Introduction
Depression is a chronic recurring illness that affects more than 120 million people worldwide. In industrialized societies, approximately five percent of the population experienced a major depressive episode. It is considered that symptoms of depression result from perturbations in monoaminergic neurotransmission. Thus, drugs currently used for treatment of depression include medications that modulate monoaminergic neurotransmission, primarily serotonin and noradrenaline pathways. Unfortunately, their efficacies are unsatisfactory, they produce multiple unwanted side effects and the mechanism of their antidepressant action remains not entirely elucidated (Hollister and Csernansky
1990). Moreover, these drugs require at least 2–4 weeks to produce a clinically meaningful improvement in depressive symptomatology (Rosenzweig-Lipson et al.
2007); therefore, novel therapeutic strategies are sought.
Over the past 20 years, numerous data demonstrated that
N-methyl-
d-aspartate (NMDA) receptors may be involved in the mechanism of action of antidepressant treatment (Skolnick et al.
1996; Skolnick
1999; Skolnick et al.
2009). In addition, significantly higher serum and plasma levels of glutamate in patients with depression than those of healthy controls were reported (Kim et al.
1982; Altamura et al.
1993; Mauri et al.
1998; Nowak et al.
2003; Mitani et al.
2006; Siwek et al.
2009). Moreover, increased levels of glutamate in the frontal cortex were demonstrated, implicating abnormality of glutamatergic neurotransmission in the pathophysiological features of major depressive disorder (Sanacora et al.
2004).
Extensive studies have shown that competitive and noncompetitive NMDA receptor antagonists, polyamine site antagonists and inorganic inhibitors of NMDA receptor function, zinc and magnesium, produced antidepressant-like activity in preclinical antidepressant screening procedures (Trullas and Skolnick
1990; Maj et al.
1992a,
b; Moryl et al.
1993; Maj et al.
1994; Layer et al.
1995; Kroczka et al.
2000,
2001; Nowak et al.
2003; Poleszak et al.
2004; Nowak et al.
2006; Szewczyk et al.
2008; Siwek et al.
2009). Furthermore, an antagonist of the NMDA receptor complex, ketamine, and memantine are effective in human depression (Berman et al.
2000; Zarate et al.
2006a,
b). Moreover, CP-101, 606 (a selective antagonist of NR2B subunit of the NMDA receptor) and zinc (non specific antagonist of NMDA receptor) enhance efficacy of antidepressant therapy in major depression (especially treatment resistant subtype) (Nowak et al.
2003; Preskorn et al.
2008; Siwek et al.
2009). However, it should be mentioned that there is a discrepancy between long-term effects of ketamine in clinical observations and experimental paradigms used to evaluate antidepressant activity (e.g., Maeng et al.
2008; Popik et al.
2008; Bechtholt-Gompf et al.
2011).
Unfortunately, both competitive and noncompetitive NMDA antagonists induce severe side effects (Willetts et al.
1990) that limit their applicability as antidepressants for clinical use in humans. Thus, an alternative strategy to the use of competitive and noncompetitive NMDA antagonist was modulation of the glycine co-agonist site at the NMDA receptor (Kemp and Leeson
1993).
Numerous behavioral studies have shown that antagonists and partial agonists at the glycine site exhibit antidepressant-like activity in experimental screening procedures (Trullas and Skolnick
1990; Przegaliński et al.
1997; Vamvakides
1998). Consequently, in this study, we assessed the effects of two glycine B receptor ligands, namely L-701,324 (antagonist) and
d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice.
Discussion
A growing amount of data supports the role of the excitatory glutamatergic neurotransmission in the pathophysiology of depressive disorders. In the clinical studies, disturbances of the glutamate level in depressed patients were found (Mathis et al.
1988; Altamura et al.
1993; Levine et al.
2000). The brain NMDA receptor abnormalities in human suicide victims (Nowak et al.
1995) and major depressives (Law and Deakin
2001; Karolewicz et al.
2005; Feyissa et al.
2009; Karolewicz et al.
2009) were observed. Moreover, a noncompetitive NMDA antagonist, ketamine, produced rapid and sustained antidepressant effects in depressed patients (Berman et al.
2000; Zarate et al.
2006a; Phelps et al.
2009; Price et al.
2009), as well as reports that riluzole, which inhibits glutamate release, is effective in patients with bipolar depression (Zarate et al.
2004,
2005). Recently, the antidepressant effect of NR2B subunit antagonist, traxoprodil (CP-101, 606) was demonstrated in patients unresponsive to a serotonin selective reuptake inhibitor (Kemp and McKernan
2002; Preskorn et al.
2008).
Numerous reports from preclinical studies have documented the antidepressant-like activity of structurally diverse NMDA receptor antagonists in animal behavioral paradigms. Thus, NMDA channel blockers (dizocilpine), a competitive antagonist of NMDA receptor (AP-7, CGP 37848), a polyamine site antagonist (eliprodil), divalent-cation antagonists (Mg
2+, Zn
2+) and a glycine site antagonist (L-701,324), and partial agonist (DCS) were all active in the FST (Skolnick et al.
1989; Trullas and Skolnick
1990; Kroczka et al.
2001; Paul and Skolnick
2003; Poleszak et al.
2004,
2005a). Additionally, the glycine partial agonist 1-aminocyclopropanecarboxylic acid (ACPC) produced a more rapid onset of action in the chronic mild stress model than it was typically observed for biogenic-amine-based agents (Papp and Moryl
1996).
The glycine binding site is the regulatory domain of the NMDA receptor complex with affinity for the endogenous ligands, glycine (or
d-serine, another endogenous agonist of the glycine site) (Wood et al.
1989,
1996). Activation of this site by glycine or
d-serine is absolutely required for NMDA receptor activation by
l-glutamate (Kemp and Leeson
1993). It was proved that glycine receptor antagonists and partial agonists have favorable safety profile compared with competitive and noncompetitive NMDA receptor antagonists (Hawkinson et al.
1997; Danysz and Parsons
1998; Bordi et al.
1999; Beardsley et al.
2002) making them a potential candidates for new antidepressant drugs (Kemp and Leeson
1993; Danysz and Parsons
1998).
In the experimental screening procedures, both full glycine antagonist (L-701,324) and partial agonists at the glycine site (ACPC, DCS) exhibit activity comparable to that of clinically used antidepressants (Trullas and Skolnick
1990; Przegaliński et al.
1997; Vamvakides
1998). In mice the effective dose of L-701,324 in this test was 2 mg/kg (Przegaliński et al.
1998), which was confirmed in our previous study (Poleszak et al.
2007a). DCS, a partial agonist of glycine site of the NMDA receptor complex (Hood et al.
1989) was also active in the FST (an effect comparable to that observed with IMI (Vamvakides
1998). Its antidepressant-like activity was first shown in tuberculosis patients (Kendig et al.
1956; Lewis et al.
1957) and provides indirect support for the hypothesis that glycine site partial agonists may be potentially useful as antidepressants (Trullas and Skolnick
1990; Skolnick et al.
1992). As partial agonist DCS may act as agonist or antagonist of the glycine B receptor depending on the dose, that is, a lower dose acts as agonist but higher doses act as antagonist of glycine binding site of the NMDA receptor (Hood et al.
1989; Watson et al.
1990; Emmett et al.
1991). In our previous study, the effective dose of DCS in the FST was the dose 5 mg/kg, while the lower dose (2.5 mg/kg) was not effective itself, but potentiated the antidepressant effects of magnesium or zinc (Poleszak et al.
2007b; Szewczyk et al.
2010).
In the present study, we have demonstrated the effects of glycine site ligands (L-701,324 and DCS) on the action of antidepressants with different pharmacological profiles: IMI—a nonselective serotonin/noradrenaline reuptake inhibitor (Westenberg
1999), FX—a selective serotonin reuptake inhibitor (SSRI) (Rickels and Schweizer
1990) and RB—a potent, selective, and specific noradrenergic reuptake inhibitor (NARI) (Versiani et al.
1999). L-701,324 and DCS given with RB (administered in subeffective doses) did not change the behavior of animals in the forced swim test, the behavioral despair procedure commonly used to detect antidepressant agents (Borsini and Meli
1988). However, a potentiating effect was seen when both tested glycine site ligands were given jointly with IMI or FX in this test. This apparent potentiation was manifested as a reduction of the immobility time, but no increase in locomotor activity was evidenced. Similarly, such interaction was demonstrated between ionic NMDA antagonists zinc and magnesium with antidepressants in the FST (Poleszak
2007; Szewczyk et al.
2009).
In the present study, in order to confirm a possible contribution of the serotonergic system to the antidepressive effect of DCS and L-701,324, mice were pretreated with p-CPA, an inhibitor of serotonin synthesis or with DSP-4, a selective noradrenergic neurotoxin, and examined in the FST. The lesion of noradrenaline nerve terminals produced by DSP-4 did no alter the baseline activity or influence antidepressant-like action caused by L-701,324 or DCS. The depletion of serotonin by p-CPA did not alter baseline activity in the FST; however, completely antagonized the antidepressant-like action caused by L-701,324 and DCS. Thus, we proved that interaction with serotonergic, but not noradrenergic system is necessary for antidepressant-like activity of glycine/NMDA site ligands.
Our recent study has demonstrated that the activation of the NMDA receptor complex by
d-serine blocks the antidepressant-like effect of an antagonist of the glycine/NMDA receptor L-701,324 and ionic antagonists, such as zinc and magnesium, in the FST (Poleszak et al.
2007a,
b,
2008). Now we show that the antidepressant-like effects of IMI, FX and RB were abolished by
d-serine pretreatment. Thus, these data indicate that antidepressant activity of both serotonin and noradrenaline-based antidepressant are related to the mechanism connected with a reduction of the activity of the NMDA receptor complex (particularly glycine/NMDA sites). Contrary to this notion, Boulay et al. (
2008) demonstrated the antidepressant-like action of glycine transporter type 1 inhibitor SSR103800 which may indicate that activation of glycine/NMDA receptor is related to an antidepressant activity. However, the glycine/NMDA receptor dependence of the antidepressant-like action of SSR103800 in the FST was not demonstrated (e.g., antagonism by glycine/NMDA antagonists). The discrepancy between present data and that of Boulay et al. (
2008) may also be due to the use of different species (mice vs. rats, gerbils). The interaction between NMDA receptor and serotonergic pathway is more obvious than NMDA receptor and noradrenergic one (Yan et al.
1997). There is emerging evidence that the interaction between excitatory amino acids and serotonin may be important for the control of many brain activities. Both NMDA and non-NMDA receptor antagonists have been found to release serotonin and to increase its turnover in some brain structures (Löscher et al.
1993).
To summarize, the present study demonstrates complex interaction between glycine/NMDA receptor ligands and conventional serotonin/noradrenaline-based antidepressants in the FST. While glycine/NMDA receptor functional antagonists enhance an antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and their such activity depends on serotonin but not noradrenaline pathway, the antidepressant-like activity of both types of antidepressants rely on the dampening of the NMDA receptor complex. This study may provide some guidelines about how to optimally use combinations of the NMDA receptor antagonists and biogenic amine-based antidepressant drugs. The NMDA receptor antagonists as antidepressants may be on the near horizon, and the ability to use lower doses of, e.g., traxoprodil when combined with the appropriate agent may be an interesting approach to antidepressant therapy.