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Journal of Neural Transmission

, Volume 118, Issue 6, pp 857–864 | Cite as

Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice

  • Ewa PoleszakEmail author
  • Katarzyna Socała
  • Aleksandra Szopa
  • Andrzej Wróbel
  • Bernadeta Szewczyk
  • Regina Kasperek
  • Eliza Blicharska
  • Gabriel Nowak
  • Piotr WlaźEmail author
Open Access
Basic Neurosciences, Genetics and Immunology - Original Article

Abstract

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors.

Keywords

Chlordiazepoxide NMDA receptor ligands Anxiety Elevated plus-maze Mice 

Introduction

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian central nervous system (Sieghart 1995; Sieghart et al. 1999). Dysfunction of the central GABA system has long been associated with anxiety spectrum disorders (Nutt and Malizia 2001; Lydiard 2003; Nemeroff 2003). It is known that in both, humans and animals, positive modulators of GABAA ionotropic receptors produce anxiolytic-like activity, while the negative modulators evoke anxiety (Kalueff and Nutt 1996; Nutt and Malizia 2001). Thus, for many years, the leading treatment of anxiety disorders was benzodiazepines that enhance GABAergic inhibitory neurotransmission through allosteric modulation of GABAA receptors. They are still preferred due to their efficacy, rapid onset of action, and safety (Stahl 2002), but their adverse effects: sedation, cognitive impairments, undesirable interactions with other drugs, drug dependence and abuse mostly limited their use (Uhlenhuth et al. 1999; Stahl 2002). Moreover, these treatments are effective only in about 70% of patients and full remission is observed only in 40% of patients; thus, the novel therapeutic strategies are extensively sought.

Glutamate, which is the chief excitatory neurotransmitter in the mammalian central nervous system, is widely distributed throughout the brain and mediates its effects via stimulation of ionotropic and metabotropic receptors (Kew and Kemp 2005). The ionotropic glutamate receptor family is ligand-gated channels divided into three groups named after their selective agonists [N-methyl-d-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), and kainate] and their density is high in cortical and limbic regions being implicated in the mediation of fear and anxiety (Krystal et al. 1999). The preclinical data indicate that a number of different classes of NMDA receptor antagonists, acting at specific sites located on the NMDA receptor complex, produced anxiolytic-like activity in tests of anxiety in rodents (Dunn et al. 1989; Sharma and Kulkarni 1993; Płaźnik et al. 1994; Karcz-Kubicha et al. 1997; Kotlińska and Liljequist 1998; Przegaliński et al. 2000; Poleszak et al. 2004). In humans, memantine and d-cycloserine are effective in obsessive–compulsive disorder (Feusner et al. 2009; Abramowitz et al. 2009; Aboujaoude et al. 2009), and moreover, d-cycloserine was effective in post-traumatic stress disorder (Amiel and Mathew 2007). Despite these findings, the numerous adverse effects produced by competitive and non-competitive NMDA antagonist limited their potential clinical use (Tricklebank et al. 1989; Willetts et al. 1990). Profound side effects, typical for competitive and non-competitive NMDA receptor antagonist, do not occur after administration glycineB site modulators (Parsons et al. 1998). This modulatory site of the NMDA receptor complex is a co-agonist site with affinity for glycine and d-serine (Wood et al. 1989, 1996). Antagonists and partial agonist of glycineB sites inhibit the function of the NMDA receptor complex and produce effects which are similar to those produced by competitive and non-competitive NMDA receptor antagonist. It was shown that glycine potentiated the action of glutamate at NMDA receptors (Johnson and Ascher 1987), and antagonists and partial agonist of the glycineB sites inhibited the function of the NMDA receptor complex and produced anxiolytic-like action in several experimental models of anxiety (Karcz-Kubicha et al. 1997; Przegaliński et al. 1998; Kotlińska and Liljequist 1998).

In this study, we investigated the interaction between glycineB sites ligands and benzodiazepine/GABAA receptor ligand, chlordiazepoxide (CDP) in the elevated plus-maze test in mice.

Materials and methods

Animals

The experiments were carried out on adult male Albino Swiss mice (25–30 g) purchased from the licensed breeder (Kołacz, Warsaw, Poland). The animals were kept in cages (up to 10 per cage) on a natural day–night cycle with free access to food and water and they were used after at least 7 days of acclimatization to laboratory conditions. Each experimental group consisted of 8–12 animals. The experimental protocol was approved by the Local Ethics Committee at the Medical University of Lublin (license no. 31/2007), and all the procedures were in strict compliance with the European Communities Council Directive of 24 November 1986 (86/609/EEC).

Drug administration

Chlordiazepoxide (CDP, Polfa-Poznań, Poland) was administered intraperitoneally (i.p.) 60 min before the test. L-701,324 (7-chloro-4-hydroxy-3-(3- phenoxy)phenylquinolin-2[1H]-one, Sigma) was suspended in a 1% aqueous solution of Tween 80 (POCH, Gliwice, Poland) and administered intraperitoneally (i.p.) 60 min before the test. NMDA (Sigma), CGP 37849 (dl-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid, Tocris), d-cycloserine (d-4-amino-3-isoxazolidone, Sigma) were dissolved in 0.9% NaCl and administered i.p. and also administered 60 min before the test. d-Serine (Sigma) was also dissolved in 0.9% NaCl and administered intracerebroventricularly (i.c.v.) 15 min before the test. I.c.v. administration was performed according to a modified method described by Lipman and Spencer (1980). Control animals received an i.p. or i.c.v. injection of a respective vehicle. The volume of vehicles or drug solutions for i.p. and i.c.v. administrations was 10 ml/kg and 5 μl per mouse, respectively.

Elevated plus-maze test

The experiments were carried out on mice according to the method of Lister (1987). The plus-maze apparatus was made of black polyvinyl chloride and consisted of two open (30 × 5 cm) and two enclosed (30 × 5 × 15 cm) arms. The arms extended from a central platform of 5 × 5 cm. The apparatus was mounted on a stable base raising it 38 cm above the floor and was illuminated by red light. The test consisted of placing a mouse in the center of the apparatus (facing an enclosed arm) and allowing it to freely explore the maze. The number of entries into the open arms and the time spent in these arms were scored for a 5-min test period. An entry was defined as placing all four paws within the boundaries of the arm. The following measures were obtained from the test: the total number of arm entries, the percentage of entries into the open arms, the time spent in the open arms expressed as a percentage of the time spent in both the open and closed arms. Anxiolytic activity was indicated by increases in time spent in open arms or in a greater number of open arm entries. Total number of entries into either type of an arm was used as a measure of the overall motor activity.

Statistical analysis

The obtained data were evaluated by two-way analysis of variance (ANOVA) followed by Bonferroni’s post hoc test. All results are presented as a mean ± standard error of the mean (SEM). A p ≤ 0.05 was considered statistically significant.

Results

Anxiolytic-like effect of joint administration of CDP and CGP 37849 in the elevated plus-maze test

Chlordiazepoxide administered at a dose of 0.5 mg/kg or CGP 37849 administered at a dose of 0.312 mg/kg, both given alone, did not change the percentage of the time spent and also entries into the open arms with the exception of CDP, which significantly increased this latter measure (Fig. 1). The joint administration of CDP and CGP 37849 significantly increased the percentage of the time spent in the open arms (Fig. 1a) and enhanced the number of entries into open arms (Fig. 1b). A two-way ANOVA demonstrated lack of effect of CDP [F(1, 28) = 1.91, p = 0.1777], significant effect of CGP 37849 [F(1, 28) = 26.38, p < 0.0001] and significant interaction [F(1, 28) = 8.02, p = 0.0085] in the time spent in open arms, while a significant effect of CDP [F(1, 28) = 15.301, p = 0.0005], no effect of CGP 37849 [F(1, 28) = 2.93, p = 0.09882] and no interaction [F(1, 28) = 0.0, p = 0.9492] in the open arm entries.
Fig. 1

Effect of joint administration of CGP 37849 and chlordiazepoxide (CDP) in the elevated plus-maze procedure in mice [the percentage of the time spent in the open arms (a), and the percentage of the open arms entries (b)]. CGP 37849 and CDP was administered i.p. 60 min before the test. The values represent the mean ± SEM (n = 8 mice per group) *p < 0.05 versus CGP 37849, ^ p < 0.001 versus CDP, # p < 0.05 versus control (vehicle-treated group) (Bonferroni’s test)

Anxiolytic-like effect of joint administration of CDP and L-701,324 in the elevated plus-maze test

Chlordiazepoxide administered at a dose of 0.5 mg/kg did not alter the percentage of time spent and increased entries into the open arms (Fig. 2). L-701,324 given alone at a dose of 2 mg/kg exhibited no effect in this test (Fig. 2a, b). The joint administration of CDP and L-701,324 (both in ineffective per se doses) significantly increased the percentage of time spent in the open arms (Fig. 2a), but not in the number of entries into open arms (Fig. 2b). A two-way ANOVA demonstrated a significant effect of CDP [F(1, 28) = 7.66, p = 0.0099], a significant effect of L-701,324 [F(1, 28) = 9.65, p < 0.0043] and not quite significant interaction [F(1, 28) = 3.83, p = 0.0603] in the time spent in open arms, while a significant effect of CDP [F(1, 28) = 7.25, p = 0.0118], no effect of L-701,324 [F(1, 28) = 1.09, p = 0.3056] and not quite significant interaction [F(1, 28) = 3.77, p = 0.0622] in the open arm entries.
Fig. 2

Effect of joint administration of L-701,324 and chlordiazepoxide (CDP) in the elevated plus-maze procedure in mice [the percentage of the time spent in the open arms (a), and the percentage of the open arms entries (b)]. L-701,324 and CDP was administered i.p. 60 min before the test. The values represent the mean ± SEM (n = 8 mice per group) *p < 0.01 versus L-701,324, ^ p < 0.01 versus CDP, # p < 0.01 versus control (vehicle-treated group) (Bonferroni’s test)

Anxiolytic-like effect of joint administration of CDP and d-cycloserine in the elevated plus-maze test

Chlordiazepoxide administered at a dose of 0.5 mg/kg did not change either the percentage of the time spent (Fig. 3a) or the number of entries into open arms (Fig. 3b). d-Cycloserine administered singly at a dose of 2.5 mg/kg remained also without any effect on both of these measures (Fig. 3a, b). CDP administered at an ineffective per se dose of 0.5 mg/kg and d-cycloserine administered at such a dose of 2.5 mg/kg significantly increased the percentage of the time spent in the open arms (Fig. 3a) and enhanced the number of entries into open arms (Fig. 3b). A two-way ANOVA demonstrated a significant effect of CDP [F(1, 34) = 24.83, p < 0.0001], a significant effect of DCS [F(1, 34) = 8.73, p = 0.0057] and a significant interaction [F(1, 34) = 13.35, p = 0.0009] in the time spent in the open arms, while a significant effect of CDP [F(1, 34) = 19.50, p < 0.0001], a significant effect of DCS [F(1, 34) = 4.31, p = 0.0451] and no interaction [F(1, 34) = 2.93, p = 0.0956] in the open arm entries.
Fig. 3

Effect of joint administration of d-cycloserine (DCS) and chlordiazepoxide (CDP) in the elevated plus-maze procedure in mice [the percentage of the time spent in the open arms (a), and the percentage of the open arms entries (b)]. L-701,324 and CDP was administered i.p. 60 min before the test. The values represent the mean ± SEM (n = 9–10 mice per group) *p < 0.001 versus DCS, ^ p < 0.05, ^^ p < 0.001 versus CDP (Bonferroni’s test)

Effect of NMDA on the anxiolytic-like activity of CDP in the elevated plus-maze test

Chlordiazepoxide given at a dose of 2 mg/kg produced anxiolytic-like effect significantly increasing the percentage of the time spent in the open arms and increasing the percentage of the entries into the open arms (Fig. 4). The increase in percentage of the time spent in the open arms induced by CDP (2 mg/kg) was significantly reversed by NMDA (75 mg/kg) (Fig. 4a). The increase in the number of the open arm entries induced by CDP (2 mg/kg) was significantly decreased by NMDA (Fig. 4b). NMDA given alone had no effect on either the time spent or the entries into the open arms (Fig. 4). A two-way ANOVA demonstrated a significant effect of CDP [F(1, 36) = 45.98, p < 0.0001], a significant effect of NMDA [F(1, 36) = 21.37, p < 0.0001] and a significant interaction [F(1, 36) = 21.19, p < 0.0001] in the time spent in open arms, and a similarly significant effect of CDP [F(1, 36 = 15.87, p = 0.0003], a significant effect of NMDA [F(1, 36) = 8.11, p = 0.0072] and a significant interaction [F(1, 36) = 11.91, p = 0.0014] in the open arm entries.
Fig. 4

Effect of N-methyl-d-aspartate (NMDA) on the action of chlordiazepoxide (CDP) in the elevated plus-maze procedure in mice [the percentage of the time spent in the open arms (a) and the percentage of the open arms entries (b)]. NMDA and CDP was administered i.p. 60 min before the test. The values represent the mean ± SEM (n = 10 mice per group) *p < 0.001 versus CDP, # p < 0.001, versus control (vehicle-treated group) (Bonferroni’s test)

Effect of d-serine on the anxiolytic-like activity of CDP in the elevated plus-maze test

Chlordiazepoxide given at a dose of 2 mg/kg produced an anxiolytic-like effect significantly increasing the percentage of the time spent in the open arms and increasing the percentage of the entries into the open arms (Fig. 5). The increase in the percentage of the time spent in the open arms induced by CDP (2 mg/kg) was significantly reversed by d-serine (100 nmol/mouse) (Fig. 5a). The increase in the number of the open arm entries induced by CDP (2 mg/kg) was significantly changed by d-serine (Fig. 5b). d-Serine given alone had no effect on either the time spent or the entries into the open arms (Fig. 5). A two-way ANOVA demonstrated a significant effect of CDP [F(1, 33) = 23.80, p < 0.0001], a significant effect of d-serine [F(1, 33) = 18.49, p = 0.0001] and a significant interaction [F(1, 33) = 16.33, p < 0.0003] in the time spent in the open arms, while a significant effect of CDP [F(1, 33) = 4.97, p = 0.0321], no effect of d-serine [F(1, 33) = 2.93, p = 0.0957] and a significant interaction [F(1, 33) = 9.11, p = 0.0046] in the open arm entries.
Fig. 5

Effect of d-serine (DS) on the action of chlordiazepoxide (CDP) in the elevated plus-maze procedure in mice [the percentage of the time spent in the open arms (a), and the percentage of the open arms entries (b)]. CDP was administered i.p. 60 min before the test, DS was administered i.c.v. 45 min after CDP injection. The values represent the mean ± SEM (n = 9–10 mice per group) *p < 0.01, **p < 0.001 versus CDP, # p < 0.01, ## p < 0.001, versus control (vehicle-treated group) (Bonferroni’s test)

Effect of CDP and NMDA ligands on the total arm entries

Chlordiazepoxide and all tested NMDA receptor ligands, administered singly or in combination, did not alter the number of the total arm entries (Table 1). A two-way ANOVA demonstrated the lack of the significant interaction between treatments in all analyzed experiments A: F(1, 28) = 0.74, p = 0.3964, B: F(1, 28) = 0.53, p = 0.4723], C: F(1, 36) = 3.25, p = 0.0797, D: F(1, 36) = 2.59, p = 0.1164, E: F(1, 36) = 1.02, p = 0.3185.
Table 1

The number of the total arm entries for all experimental groups

Treatment and dose

Number of total entries

A

Vehicle

12.63 ± 0.46

CDP 0.5 mg/kg

12.00 ± 1.00

CGP 37849 0.312 mg/kg

13.25 ± 1.21

CDP 0.5 mg/kg and CGP 37849 0.312 mg/kg

14.75 ± 1.85

B

Vehicle

14.38 ± 1.75

CDP 0.5 mg/kg

15.75 ± 1.46

L-701,324 2 mg/kg

13.50 ± 1.04

CDP 0.5 mg/kg and L-701,324 mg/kg

16.75 ± 0.59

C

Vehicle

14.50 ± 0.74

CDP 0.5 mg/kg

11.44 ± 0.67

d-cycloserine 2.5 mg/kg

12.80 ± 0.70

CDP 0.5 mg/kg and d-cycloserine 2.5 mg/kg

12.00 ± 0.92

D

Vehicle

11.80 ± 1.07

CDP 2 mg/kg

15.30 ± 1.90

NMDA 75 mg/kg

13.20 ± 0.53

CDP 2 mg/kg and NMDA 75 mg/kg

12.80 ± 0.92

E

Vehicle

15.10 ± 1.65

CDP 2 mg/kg

19.30 ± 0.71

d-serine 100 nmol/mouse

12.40 ± 1.33

CDP 2 mg/kg and d-serine 100 nmol/mouse

17.40 ± 1.32

Data represent the mean ± SEM; n = 9–12. Chlordiazepoxide (CDP), CGP 37849, L-701,324, d-cycloserine and N-methyl-d-aspartate (NMDA) were administered i.p. 60 min before the test. d-serine was administered i.c.v. 15 min before the test

Discussion

A number of behavioral data have suggested the involvement of the glutamate-mediated neurotransmission in an anxiolytic-like behavior. The anxiolytic-like activity was demonstrated for different modulatory sites of NMDA receptor complex: for a non-competitive NMDA antagonist, dizocilpine (MK-801) (Dunn et al. 1989; Sharma and Kulkarni 1993; Karcz-Kubicha et al. 1997), a competitive NMDA antagonist, 2-amino-7-phosphoheptanoic acid (AP7) (Płaźnik et al. 1994), CGP 37849 (Przegaliński et al. 2000), and partial agonists of glycineB sites, d-cycloserine (Karcz-Kubicha et al. 1997) and 1-aminocyclo-propane-carboxylic acid (ACPC) (Trullas et al. 1989; Trullas et al. 1991), and antagonist of glycineB sites: L-701,324 (Karcz-Kubicha et al. 1997; Przegaliński et al. 1998; Kotlińska and Liljequist 1998). The anxiolytic-like profile of different NMDA antagonists was similar to that of benzodiazepines (Płaźnik et al. 1994) and the excitatory amino acid agonist, NMDA, produced anxiogenic-like effects in the elevated plus-maze test (Dunn et al. 1989). Moreover, genetic studies indicated an anxiolytic-like activity of NR2A subunit of NMDA receptor knockout mice (Boyce-Rustay and Holmes 2006). Validation of the elevated plus-maze procedure has shown that it is sensitive to drugs that produce anxiolytic or anxiogenic effects in human (Pellow et al. 1985), including drugs that have non-benzodiazepine sites of action (Pellow 1986). Moreover, in the clinical study showed useful of memantine (non-competitive NMDA receptor antagonist) augmentation in treatment-resistant obsessive–compulsive disorder (Feusner et al. 2009; Aboujaoude et al. 2009), d-cycloserine (partial agonists of glycineB sites) (Hood et al. 1989; Emmett et al. 1991) as a potential therapeutic agent for post-traumatic stress disorder and specific phobia (Heresco-Levy et al. 2002; Ressler et al. 2004), and riluzole in the treatment of symptoms obsessive–compulsive disorder (Coric et al. 2005) and general anxiety disorder (Mathew et al. 2005).

In the present study, we have demonstrated the influence of NMDA receptor ligands on anxiolytic-like activity of CDP in the elevated plus-maze in mice. We have shown that a competitive NMDA antagonist (CGP 37849), partial agonist of the glycineB site (d-cycloserine) and glycineB antagonist (L-701,324) enhanced the anxiolytic-like activity of CDP in the elevated plus-maze. The previous study has shown that CGP 37849 evoked potentially anxiolytic-like effects in the Vogel conflict drinking test, an open field test (Płaźnik et al. 1994) and in the elevated plus-maze test in rats and its anxiolytic-like activity was abolished by flumazenil (Przegaliński et al. 2000). In our study, 0.312 mg/kg CGP 37849 produced synergistic effects with CDP (0.5 mg/kg) in the elevated plus-maze test in mice. Unfortunately, the side effects produced by competitive and uncompetitive NMDA antagonist (motor impairment, hyperactivity, stereotypy and psychotomimetic actions (Willetts et al. 1990) limited their potential use for the treatment in humans. After the discovery that the NMDA receptor activity is regulated by co-agonist (glycine or d-serine), numerous studies concentrated on this pathway. It is known that a co-agonist site exerts major regulatory roles in the activity of NMDA receptor complex. The binding of the co-agonist (glycine or d-serine) is an obligatory requirement for NMDA receptor/channel activity (Johnson and Ascher 1987; Kleckner and Dingledine 1988). More recently, studies have shown that selective blockers of the co-agonist site abolish NMDA receptor activity (Kessler et al. 1989; Kleckner and Dingledine 1989) and produced pharmacological effects similar to those exerted after the administration of a competitive and non-competitive NMDA antagonist. d-Cycloserine has a profile of a partial agonist acting at the glycine binding site (Hood et al. 1989; Watson et al. 1990). In the preclinical data d-cycloserine exhibits anxiolytic-like effects in the Vogel conflict test (Kłodzińska and Chojnacka-Wójcik 2000), in the elevated plus-maze (time in open arms) (Karcz-Kubicha et al. 1997; Ho et al. 2005; Poleszak et al. 2008), and in a fear-potentiated startle response test (Anthony and Nevins 1993) (Campeau et al. 1992; Fendt et al. 1996). The glycineB receptor antagonist (L-701,324) has produced anxiolytic-like effects in the elevated plus-maze test and the four-plate test (Karcz-Kubicha et al. 1997; Przegaliński et al. 1998; Kotlińska and Liljequist 1998).

In our study, the combined treatment with CDP and L-701,324 (a glycineB site antagonist) or d-cycloserine (a glycine site partial agonist), all at low, ineffective doses, increased the time spent in the open arms of the elevated plus-maze, with no effects on the number of total entries (Table 1). Because the obtained data indicate a lack of effect on the locomotor activity, we can assume that this combination produced an anxiolytic-like activity. The anxiolytic-like activity of CDP was reduced by NMDA or by d-serine, what suggests the involvement of NMDA receptor complex in the anxiolytic activity of CDP in the elevated plus-maze in mice. The interaction between NMDA and GABAergic neurotransmission in anxiety assessments in animals was shown in other experiments. The anxiolytic-like activity of MK-801 was enhanced by diazepam, antagonized by the benzodiazepine receptor antagonist (Ro-15-1788) and reversed by the anxiogenic agent, β-carboline FG-7142 (Sharma and Kulkarni 1993).

To summarize, the present study indicates the involvement of the NMDA receptor complex in the anxiolytic-like activity of CDP in the EMP in mice. Our results also suggest that full anxiolysis might be possible with a reduced dose of benzodiazepines when co-administered with NMDA receptor antagonists and this might substantially reduce side effects and the risk of the benzodiazepine dependence. Clinical trials are necessary to determine if such a combination is of a potentially therapeutic value in humans with anxiety disorders.

Notes

Acknowledgments

This study was supported by Funds for Statutory Activity of Medical University of Lublin, Maria Curie-Skłodowska University, Lublin, Institute of Pharmacology, Polish Academy of Sciences, and Jagiellonian University Collegium Medicum, Kraków, Poland.

Conflict of interest

The authors declare they have no conflict of interest.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

  1. Aboujaoude E, Barry JJ, Gamel N (2009) Memantine augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial. J Clin Psychopharmacol 29:51–55PubMedCrossRefGoogle Scholar
  2. Abramowitz JS, Taylor S, McKay D (2009) Obsessive–compulsive disorder. Lancet 374:491–499PubMedCrossRefGoogle Scholar
  3. Amiel JM, Mathew SJ (2007) Glutamate and anxiety disorders. Curr Psychiatry Rep 9:278–283PubMedCrossRefGoogle Scholar
  4. Anthony EW, Nevins ME (1993) Anxiolytic-like effects of N-methyl-d-aspartate-associated glycine receptor ligands in the rat potentiated startle test. Eur J Pharmacol 250:317–324PubMedCrossRefGoogle Scholar
  5. Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31:2405–2414PubMedCrossRefGoogle Scholar
  6. Campeau S, Miserendino MJ, Davis M (1992) Intra-amygdala infusion of the N-methyl-d-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus. Behav Neurosci 106:569–574PubMedCrossRefGoogle Scholar
  7. Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, Saksa J, Wu YT, Gueorguieva R, Sanacora G, Malison RT, Krystal JH (2005) Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 58:424–428PubMedCrossRefGoogle Scholar
  8. Dunn RW, Corbett R, Fielding S (1989) Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur J Pharmacol 169:1–10PubMedCrossRefGoogle Scholar
  9. Emmett MR, Mick SJ, Cler JA, Rao TS, Iyengar S, Wood PL (1991) Actions of d-cycloserine at the N-methyl-d-aspartate-associated glycine receptor site in vivo. Neuropharmacology 30:1167–1171PubMedCrossRefGoogle Scholar
  10. Fendt M, Koch M, Schnitzler HU (1996) NMDA receptors in the pontine brainstem are necessary for fear potentiation of the startle response. Eur J Pharmacol 318:1–6PubMedCrossRefGoogle Scholar
  11. Feusner JD, Kerwin L, Saxena S, Bystritsky A (2009) Differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: an open-label trial. Psychopharmacol Bull 42:81–93PubMedGoogle Scholar
  12. Heresco-Levy U, Kremer I, Javitt DC, Goichman R, Reshef A, Blanaru M, Cohen T (2002) Pilot-controlled trial of d-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol 5:301–307PubMedCrossRefGoogle Scholar
  13. Ho YJ, Hsu LS, Wang CF, Hsu WY, Lai TJ, Hsu CC, Tsai YF (2005) Behavioral effects of d-cycloserine in rats: the role of anxiety level. Brain Res 1043:179–185PubMedCrossRefGoogle Scholar
  14. Hood WF, Compton RP, Monahan JB (1989) d-cycloserine: a ligand for the N-methyl-d-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett 98:91–95PubMedCrossRefGoogle Scholar
  15. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531PubMedCrossRefGoogle Scholar
  16. Kalueff A, Nutt DJ (1996) Role of GABA in memory and anxiety. Depress Anxiety 4:100–110PubMedCrossRefGoogle Scholar
  17. Karcz-Kubicha M, Jessa M, Nazar M, Plaźnik A, Hartmann S, Parsons CG, Danysz W (1997) Anxiolytic activity of glycine-B antagonists and partial agonists–no relation to intrinsic activity in the patch clamp. Neuropharmacology 36:1355–1367PubMedCrossRefGoogle Scholar
  18. Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated with N-methyl-d-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52:1319–1328PubMedCrossRefGoogle Scholar
  19. Kew JN, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl) 179:4–29CrossRefGoogle Scholar
  20. Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241:835–837PubMedCrossRefGoogle Scholar
  21. Kleckner NW, Dingledine R (1989) Selectivity of quinoxalines and kynurenines as antagonists of the glycine site on N-methyl-d-aspartate receptors. Mol Pharmacol 36:430–436PubMedGoogle Scholar
  22. Kłodzińska A, Chojnacka-Wójcik E (2000) Anticonflict effect of the glycineB receptor partial agonist, d-cycloserine, in rats. Pharmacological analysis. Psychopharmacology (Berl) 152:224–228CrossRefGoogle Scholar
  23. Kotlińska J, Liljequist S (1998) A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701, 324. Psychopharmacology (Berl) 135:175–181CrossRefGoogle Scholar
  24. Krystal JH, D’Souza DC, Petrakis IL, Belger A, Berman RM, Charney DS, Abi-Saab W, Madonick S (1999) NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv Rev Psychiatry 7:125–143PubMedGoogle Scholar
  25. Lipman JJ, Spencer PS (1980) Rapid intracerebroventricular injection assisted by an automatic syringe. J Pharmacol Methods 4:327–333PubMedCrossRefGoogle Scholar
  26. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl) 92:180–185Google Scholar
  27. Lydiard RB (2003) The role of GABA in anxiety disorders. J Clin Psychiatry 64(Suppl 3):21–27PubMedGoogle Scholar
  28. Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM (2005) Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 162:2379–2381PubMedCrossRefGoogle Scholar
  29. Nemeroff CB (2003) The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 37:133–146PubMedGoogle Scholar
  30. Nutt DJ, Malizia AL (2001) New insights into the role of the GABAA-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 179:390–396PubMedCrossRefGoogle Scholar
  31. Parsons CG, Danysz W, Quack G (1998) Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect 11:523–569PubMedCrossRefGoogle Scholar
  32. Pellow S (1986) Anxiolytic and anxiogenic drug effects in a novel test of anxiety: are exploratory models of anxiety in rodents valid? Methods Find Exp Clin Pharmacol 8:557–565PubMedGoogle Scholar
  33. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167PubMedCrossRefGoogle Scholar
  34. Płaźnik A, Pałejko W, Nazar M, Jessa M (1994) Effects of antagonists at the NMDA receptor complex in two models of anxiety. Eur Neuropsychopharmacol 4:503–512PubMedCrossRefGoogle Scholar
  35. Poleszak E, Szewczyk B, Kędzierska E, Wlaź P, Pilc A, Nowak G (2004) Antidepressant- and anxiolytic-like activity of magnesium in mice. Pharmacol Biochem Behav 78:7–12PubMedCrossRefGoogle Scholar
  36. Poleszak E, Wlaź P, Wróbel A, Fidecka S, Nowak G (2008) NMDA/glutamate mechanism of magnesium-induced anxiolytic-like behavior in mice. Pharmacol Rep 60:655–663PubMedGoogle Scholar
  37. Przegaliński E, Tatarczyńska E, Chojnacka-Wójcik E (1998) Anxiolytic- and antidepressant-like effects of an antagonist at glycineB receptors. Pol J Pharmacol 50:349–354PubMedGoogle Scholar
  38. Przegaliński E, Tatarczyńska E, Chojnacka-Wójcik E (2000) The influence of the benzodiazepine receptor antagonist flumazenil on the anxiolytic-like effects of CGP 37849 and ACPC in rats. Neuropharmacology 39:1858–1864PubMedCrossRefGoogle Scholar
  39. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61:1136–1144PubMedCrossRefGoogle Scholar
  40. Sharma AC, Kulkarni SK (1993) Evidence for benzodiazepine receptor interaction with MK 801 in anxiety related behaviour in rats. Indian J Exp Biol 31:191–193PubMedGoogle Scholar
  41. Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:181–234PubMedGoogle Scholar
  42. Sieghart W, Fuchs K, Tretter V, Ebert V, Jechlinger M, Hoger H, Adamiker D (1999) Structure and subunit composition of GABAA receptors. Neurochem Int 34:379–385PubMedCrossRefGoogle Scholar
  43. Stahl SM (2002) Don’t ask, don’t tell, but benzodiazepines are still the leading treatments for anxiety disorder. J Clin Psychiatry 63:756–757PubMedCrossRefGoogle Scholar
  44. Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167:127–135PubMedCrossRefGoogle Scholar
  45. Trullas R, Jackson B, Skolnick P (1989) Anxiolytic properties of 1-aminocyclopropanecarboxylic acid, a ligand at strychnine-insensitive glycine receptors. Pharmacol Biochem Behav 34:313–316PubMedCrossRefGoogle Scholar
  46. Trullas R, Folio T, Young A, Miller R, Boje K, Skolnick P (1991) 1-Aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models. Eur J Pharmacol 203:379–385PubMedCrossRefGoogle Scholar
  47. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999) International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. J Clin Psychopharmacol 19:23S–29SPubMedCrossRefGoogle Scholar
  48. Watson GB, Bolanowski MA, Baganoff MP, Deppeler CL, Lanthorn TH (1990) d-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res 510:158–160PubMedCrossRefGoogle Scholar
  49. Willetts J, Balster RL, Leander JD (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 11:423–428PubMedCrossRefGoogle Scholar
  50. Wood PL, Emmett MR, Rao TS, Mick S, Cler J, Iyengar S (1989) In vivo modulation of the N-methyl-d-aspartate receptor complex by d-serine: potentiation of ongoing neuronal activity as evidenced by increased cerebellar cyclic GMP. J Neurochem 53:979–981PubMedCrossRefGoogle Scholar
  51. Wood PL, Hawkinson JE, Goodnough DB (1996) Formation of d-serine from l-phosphoserine in brain synaptosomes. J Neurochem 67:1485–1490PubMedCrossRefGoogle Scholar

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© The Author(s) 2011

Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  • Ewa Poleszak
    • 1
    Email author
  • Katarzyna Socała
    • 2
  • Aleksandra Szopa
    • 1
  • Andrzej Wróbel
    • 3
  • Bernadeta Szewczyk
    • 4
  • Regina Kasperek
    • 1
  • Eliza Blicharska
    • 5
  • Gabriel Nowak
    • 4
    • 6
  • Piotr Wlaź
    • 2
    Email author
  1. 1.Department of Applied PharmacyMedical University of LublinLublinPoland
  2. 2.Department of Animal Physiology, Institute of BiologyMaria Curie-Skłodowska UniversityLublinPoland
  3. 3.Second Department of GynecologyMedical University of LublinLublinPoland
  4. 4.Department of Neurobiology, Institute of PharmacologyPolish Academy of SciencesKrakówPoland
  5. 5.Department of Analytical ChemistryMedical University of LublinLublinPoland
  6. 6.Department of CytobiologyJagiellonian University, Collegium MedicumKrakówPoland

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