocioppo et al., 1999).
Various neuromodulators, including serotonin (5-HT), gammaaminobutyric acid (GABA), noradrenaline (NA), opiates, acetylcholine, histamine, and dopamine (Besheer, Lepoutre, & Hodge, 2009; Hirani et al., 2002; Imperato & Di Chiara, 1989; Jain et al., 2017; Verma & Jain, 2016; Walden, Nicholls, Smith, & Tucker, 2007; Yim & Gonzales, 2000) have been reported to mediate the antidepressantlike effect of ethanol. Ethanol strongly blocks NMDA receptors (Faingold, N’Gouemo, & Riaz, 1998; Kumari & Ticku, 2000; Weight, 1992; Woodward, 1999). Similarly, the interaction of ethanol with NMDA receptors can mediate numerous ethanol-related behavioral effects (Hoffman et al., 1990; Wirkner et al., 1999), including withdrawal, dependence, tolerance, craving, and relapse (Krystal, Petrakis, Mason, Trevisan, & D’Souza, 2003; Moykkynen€ & Korpi, 2012).
Glutamate acts as a candidate neurotransmitter, playing a crucial role in various physiological processes of the brain. Changes in the glutamatergic pathway can result in several types of neurological disorders, including depression (Sanacora, Zarate, Krystal, & Manji, 2008). It has been reported that NMDA receptor inhibitors such as ketamine are highly effective in the treatment of depressive disorders (Berman et al., 2000). Similarly, various antidepressant drugs possess the potential to inhibit the NMDA receptors (Ostadhadi et al., 2017a,b; Sanacora et al., 2008; Skolnick, 1999). It is obvious that activation of NMDA receptors triggers the activity of the nitric oxide synthase (NOS) enzyme, thereby augmenting the formation of nitric oxide (NO) (Esplugues, 2002). Nitric oxide is an essential molecule required to activate soluble guanylate cyclase (sGC), subsequently increasing the levels of cyclic guanosine monophosphate (cGMP). It has been reported in various pathophysiological processes such as drug dependence, tolerance, and pruritis, apart from depression (Khan et al., 2017, 2018; Shafizadeh et al., 2014). It is wellestablished that NO production can potentiate depression, and decreased levels of NO can diminish the symptoms of depression (Harkin, Connor, Burns, & Kelly, 2004; Kaster, Rosa, Santos, &Rodrigues, 2005; Mantovani, Pertile, Calixto, Santos, & Rodrigues, 2003; Mohseni et al., 2017; Ostadhadi, Ahangari, et al., 2016; Ostadhadi, Khan, Norouzi-Javidan, & Dehpour, 2016; Sakhaee et al., 2017; Zomkowski, Engel, Gabilan, &Rodrigues, 2010).
The NMDA in the central nervous system is extensively studied in various effects of ethanol; however, to date, no study has reported its involvement in the antidepressant-like effect of acute ethanol treatment. Hence, the current study is aimed at investigating the interaction of NMDA with its receptor and its effect on downstream signaling of NO-cGMP, in the antidepressant-like effect of ethanol in animal models of behavior despair. Additionally, the effect of ethanol on central nitrite levels was also the focus of the current study.

Materials and methods

Animals

In the present study, male adult Balb/C mice weighing 25e30 g were used. All animals were kept in a group and had ad libitum access to food and water except for the periods of experimentation. Standard temperature (22 ± 2 C) and light (12-h light/dark cycles) were maintained throughout the study. Six to eight animals were used in each investigational group, and all the protocols were approved by the Life Sciences Ethical Committee of TUMS and Research Ethics Committee (REC) of RIPS, Riphah InternationalUniversity.

Open-field test (OFT)

The open-field test is a well-identified standard protocol usually employed to assess the locomotor activities of animals (Farhan & Haleem, 2016; Nikoui et al., 2016; Yang & Wang, 2018). Briefly, the apparatus consists of a Plexiglas® box (40 cm 60 cm 50 cm), the floor of which is divided into 12 equal squares with the same dimensions. The mouse was placed in the left corner of the box and then the number of squares crossed with the whole body was recorded for a period of 6 min (Haj-Mirzaian, Ostadhadi, Kordjazy, Dehpour, & Mehr, 2014; Kordjazy et al., 2015). The activity for the last 4 min was analyzed in the current study.

Forced swimming test (FST)

The forced swimming test is a well-recognized paradigm for screening the antidepressant-like effect of drugs (Miao, Yan, Guo, & Li, 2017; Ostadhadi et al., 2017a,b; Porsolt, Bertin, & Jalfre, 1977). The apparatus consists of a cylinder 25 cm high and 10 cm in diameter. Before the test, the cylinder was filled with fresh water having a temperature of 25 ± 1 C (Haj-Mirzaian et al., 2016; Nazari et al., 2016; Ostadhadi, Haj-Mirzaian, Nikoui, Kordjazy, & Dehpour, 2015), and then the animals were gently immersed in it. The immobility time of each animal was recorded through an autovision camera. Later, the last 4- minute period was analyzed.

Measurement of nitrite levels

Nitric oxide is a short-lived molecule that rapidly metabolizes into nitrite. In order to evaluate the possible effect of ethanol on nitric oxide synthesis, an indirect measurement of NO production was done by quantifying the level of nitrite. Animals were injected with either saline or ethanol (1.5 and 2.5 g/kg, intraperitoneally; i.p.). After 50 min, animals were sacrificed by decapitation. The hippocampi and prefrontal cortices were quickly isolated on an icecold surface and then were dipped into liquid nitrogen. Tissue homogenates were prepared, and the proteins were extracted from the samples by adding NaOH and ZnSO4, as described previously (Granger, Traintor, Boockvar, & Hibbs, 1996). The total nitrite level was determined via the established Griess reaction protocol. A standard curve was achieved by sodium nitrate (0e80 mМ).

Drugs and reagents

The following drugs and reagents were used: ethanol, fluoxetine, a non-specific NOS inhibitor (NG-l-arginine methyl ester, LNAME), nNOS specific inhibitor (7-nitroinidazole [7-NI]), iNOS specific inhibitor (aminoguanidine), NO precursor (L-arginine), NMDA receptor agonist (N-methyl-D-aspartate [NMDA]), NMDA receptor antagonists (MK-801, ketamine, and ifenprodil), an inhibitor of sGC (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one [ODQ]), an inhibitor of both NOS and sGC (methylene blue), and phosphodiesterase 5 inhibitor (sildenafil). All drugs were purchased from Sigma, St. Louis, Missouri, United States. The ethanol in 20% w/v concentration was diluted with 0.9% saline (Hirani et al., 2002; Jain et al., 2017). Drugs were prepared in saline (0.9%), except for ODQ, which was dissolved in saline with 1% DMSO and 7NI, which was prepared using 1% Tween 80 solution. All the drugs were injected by an intraperitoneal route using an equal volume of 10 mL/kg body weight. Drugs along with their doses are shown in Table 1.

Drug treatment

To investigate the antidepressant-like properties of ethanol, several doses of ethanol (1,1.5, 2, and 2.5 g/kg, i.p.) were injected via the intraperitoneal route, 50 min prior to the various behavioral investigations. This time period was selected based on a previously published reports and our pilot study for performing subsequent tests (Hirani et al., 2002; Jain et al., 2017). Fluoxetine (20 mg/kg) as a reference and positive control was administered 30 min before the test (Ostadhadi, Ahangari, et al., 2016).
To examine the possible involvement of an NMDA receptor in the antidepressant-like effect of ethanol, a subeffective dose of ethanol (1.5 g/kg injected 50 min prior to the FST) was co-injected with NMDA receptor antagonists, including ketamine (1 mg/kg), MK-801 (0.05 mg/kg), or ifenprodil (0.5 mg/kg), 60 min, 45 min, and 45 min before the FST, respectively. These agents at the aforementioned doses did not show any remarkable antidepressant-like response. The main goal of these combinations was to examine the combined additive effect of these agents.
For more evidence about the role of NMDA receptor in the antidepressant-like effect of ethanol, we co-injected a subeffective dose of NMDA (75 mg/kg), 30 min prior to FST in animals treated with an effective dose of ethanol (2.5 g/kg, i.p.). The subeffective dose of NMDA was chosen based on a previously published report (Haj-Mirzaian et al., 2015).
In order to show evidence for the involvement of nitric oxide, we investigated the effects of L-NAME (anon-selective NOS inhibitor,10 mg/kg, 45 min prior to the FST), aminoguanidine (a selective inducible nitric oxide synthase [iNOS] inhibitor, 50 mg/kg, 45 min prior to the FST), and 7-NI (a selective neuronal nitric oxide synthase [nNOS] inhibitor, 30 mg/kg, 30 min prior to FST) in animals treated with a subeffective dose of ethanol (1.5 g/kg, i.p.). Also, these selected doses were based on the previously published data (Ghasemi et al., 2008; Ostadhadi, Kordjazy, et al., 2016). To null out the effect of the vehicle, a group of control animals was also treated with saline or Tween 80 1% (5 mL/kg) 30 min and 45 min prior to the tests, respectively.
To confirm the role of NO in the antidepressant-like effect of ethanol, a subeffective dose (750 mg/kg, i.p.) of L-arginine was administered 30 min before the FST in animals treated with an effective dose of ethanol (2.5 g/kg, i.p.) (Kaster, Rosa, et al., 2005; Khan et al., 2015; Ostadhadi, Kordjazy, et al., 2016).
The participation of the secondary messenger cGMP in the antidepressant-like effect of ethanol was examined by injection of sildenafil (PDE5 inhibitor). Sildenafil (5 mg/kg) (Ghasemi et al., 2008; Ostadhadi, Kordjazy, et al., 2016) was injected 30 min prior to the FST in mice treated with an effective dose of ethanol (2.5 g/ kg, i.p.).
In another set of experiments, we studied the effect of coadministration of a subeffective dose of ethanol (1.5 g/kg) with a subeffective dose of ODQ (20 mg/kg, i.p., a sGC inhibitor) (Ghasemi et al., 2008) or methylene blue (10 mg/kg, i.p., an inhibitor of both NOS and sGC) (Ostadhadi, Khan, Norouzi-Javidan, & Dehpour, 2016). Ethanol or vehicle/saline were injected 20 min before ODQ or methylene blue. An additional 30 min (after i.p. administration of methylene blue or ODQ) elapsed before beginning the FST.

Statistical analysis

Statistical analysis was carried out using Graph Pad Prism 5 software (San Diego, California, United States). The results are presented as mean ± S.E.M. One-way analysis of variance (ANOVA) followed by Dunnett’s post hoc test was carried out to investigate the dose-related effects of ethanol between groups. Two-way ANOVA followed by the Bonferroni post hoc test was used to analyze the other results. p values less than 0.05 were considered statistically significant.

Results

Antidepressant-like effect of ethanol in the FST

An acute injection of ethanol (2 and 2.5 g/kg) significantly reduced the immobility time of mice as compared to the saline group in the FST [F(5,42) ¼ 8.346, p < 0.05, p < 0.001, respectively]. However, injection of lower doses (1 and 1.5 g/kg) did not alter the immobility time (p > 0.05). Therefore, the lower dose of ethanol (1.5 g/kg, i.p.) was chosen as the subeffective dose of ethanol, while 2.5 g/kg (i.p.) was selected as the effective dose. Fluoxetine (20 mg/kg) as a positive control also diminished the immobility time of mice, compared to the saline group(p < 0.001, Fig. 1A). All administered drugs did not significantly change the locomotor activity of mice in the OFT [F(5,42) ¼ 0.142, p > 0.05, Fig. 1B].

Role of NMDA receptor in the antidepressant-like effect of ethanol

To clarify the involvement of NMDA receptors in the antidepressant-like effect of ethanol, several antagonists and agonists were injected. As illustrated in Fig. 2, co-injection of asubeffective dose of ethanol (1.5 g/kg) with MK-801 (0.05 mg/kg) significantly reduced the time of immobility in the FST [F(1,28) ¼ 4.424, p < 0.05, Fig. 2A]. Similar significant antidepressant-like effects were observed in the FST with other antagonists of NMDA, such as ketamine (1 mg/kg) [F(1,28) ¼ 4.945, p < 0.01, Fig. 2B] and ifenprodil (0.5 mg/kg) [F(1,28) ¼ 12.650, p < 0.001, Fig. 2C] when given with a subeffective dose of ethanol (1.5 g/kg). Nevertheless, no significant change was detected in the locomotor activity of mice in the OFTcompared to the control group when injected with similar doses of the mentioned drugs [F(1,28) ¼ 0.020, F(1,28) ¼ 0.180, F(1,28) ¼ 0.000, respectively, p > 0.05, Fig. 2D, E, F)].
As shown in Fig. 3A, when NMDA was administered alone, it did not significantly alter the time of immobility in the FST (p > 0.05). However, when it was injected with ethanol (2.5 g/kg), it reversed the antidepressant-like effect of ethanol [F(1,28) ¼ 7.671, p < 0.001].Co-administration of NMDA (75 mg/kg) with an effective dose of ethanol per se did not show any significant effect on locomotor activity of mice in the OFT [F(1,28) ¼ 0.128, p > 0.05, Fig. 3B].

Role of nitric oxide in antidepressant-like effect of ethanol

As illustrated in Fig. 4A, a subeffective dose of L-NAM (10 mg/kg) significantly increased the effect of a subeffective dose of ethanol (1.5 g/kg) in the FST [F(1,28) ¼ 8.953, p < 0.001]. Fig. 4B demonstrates that co-injection of a subeffective dose of ethanol (1.5 g/kg) along with 7-NI (30 mg/kg) also diminished the time of immobility significantly in comparison to vehicle-treated (Tween 80) animals [F(1,28) ¼ 3.034, p < 0.01]. Nevertheless, co-injection of aminoguanidine (50 mg/kg) with a subeffective dose (1.5 g/kg) of ethanol did not change the immobility time during the FST [F(1,28) ¼ 0.157, p > 0.05, Fig. 4C]. Co-administration of L-NAME (Fig. 4D), 7-NI (Fig. 4E), or aminoguanidine (Fig. 4F) with ethanol (1.5 g/kg) did not alter the locomotor activity of animals in the OFT[F(1,28) ¼ 0.006, F(1,28) ¼ 0.023, F(1,28) ¼ 0.009, respectively, p > 0.05].
As shown in Fig. 5A, L-arginine (750 mg/kg) alone did not change the immobility time in the FST. However, co-injection of Larginine (750 mg/kg) with ethanol (2.5 g/kg) reversed the antidepressant-like effect of ethanol in the FST [F(1,28) ¼ 5.316, p < 0.01]. Neither L-arginine nor its combination with ethanol (2.5 g/kg) altered the locomotor activity of animals in the OFT [F(1,28) ¼ 0.111, p > 0.05, Fig. 5B].

Role of cGMP in the antidepressant-like effect of ethanol

Methylene blue (10 mg/kg), as a direct inhibitor of both NOS and sGC, failed to change the immobility time in FST when injected alone. However, when co-injected with a subeffective dose of ethanol (1.5 g/kg), it significantly augmented the antidepressantlike effect of a subeffective dose of ethanol [F(1,28) ¼ 3.365, p < 0.05, Fig. 6A]. Fig. 6C reveals that ODQ (20 mg/kg, a specific inhibitor of sGC) in combination with ethanol (1.5 g/kg) exerted an antidepressant-like effect in the FST [F(1,28) ¼ 8.212, p < 0.01]. Administration of methylene blue or ODQ alone or along with ethanol did not significantly change the locomotor activity of animals in the OFT [F(1,28) ¼ 0.336, F(1,28) ¼ 1.025, respectively, p > 0.05, Fig. 6 B, D].
Pretreatment of animals with sildenafil (5 mg/kg, a PDE5 inhibitor) alone could not change the immobility time. However, sildenafil reversed the antidepressant-like effect of ethanol (2.5 g/ kg) in the FST [F(1,28) ¼ 15.22, p < 0.001, Fig. 7A]. Also, combination of sildenafil with ethanol, or when sildenafil was injected alone, did not alter the locomotor activity of mice in the OFT [F(1,28) ¼ 0.323, p > 0.05, Fig. 7B].

Effect of ethanol on nitrite levels in hippocampus and prefrontal cortex

Fig. 8A and B demonstrate the hippocampal and prefrontal cortex nitrite content in ethanol-injected groups. A significantly lower nitrite level with alcohol (2.5 g/kg) was observed in the hippocampus and prefrontal cortex in comparison to salineinjected animals [F(2,15) ¼ 10.00, F(2,15) ¼ 6.556, respectively, p < 0.01), while a subeffective dose of ethanol (1.5 g/kg) did not exert a significant alteration in hippocampal or prefrontal cortex nitrite levels (p > 0.05). Injection of 7-NI (30 mg/kg, subeffective dose) per se could not alter the hippocampal or prefrontal cortex nitrite levels (p > 0.05). However, when it was co-administered with a subeffective dose of ethanol (1.5 g/kg), it significantly lowered the nitrite levels in hippocampus [F(1,20) ¼ 5.285, p < 0.01, Fig. 8C) and prefrontal cortex [F(1,20) ¼ 4.771, p < 0.05, Fig. 8D) compared to control animals.

Discussion

The results of the present study for the first time revealed that ethanol has an antidepressant-like effect in the FST, with possible involvement of the NMDA and L-arginineeNOecGMP pathway. The FST is one of the best screening tools for uncovering the antidepressants effect of drugs in rodents (Porsolt et al., 1977). There are some limitations with the use of the FST, as drugs affecting the locomotor activity may provide a “false” positive result during the FST (Borsini & Meli, 1988). Hence, this model is not suitable for agents such as bupropion, nomifensine, and amineptine, which can increase the locomotor activity of animals (Borsini & Meli, 1988). In the present study, effective doses of ethanol in the FST had no impact on the locomotor activity of mice in the OFT. Hence, it rejects the possibility that the antidepressant-like effects of ethanol in the FST might be due to its effect on the locomotor activity. In agreement with our current results, it is also reported that ethanol produces antidepressant-like effects in the FST in mice without altering the locomotor activity (Ciccocioppo et al., 1999; Fernandez-Pardal & Hilakivi, 1989; Jain et al., 2017; Kampov-Polevoy et al., 1993).
Many investigators have reported that NMDARs are principally essential targets for various actions of ethanol (Kumari & Ticku, 2000; Wirkner et al., 1999). NMDAR is widely considered as the most essential glutamate receptor in a diversity of ethanolrelated behavioral effects such as tolerance, dependence, withdrawal, craving, and relapse (Krystal et al., 2003). Acute ethanol administration strongly antagonizes NMDARs, and chronic ethanol administration causes ‘up-regulation’ of compensatory NMDAR-related functions. It has been revealed that ethanol diminished the probability of opening channel and the mean open period of native NMDARs in in vitro experiments of cultured cortical neurons (Wright, Peoples, & Weight, 1996). The exact mechanism by which ethanol promptly inhibits and interacts with NMDARs is still elusive and is under investigation. However, a rapid decrease in channel activity due to ethanol exposure suggests a direct interaction with NMDAR subunits. It is also reported that ethanol controls channel gating in non-neuronal mammalian cells such as HEK-293 cells. In addition, Ron and Wang tried to uncover the sensitivity of specific NMDAR subunits with which ethanol interacts by transfecting it in Xenopus oocytes (Ron & Wang, 2009).
Numerous studies suggest that NMDARs possess a substantial role in the pathophysiology of various neuropsychological diseases, including depression (Krystal et al., 2003; Sanacora et al., 2008; Skolnick, 1999). Clinical and experimental studies reported a prompt antidepressant effect of ketamine, which is due to an NMDA receptor antagonism. Numerous experiments have demonstrated that antidepressants diminish binding, expression, and function of NMDARs (Javitt, 2004; Paul & Skolnick, 2003; Skolnick, 1999; Zarate et al., 2006). Given the value of these receptors in the pathophysiology of depression and its involvement in the mechanism of action of various antidepressants, we tested the role of NMDARs in the antidepressant-like effect of ethanol in mice in FST.
In the present study, we revealed that ethanol induced decreases in the immobility time during the FST, which was blocked by the administration of NMDA agonist. In line with our current results, it is reported that the antidepressant-like effect of baclofen, nicotine, and agmatine in the FST was reversed, when the animals were pretreated with NMDA (Haj-Mirzaian et al., 2015; Khan et al., 2015; Mohseni et al., 2017). Similarly, it is reported that NR2A subunit knock-out mice exhibit anxiolytic-like effects in the elevated plus maze and antidepressant-like properties when subjected to the FST and tail suspension test (TST) (Boyce-Rustay & Holmes, 2006). Additionally, it is revealed that antidepressant drugs reduce the expression, binding, and activity of NMDA receptors (Boyer, Skolnick, & Fossom, 1998; Szasz et al., 2007). A recent approach also showed that stimulation of NMDA receptors by NMDA and D-serine reversed the antidepressant-like effect of NMDA receptor antagonists in the FST, hence confirming the involvement of NMDA receptors in depression (Poleszak et al., 2007). The synergistic response that is shown when the animals were pretreated by NMDA receptor antagonists such as MK-801, ifenprodil, or ketamine in ethanol-treated animals supports our hypothesis that ethanol exerts its antidepressant-like properties through inhibition of NMDA receptor activity. In agreement with our current findings, it was reported that co-administration of subeffective doses of baclofen or pramipexole with MK-801 exerted an antidepressant-like effect in the FST in mice (Khan et al., 2015; Ostadhadi, Khan, et al., 2016). A microdialysis study has shown that acute injection of subeffective doses of the NMDA antagonist amantadine, along with subeffective doses of various antidepressant agents (paroxetine, reboxetine, budipine, and clomipramine) boosts the cortical release of serotonin in freely moving rats (Owen & Whitton, 2005). It has also been reported that central serotonin transmission is involved in the antidepressant-like effects of ethanol in mice (Jain et al., 2017).
It is well-documented that the NMDA receptor strongly interacts with the NO/cGMP system. Activation of postsynaptic neuronal NMDA receptors in several brain areas elevates the levels of intracellular Ca2þ ions, which triggers the activity of Cacalmodulin (CaM) followed by nNOS stimulation and subsequent increases of NO levels. Moreover, it is reported that PSD-95 protein accelerates the interaction of the NMDA receptor and NOS through Ca2þ influx, and hence augments the NO production (Ledo, Frade, Barbosa, & Laranjinha, 2004; Moncada & Bolanos, 2006~ ).
The role of the NO-cGMP signaling pathway is well-established in the pathogenesis of depression (Kaster, Ferriera, Santos, & Rodrigues, 2005; Ostadhadi, Khan, et al., 2016; Ostadhadi, Kordjazy, et al., 2016). Nitric oxide plays an important role in various activities of the central nervous system. Pharmacological control of the NO pathway may introduce a new therapeutic approach for the management of depression (Harkin et al., 2004). In our study, we reported that reduction of immobility time in the FST caused by ethanol was blocked by pretreatment of mice with Larginine (NOS substrate). Similarly, antidepressant-like effects of escitalopram (Zomkowski et al., 2010), paroxetine (Ghasemi et al., 2009), venlafaxine (Dhir & Kulkarni, 2007), gabapentin (Ostadhadi, Kordjazy, et al., 2016), topiramate (Ostadhadi, Khan, Norouzi-Javidan, Chamanara, et al., 2016), memantine (Almeida, Felisbono, Lopez, Rodrigues, & Gabilan, 2006), and folic acid (de Souza Brocardo, Budni, Lobato, Kaster, & Rodrigues, 2008) were blocked by pretreatment with L-arginine. Hence, major literature supports the important function of the nitrergic system in the antidepressant mechanism of various drugs. Our data also suggest that the antidepressant-like effect of ethanol is through inhibition of NO synthesis. Furthermore, we showed that pretreatment of mice with a subeffective dose of L-NAME (a nonspecific nNOS inhibitor), 7-NI (a specific nNOS inhibitor), methylene blue (direct inhibitor of both NOS and sGC), or ODQ (a specific inhibitor of sGC) significantly increased the antidepressant-like effect of ethanol. Decreased nitrite levels in the hippocampus and prefrontal cortex further confirm our hypothesis that ethanol strongly interacts with NO signaling. Other studies also reported the fact that NOS inhibitors exert antidepressant-like effects in experimental studies (Eroglu & Caglayan, 1997 ; Yildiz, Erden, Ulak, & Gacar, 2000).
In accordance with the results of the present study, it has been reported that 7-NI significantly improves the antidepressant-like effect of venlafaxine (Dhir & Kulkarni, 2007), imipramine, and fluoxetine (Harkin et al., 2004) in the FST. Similarly, methylene blue was found to potentiate the antidepressant-like effect of venlafaxine (Dhir & Kulkarni, 2007), while the antidepressant-like effect induced by ODQ was reversed by pretreatment with L-arginine during the FST (Heiberg, Wegener, & Rosenberg, 2002). It is also reported that ODQ potentiated the antidepressant-like effects of lithium (Ghasemi et al., 2008), adenosine (Kaster, Rosa, et al., 2005), and memantine in mice tested in the FST (Almeida et al., 2006). Together these studies strongly support our current results.
Taking into consideration the above facts, our findings confirm that the antidepressant-like effect of ethanol in the FST is through inhibition of NO and cGMP production. In order to further investigate the involvement of cGMP, animals were pretreated with sildenafil (selective PDE5 inhibitor). Sildenafil elevates the cGMP content in target tissues (Beavo, 1995). The antidepressant-like effect of ethanol was significantly inhibited by sildenafil in the FST. Previously, it has been shown that sildenafil can reverse the antidepressant-like effect of ODQ in mice tested in the FST (Kaster, Rosa, et al., 2005). The results of the present experiment are also in agreement with the previous studies where the antidepressant effects of venlafaxine (Dhir & Kulkarni, 2007) and escitalopram (Zomkowski et al., 2010) were reversed by pretreatment with sildenafil. Thus, our finding confirms that ethanol exerts its antidepressant-like effect through decreasing the levels of cGMP.

Conclusion

The results of the present study revealed that acute ethanol treatment exerts antidepressant-like properties in mice tested in the FST (Ciccocioppo et al., 1999; Hirani et al., 2002; Jain et al., 2017). This effect is mediated through inhibition of NMDA receptors and the L-arginineeNOecGMP pathway. We also showed that acute ethanol treatment can diminish nitrite levels in the hippocampus and prefrontal cortex.

Limitations

The current study addressed the antidepressant-like effects of ethanol with possible involvement of the NMDA/NO/cGMP pathway in the brain, which is a fairly convincing explanation for the mechanism involved. However, there are still certain limitations of the current study that could not be ignored and must be addressed in future research. Ethanol interacts with other major neurotransmitters such as serotonin, GABA, and dopamine (Bowirrat & OscarBerman, 2005; Koob, 2004; Lovinger, 1997). It has been reported that the discriminative stimulus effects of ethanol in the limbic brain region is mediated by NMDA and GABAA receptors (Hodge & Cox, 1998). Alcohol also affects GABA receptors and glutamate receptors in various brain regions. In the case of alcohol withdrawal, alterations in GABA and the glutamatergic system have been reported (Samson & Harris, 1992). Deficiency in serotonin in genetically modified animal models produces depressive-like symptoms. A preliminary study shows that such animals prefer a high intake of alcohol. Hence, this suggests that alcohol modulates the level of serotonin in the brain (Rezvani, Overstreet, & Janowsky, 1990). So, it is proven that alcohol interacts with other neurotransmitters as well. These limitations do not undermine the current findings. However, they do suggest that other neurotransmitters should also be taken into consideration. We were unable to study the effect of alcohol on these neurotransmitters all together. However, this study can be the future focus of research where the interaction of such neurotransmitters should be simultaneously considered along with NMDA/NO/cGMP in the antidepressant-like effect of ethanol.

References

Almeida, R. C., Felisbono, C., Lopez, M. G., Rodrigues, A. L. S., & Gabilan, N. H. (2006). Evidence for the involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of memantine in mice. Behavioural Brain Research, 168(2), 318e322. https://doi.org/10.1016/ j.bbr.2005.11.023
Beavo, J. A. (1995). Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiological Reviews, 75(4), 725e748. https://doi.org/ 10.1152/physrev.1995.75.4.725
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., et al. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351e354. https://doi.org/10.1016/s0006-3223(99) 00230-9
Besheer, J., Lepoutre, V., & Hodge, C. W. (2009). Preclinical evaluation of riluzole: Assessments of ethanol self-administration and ethanol withdrawal symptoms. Alcoholism: Clinical and Experimental Research, 33(8), 1460e1468. https:// doi.org/10.1111/j.1530-0277.2009.00976.x
Borsini, F., & Meli, A. (1988). Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology, 94(2), 147e160. https:// doi.org/10.1007/BF00176837
Bowirrat, A., & Oscar-Berman, M. (2005). Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 132B(1), 29e37. https://doi.org/10.1002/ajmg.b.30080
Boyce-Rustay, J. M., & Holmes, A. (2006). Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology, 1(11), 2405e2414. https://doi.org/10.1038/sj.npp.1301039
Boyer, P.-A., Skolnick, P., & Fossom, L. H. (1998). Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. Journal of Molecular Neuroscience, 10(3), 219e233. https://doi.org/ 10.1007/BF02761776
Ciccocioppo, R., Panocka, I., Froldi, R., Colombo, G., Gessa, G. L., & Massi, M. (1999). Antidepressant-like effect of ethanol revealed in the forced swimming test in Sardinian alcohol-preferring rats. Psychopharmacology, 144(2), 151e157. https:// doi.org/10.1007/s002130050988
Dhir, A., & Kulkarni, S. K. (2007). Involvement of L-arginineenitric oxideecyclic guanosine monophosphate pathway in the antidepressant-like effect of venlafaxine in mice. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 31(4), 921e925. https://doi.org/10.1016/j.pnpbp.2007.02.008
Eroglu, L., & Ca glayan, B. (1997). Anxiolytic and antidepressant properties of methylene blue in animal models. Pharmacological Research, 36(5), 381e385.https://doi.org/10.1006/phrs.1997.0245
Esplugues, J. V. (2002). NO as a signalling molecule in the nervous system. British Journal of Pharmacology, 135(5), 1079e1095. https://doi.org/10.1038/ sj.bjp.0704569
Faingold, C., N'Gouemo, P., & Riaz, A. (1998). Ethanol and neurotransmitter interactions–from molecular to integrative effects. Progress in Neurobiology, 55(5), 509e535. https://doi.org/10.1016/s0301-0082(98)00027-6
Farhan, M., & Haleem, D. J. (2016). Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress.Saudi Pharmaceutical Journal, 24(5), 571e578. https://doi.org/10.1016/ j.jsps.2015.03.006
Fernandez-Pardal, J., & Hilakivi, L. A. (1989). Effect of low alcohol dose on behavioral “despair” in rats neonatally treated with antidepressant drugs. Alcohol, 6(2), 93e95. https://doi.org/10.1016/0741-8329(89)90031-1
Ghasemi, M., Montaser-Kouhsari, L., Shafaroodi, H., Nezami, B. G., Ebrahimi, F., & Dehpour, A. R. (2009). NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test. Psychopharmacology, 206(2), 325e333. https://doi.org/10.1007/s00213-0091609-1
Ghasemi, M., Sadeghipour, H., Mosleh, A., Sadeghipour, H. R., Mani, A. R., & Dehpour, A. R. (2008). Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. European Neuropsychopharmacology, 18(5), 323e332. https://doi.org/10.1016/ j.euroneuro.2007.07.011
Godfrey, C. D., Froehlich, J. C., Stewart, R. B., & Murphy, J. M. (1997). Comparison of rats selectively bred for high and low ethanol intake in a forced-swim-test model of depression: Effects of desipramine. Physiology & Behavior, 62(4), 729e733. https://doi.org/10.1016/s0031-9384(97)00171-6
Granger, D. L., Traintor, R. R., Boockvar, K. S., & Hibbs, J. B., jr. (1996). Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods in Enzymology, 268, 142e151. https://doi.org/10.1016/s00766879(96)68016-1
Haj-Mirzaian, A., Kordjazy, N., Haj-Mirzaian, A., Ostadhadi, S., Ghasemi, M., Amiri, S., et al. (2015). Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests. Psychopharmacology, 232(19), 3551e3561. https://doi.org/ 10.1007/s00213-015-4004-0
Haj-Mirzaian, A., Kordjazy, N., Ostadhadi, S., Amiri, S., Haj-Mirzaian, A., & Dehpour, A. (2016). Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: Role of N-methyl-d-aspartate and opioid receptors. Canadian Journal of Physiology and Pharmacology, 94(6), 599e612. https:// doi.org/10.1139/cjpp-2015-0429
Haj-Mirzaian, A., Ostadhadi, S., Kordjazy, N., Dehpour, A. R., & Mehr, S. E. (2014). Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test. European Journal of Pharmacology, 735, 26e31. https://doi.org/10.1016/j.ejphar.2014.03.053
Harkin, A., Connor, T. J., Burns, M. P., & Kelly, J. P. (2004). Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. European Neuropsychopharmacology, 14(4), 274e281. https:// doi.org/10.1016/j.euroneuro.2003.08.010
Heiberg, I. L., Wegener, G., & Rosenberg, R. (2002). Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behavioural Brain Research, 134(1e2), 479e484. https://doi.org/10.1016/s01664328(02)00084-0
Hirani, K., Khisti, R. T., & Chopde, C. T. (2002). Behavioral action of ethanol in porsolt's forced swim test: Modulation by 3alpha-hydroxy-5alpha-pregnan-20one. Neuropharmacology, 43(8), 1339e1350. https://doi.org/10.1016/s00283908(02)00330-1
Hodge, C. W., & Cox, A. A. (1998). The discriminative stimulus effects of ethanol are mediated by NMDA and GABA(A) receptors in specific limbic brain regions. Psychopharmacology, 139(1e2), 95e107. https://doi.org/10.1007/ s002130050694
Hoffman, P. L., Rabe, C. S., Grant, K. A., Valverius, P., Hudspith, M., & Tabakoff, B. (1990). Ethanol and the NMDA receptor. Alcohol, 7(3), 229e231. https://doi.org/ 10.1016/0741-8329(90)90010-a
Imperato, A., & Di Chiara, G. (1989). Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. Journal of Pharmacology and Experimental Therapeutics, 239(1), 219e228.
Jain, N. S., Kannamwar, U., & Verma, L. (2017). Ethanol induced antidepressant-like effect in the mouse forced swimming test: Modulation by serotonergic system. Psychopharmacology, 234(3), 447e459. https://doi.org/10.1007/s00213-0164478-4
Javitt, D. C. (2004). Glutamate as a therapeutic target in psychiatric disorders. Molecular Psychiatry, 9(11), 984e997. https://doi.org/10.1038/sj.mp.4001551
Kampov-Polevoy, A., Dubtchenko, V. V., Crosby, R. D., & Halikas, J. A. (1993). Reduction in the level of immobilization in forced swim test and ethanol intake in rats by oxygen therapy. Alcohol, 10(5), 419e424. https://doi.org/10.1016/07418329(93)90031-i
Kaster, M. P., Ferriera, P. K., Santos, A. R. S., & Rodrigues, A. L. S. (2005a). Effects of potassium channel inhibitors in the forced swimming test: Possible involvement of L-arginine-nitric oxide-soluble guanylate cyclase pathway. Behavioural Brain Research, 165(2), 204e209. https://doi.org/10.1016/j.bbr.2005.06.031
Kaster, M. P., Rosa, A. O., Santos, A. R. S., & Rodrigues, A. L. S. (2005b). Involvement of nitric oxideecGMP pathway in the antidepressant-like effects of adenosine in the forced swimming test. The International Journal of Neuropsychopharmacology,8(4), 601e606. https://doi.org/10.1017/S1461145705005316
Khan, M., Momeny, M., Ostadhadi, S., Jahanabadi, S., Ejtemaei-Mehr, S., Sameem, B., et al. (2018). Thalidomide attenuates development of morphine dependence in mice by inhibiting PI3K/Akt and nitric oxide signaling pathways. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 82, 39e48. https://doi.org/ 10.1016/j.pnpbp.2017.12.002
Khan, M., Ostadhadi, S., Mumtaz, F., Momeny, M., Moghaddashko, F., Hassanipour, M., et al. (2017). Thalidomide attenuates the development and expression of antinociceptive tolerance to m-opioid agonist morphine through larginine-iNOS and nitric oxide pathway. Biomedicine & Pharmacotherapy, 85, 493e502. https://doi.org/10.1016/j.biopha.2016.11.056
Khan, M., Ostadhadi, S., Zolfaghari, S., Mehr, S. E., Hassanzadeh, G., & Dehpour, A. (2015). The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test. Neuroscience Letters, 612, 52e61. https://doi.org/10.1016/j.neulet.2015.12.006
Koob, G. F. (2004). A role for GABA mechanisms in the motivational effects of alcohol. Biochemical Pharmacology, 68(8), 1515e1525. https://doi.org/10.1016/ j.bcp.2004.07.031
Kordjazy, N., Haj-Mirzaian, Amiri, S., Ostadhadi, S., Kordjzay, M., Sharifzadeh, M., et al. (2015). Elevated level of nitric oxide mediates the anti-depressant effect of rubidium chloride in mice. European Journal of Pharmacology, 762, 411e418. https://doi.org/10.1016/j.ejphar.2015.06.030
Krystal, J. H., Petrakis, I. L., Mason, G., Trevisan, L., & D'Souza, D. C. (2003). N-methylD-aspartate glutamate receptors and alcoholism: Reward, dependence, treatment, and vulnerability. Pharmacology & Therapeutics, 99(1), 79e94. https:// doi.org/10.1016/s0163-7258(03)00054-8
Kumari, M., & Ticku, M. K. (2000). Regulation of NMDA receptors by ethanol. In Progress in drug research (pp. 151e189). Springer.
Ledo, A., Frade, J., Barbosa, R. M., & Laranjinha, J. (2004). Nitric oxide in brain: Diffusion, targets and concentration dynamics in hippocampal subregions. Molecular Aspects of Medicine, 25(1e2), 75e89. https://doi.org/10.1016/ j.mam.2004.02.010
Lovinger, D. M. (1997). Serotonin's role in alcohol's effects on the brain. Alcohol Health & Research World, 21(2), 114e120.
Mantovani, M., Pertile, R., Calixto, J. B., Santos, A. R. S., & Rodrigues, A. L. S. (2003). Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: Evidence for involvement of N-methyl-D-aspartate receptors and the Larginine-nitric oxide pathway. Neuroscience Letters, 343(1), 1e4. https://doi.org/ 10.1016/s0304-3940(03)00306-9
Miao, M., Yan, X., Guo, L., & Li, P. (2017). Effect of Cynomorium total flavone on depression model of perimenopausal rat. Saudi Journal of Biological Sciences, 24(1), 139e148. https://doi.org/10.1016/j.sjbs.2016.09.009
Mohseni, G., Ostadhadi, S., Khan, M., Norouzi-Javidan, A., Zolfaghari, S., Haddadi, N. M., et al. (2017). Agmatine enhances the antidepressant-like effect of lithium in mouse forced swimming test through NMDA pathway. Biomedicine & Pharmacotherapy, 88, 931e938. https://doi.org/ 10.1016/j.biopha.2017.01.119
Moncada, S., & Bolanos, J. P. (2006). Nitric oxide, cell bioenergetics and neuro-~ degeneration. Journal of Neurochemistry, 97(6), 1676e1689. https://doi.org/ 10.1111/j.1471-4159.2006.03988.x
Moykkynen, T., & Korpi, E. R. (2012). Acute effects of ethanol on glutamate re-€ ceptors. Basic and Clinical Pharmacology and Toxicology, 111(1), 4e13. https:// doi.org/10.1111/j.1742-7843.2012.00879.x
Nazari, S. K., Nikoui, V., Ostadhadi, S., Chegini, Z. H., Oryan, S., & Bakhtiarian, A. (2016). Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effect of baclofen in mouse forced swimming test. Pharmacological Reports, 68(6), 1214e1220. https://doi.org/10.1016/j.pharep.20 16.07.006
Nikoui, V., Ostadhadi, S., Azhand, P., Zolfaghari, S., Amiri, S., Foroohandeh, M., et al. (2016). The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels. European Journal of Pharmacology, 791, 369e376. https://doi.org/10.1016/j.ejphar.2016.09.017
Ostadhadi, S., Ahangari, M., Nikoui, V., Norouzi-Javidan, A., Zolfaghari, S., Jazaeri, F., et al. (2016). Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test. Biomedicine & Pharmacotherapy, 82,713e721. https://doi.org/10.1016/j.biopha.2016.05.035
Ostadhadi, S., Akbarian, R., Norouzi-Javidan, A., Nikoui, V., Zolfaghari, S., Chamanara, M., et al. (2017a). Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effects of gabapentin in mouse forced swimming test. Canadian Journal of Physiology and Pharmacology, 95(7), 795e802. https://doi.org/10.1139/cjpp-2016-0292
Ostadhadi, S., Haj-Mirzaian, A., Nikoui, V., Kordjazy, N., & Dehpour, A. R. (2015). Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice. Clinical and Experimental Pharmacology and Physiology, 43(2), 203e212. https://doi.org/ 10.1111/1440-1681.12518
Ostadhadi, S., Khan, M., Norouzi-Javidan, A., Chamanara, M., Jazaeri, F., Zolfaghari, S., et al. (2016a). Involvement of NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effects of topiramate in mice forced swimming test. Brain Research Bulletin, 122, 62e70. https://doi.org/10.1016/j.brainresbull.2016.03.004
Ostadhadi, S., Khan, M., Norouzi-Javidan, A., & Dehpour, A. R. (2016). Antidepressant effect of pramipexole in mice forced swimming test: A cross talk between dopamine receptor and NMDA/nitric oxide/cGMP pathway. Biomedicine &
Pharmacotherapy, 81, 295e304. https://doi.org/10.1016/j.biopha.2016.04.026 Ostadhadi, S., Kordjazy, N., Haj-Mirzaian, A., Ameli, S., Akhlaghipour, G., & Dehpour, A. (2016). Involvement of NO/cGMP pathway in the antidepressantlike effect of gabapentin in mouse forced swimming test. Naunyn-Schmiedeberg's Archives of Pharmacology, 389(4), 393e402. https://doi.org/10.1007/ s00210-015-1203-5
Ostadhadi, S., Norouzi-Javidan, A., Chamanara, M., Akbarian, R., Khan, M., Ghasemi, M., et al. (2017b). Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test. Brain Research Bulletin, 134, 136e141. https://doi.org/10.1016/j.brainresbull.2017.0 7.016
Owen, J. C., & Whitton, P. S. (2005). Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats. British Journal of Pharmacology, 145(5), 587e592. https:// doi.org/10.1038/sj.bjp.0706188
Paul, I. A., & Skolnick, P. (2003). Glutamate and depression: Clinical and preclinical studies. Annals of the New York Academy of Sciences, 1003, 250e272. https:// doi.org/10.1196/annals.1300.016
Poleszak, E., Wlaz, P., Wrobel, A., Dybała, M., Sowa, M., Fidecka, S., et al. (2007). Activation of the NMDA/glutamate receptor complex antagonizes the NMDA antagonist-induced antidepressant-like effects in the forced swim test. Pharmacological Reports, 59(5), 595e600.
Porsolt, R. D., Bertin, A., & Jalfre, M. (1977). Behavioral despair in mice: A primary screening test for antidepressants. Archives Internationales de Pharmacodynamie et de Therapie, 229(2), 327e336.
Rezvani, A. H., Overstreet, D. H., & Janowsky, D. S. (1990). Genetic serotonin deficiency and alcohol preference in the fawn hooded rats. Alcohol and Alcoholism, 25(5), 573e575.
Ron, D., & Wang, J. (2009). The NMDA receptor and alcohol addiction. In Biology of the NMDA receptor. CRC Press.
Sakhaee, E., Ostadhadi, S., Khan, M., Yousefi, F., Norouzi-Javidan, A., Akbarian, R., et al. (2017). The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test. Biomedicine & Pharmacotherapy, 85, 627e634. https://doi.org/10.1016/j.biopha.2016.11.073
Samson, H. H., & Harris, R. A. (1992). Neurobiology of alcohol abuse. Trends in Pharmacological Sciences, 13(5), 206e211. https://doi.org/10.1016/0165-6147(92) 90065-e
Sanacora, G., Zarate, C. A., Krystal, J. H., & Manji, H. K. (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders.
Nature Reviews Drug Discovery, 7(5), 426e437. https://doi.org/10.1038/nrd2462 Shafizadeh, M., Rajaba, A., Khan, M., Ostadhadi, S., Rastegar, H., & Dehpour, A. (2014). Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: Possible involvement of PPAR-gamma receptor and nitric oxide. European Journal of Pharmacology, 744, 103e107. https://doi.org/10.1016/j.ejphar.2014 .10.002
Skolnick, P. (1999). Antidepressants for the new millennium. European Journal of Pharmacology, 375(1e3), 31e40. https://doi.org/10.1016/s0014-2999(99)00330-de Souza Brocardo, P., Budni, J., Lobato, K. R., Kaster, M. P., & Rodrigues, A. L. S. (2008). Antidepressant-like effect of folic acid: Involvement of NMDA receptors and L-arginine-nitric oxide-cyclic guanosine monophosphate pathway. European Journal of Pharmacology, 598(1e3), 37e42. https://doi.org/10.1016/ j.ejphar.2008.08.033
Szasz, B. K., Mike, A., Karoly, R., Gerevich, Z., Illes, P., Vizi, E. S., et al. (2007). Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system. Biological Psychiatry, 62(11), 1303e1309. https://doi.org/ 10.1016/j.biopsych.2007.04.014
Verma, L., & Jain, N. S. (2016). Central histaminergic transmission modulates the ethanol induced anxiolysis in mice. Behavioural Brain Research, 313, 38e52. https://doi.org/10.1016/j.bbr.2016.07.012
Walden, M., Nicholls, F. A., Smith, K. J., & Tucker, G. F. (2007). The effect of ethanol on the release of opioids from oral prolonged-release preparations. Drug Development and Industrial Pharmacy, 33(10), 1101e1111. https://doi.org/10.1080/ 03639040701377292
Weight, F. F. (1992). Cellular and molecular physiology of alcohol actions in the nervous system. In International review of neurobiology (pp. 289e348). Elsevier.
Wirkner, K., Poelchen, W., Koles, L., Mühlberg, K., Scheibler, P., Allgaier, C., et al.€ (1999). Ethanol-induced inhibition of NMDA receptor channels. Neurochemistry International, 35(2), 153e162. https://doi.org/10.1016/s0197-0186(99)00057-1
Woodward, J. J. (1999). Ionotropic glutamate receptors as sites of action for ethanol in the brain. Neurochemistry International, 35(2), 107e113.
Wright, J. M., Peoples, R. W., & Weight, F. F. (1996). Single-channel and whole-cell analysis of ethanol inhibition of NMDA-activated currents in cultured mouse cortical and hippocampal neurons. Brain Research, 738(2), 249e256. https:// doi.org/10.1016/s0006-8993(96)00780-9
Yang, W., & Wang, H. (2018). 5,7-Dimethoxycoumarin prevents chronic mild stress induced depression in rats through increase in the expression of heat shock protein-70 and inhibition of monoamine oxidase-A levels. Saudi Journal of Biological Sciences, 25(2), 253e258. https://doi.org/10.1016/j.sjbs.2016.10.016
Yildiz, F., Erden, B. F., Ulak, G., & Gacar, N. (2000). Antidepressant-like effect of 7nitroindazole in the forced swimming test in rats. Psychopharmacology, 149(1), 41e44. https://doi.org/10.1007/s002139900316
Yim, H. J., & Gonzales, R. A. (2000). Ethanol-induced increases in dopamine extracellular concentration in rat nucleus accumbens are accounted for by increased release and not uptake inhibition. Alcohol, 22(2), 107e115. https://doi.org/ 10.1016/s0741-8329(00)00121-x
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., et al. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63(8), 856e864. https://doi.org/10.1001/archpsyc.63.8.856
Zomkowski, A. D. E., Engel, D., Gabilan, N. H., & Rodrigues, A. L. S. (2010). Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test. European Neuropsychopharmacology, 20(11), 793e801.https://doi.org/10.1016/j.euroneuro.2010.07.011