Short communication
Involvement of NMDA receptors in
the antidepressant-like action of adenosine
Manuella P. Kaster1,3, Daniele G. Machado1, Adair R.S. Santos2, Ana Lúcia S. Rodrigues1
1Departamento de Bioquímica,2Laboratório de Neurobiologia da Dor e da Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil
3Laboratório de Neurociências Clínicas, Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas, Pelotas, RS, 96010-280, Brazil
Correspondence: Manuella P. Kaster, e-mail: manu.kaster@gmail.com
Abstract:
Background and Method: In this work, the contribution of NMDA receptors to the antidepressant-like effect of adenosine in the forced swimming test (FST) was investigated.
Results: The pretreatment of mice with NMDA or D-serine was able to prevent the anti-immobility effect of either adenosine or MK-801 in the FST. In addition, the administration of a sub-effective dose of adenosine produced a synergistic effect with sub- effective doses of MK-801, ketamine and zinc chloride. Moreover, the immobility time of the mice treated with active doses of adenosine or N6-cyclohexyladenosine (CHA) plus MK-801 was not significantly different from that obtained with adenosine, CHA and MK-801 alone; by contrast, the combination between active doses of adenosine and CHA plus an active dose of the tricyclic anti- depressant imipramine produced a greater effect in the FST than the administration of either drug alone.
Conclusion: Together, the results suggest that the effect of adenosine in the FST is likely dependent on the inhibition of NMDA receptors mediated by the activation of adenosine A1receptors.
Key words:
adenosine, forced swimming test, NMDA receptors, adenosine A1receptors
Abbreviations: cAMP – cyclic adenosine monophosphate, CHA – N6-cyclohexyladenosine, CNS – central nervous system, DPMA – N6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)-ethyl]- adenosine, FST – forced swimming test, icv – intracerebroven- tricular, ip – intraperitoneal, NMDA – N-methyl-D-aspartate, TST – tail suspension test
Introduction
Adenosine is a ubiquitous neuromodulator widely dis- tributed in the central nervous system (CNS) that is implicated in a variety of brain functions. Multiple
adenosine actions are mediated through adenosine re- ceptors, namely A1, A2A, A2Band A3[4, 8, 9]. These receptors are composed by seven transmembrane gly- coproteins coupled to G proteins. Adenosine A2Aand A2Breceptors are coupled to adenylate cyclase activ- ity, and their stimulation increases the intracellular cy- clic adenosine monophosphate (cAMP) concentra- tion. Alternatively, stimulation of adenosine A1 and A3 receptors decreases cAMP concentration and raises intracellular Ca2+levels by a pathway involv- ing phospholipase C activation [8]. Physiological ac- tions of adenosine in the CNS are mainly mediated by adenosine A1 and A2A receptors, since both are
widely expressed in the brain and bind adenosine at physiological concentrations [4, 8].
The involvement of the adenosinergic system in the pathophysiology of mood related disorders is strongly supported by its neuromodulatory role. Adenosine re- ceptors, especially A1and A2Areceptors, are capable of controlling the release of serotonin, corticotrophin and cortisol/corticosterone and glutamate. Adenosine can also modulate excitability in the hippocampus, a key region in the control of hypothalamic-pituitary- adrenal axis [8, 9].
Preclinical and clinical data have suggested that compounds that reduce transmission at N-methyl-D- aspartate (NMDA) receptors exhibit antidepressant properties and NMDA receptor abnormalities are ob- served in suicidal and depressed individuals [18, 20, 25]. In addition, Boyce-Rustay and Holmes [1]
showed that knockout mice for the NMDA receptor subunit NR2A exhibit an antidepressant-like behavior in the forced swimming test (FST) and tail suspension test (TST), as compared to wild-type controls. Finally, alterations in the NMDA receptor function that occur after an antidepressant treatment might be considered a general consequence of antidepressant therapy. Sev- eral studies demonstrated a reduction of NMDA re- ceptor reactivity and function after chronic treatment with antidepressants (both classical and atypical anti- depressants) or after electroconvulsive therapy [18].
It is known that postsynaptic or presynaptic activa- tion of adenosine A1 receptors is associated with the inhibition of NMDA receptor activation [4, 8]. We have demonstrated that acute administration of adeno- sine elicits an antidepressant-like effect in the FST in mice by a mechanism that involves an interaction with adenosine A1 and A2A receptors, L-arginine- nitric oxide pathway and K+ channels [10–13]. The aim of the present study was to investigate if NMDA receptors could represent one of the targets involved in the anti-immobility effect of adenosine in the FST in mice.
Materials and Methods
Animals
Male Swiss mice, weighing 30–40 g were maintained at 21–23°C with free access to water and food, under a 12:12 h light:dark cycle (lights on at 7:00 a.m.). All
manipulations were carried out between 9:00 and 16:00 h, with each animal used only once. All proce- dures in this study were performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The experiments were performed after the approval of the Institution’s Ethics Committee and all efforts were made to mini- mize animal suffering.
Drugs and treatment
Adenosine, N6-cyclohexyladenosine (CHA), imipramine, ketamine, MK-801, N-methyl-D-aspartate (NMDA), D-serine and zinc chloride (Sigma Chemical Co., USA) were used. All drugs were dissolved in saline and administered by intraperitoneal (ip) route in a constant volume of 10 ml/kg body weight, except NMDA and D-serine, which were administered by in- tracerebroventricular (icv) route in a volume of 5 µl/site. Briefly, icv administration was performed using a microsyringe (25 µl, Hamilton) connected to a 26-gauge stainless-steel needle that was inserted perpendicularly 2 mm deep through the mouse skull.
Under light ether anesthesia (i.e., just the necessary for the loss of the postural reflex), the needle was in- serted unilaterally 1 mm to the midline point equidis- tant from each eye, at an equal distance between the eyes and the ears and perpendicular to the plane of the mouse skull. A volume of 5 µl was then administered in the left lateral ventricle. The injection was given during 30 s, and the needle remained in place for an- other 30 s in order to avoid the reflux of the sub- stances injected [2, 10]. After completion of the ex- periments, all animals were decapitated and their brains were examined freshly. Results from mice pre- senting misplacement of the injection site or any sign of cerebral hemorrhage were excluded from the statis- tical analysis (overall less than 5% of the total number of animals used).
In order to verify the effect of NMDA receptor acti- vation in the antidepressant-like effect of adenosine, mice were treated according to the protocol described in Figure 1A. NMDA receptors were activated by the pretreatment of mice with NMDA (0.1 pmol/site, icv, a selective NMDA receptor agonist) or D-serine (57 mmol/site, icv, an agonist to the glycine site on the NMDA receptor). After 15 min, the animals received an active dose of adenosine (10 mg/kg, ip) or MK-801 (0.01 mg/kg, ip, a noncompetitive NMDA receptor antagonist, positive control) before being tested in the
NMDA receptors in the antidepressant-like effect of adenosine
Manuella P. Kaster et al.
FST 30 min later [2]. In order to verify the synergistic antidepressant-like effect of adenosine with NMDA receptor antagonists, mice were treated according to the protocol described in Figure 1B. A sub-effective dose of adenosine in the FST (1 mg/kg, ip) was given 20 min before the administration of sub-effective doses of ketamine (0.1 mg/kg, ip, a noncompetitive NMDA receptor antagonist) or zinc chloride (5 mg/
kg, ip, an inhibitor of NMDA receptor function). Due to the binding properties of MK-801, which only in- teracts with the activated NMDA receptor complex, in a site located within the channel pore, adenosine was co-administered with MK-801 (0.001 mg/kg, ip).
A further 20 min was allowed to elapse before the ani- mals were tested in the FST [22], Figure 1C.
In a separate series of experiments, we also investi- gated the effect of active doses of adenosine (10 mg/kg, ip), CHA (0.1 mg/kg, ip, an adenosine A1 receptor agonist), MK-801 (0.01 mg/kg, ip) and imi- pramine (15 mg/kg, ip, a tricyclic antidepressant), alone or in combination, in the immobility time in the FST. This protocol of treatment is described in Figure 1D and was performed in order to investigate a possi- ble additive effect of these compounds. MK-801 was injected 15 min earlier, whereas the other drugs were
injected 30 min earlier to the FST. The doses of the drugs used were selected based on literature data and have been previously reported not to increase locomo- tor activity in rodents [2, 7, 11, 22, 24]. Also, the ap- propriated vehicle groups were always assessed si- multaneously.
FST
Mice were individually forced to swim in an open cy- lindrical container (diameter 10 cm, height 25 cm), containing 19 cm of water at 25 ± 1°C; the total dura- tion of immobility during a 6 min test was scored as described previously [10]. Each mouse was judged to be immobile when it ceased struggling and remained floating motionless in the water, making only those movements necessary to keep its head above water.
Statistical analysis
Comparisons between experimental and control groups were performed by a one or two factor analy- sis of variance (ANOVA) followed by Newman- Keuls post-hoc comparison test when appropriate.
A value of p < 0.05 was considered to be significant.
Results
Figure 2 shows that the pretreatment of mice with NMDA (0.1 pmol/site, icv, panel A) or D-serine (57 mmol/site, icv, panel B) completely prevented (p < 0.01) the anti-immobility effect of adenosine (10 mg/kg, ip) or MK-801 (0.01 mg/kg, ip, positive control) in the FST. The results depicted in Figure 3 show that the administration of a sub-effective dose of adenosine (1 mg/kg, ip) produced a synergistic antidepressant-like effect with MK-801 (0.001 mg/kg, ip, panel A), ketamine (0.1 mg/kg, ip, panel B) or zinc chloride (5 mg/kg, ip, panel C) in the FST. Post-hoc analyses revealed that MK-801, ketamine and zinc chloride augmented the response to adenosine, since the immobility times in the adenosine/MK-801, adeno-
sine/ketamine or adenosine/zinc chloride groups were lower than in the groups treated with each drug alone.
Figure 4A shows the effects of adenosine (10 mg/kg, ip), MK-801 (0.01 mg/kg, ip) and imi-
NMDA receptors in the antidepressant-like effect of adenosine
Manuella P. Kaster et al.
Fig. 3. Effect of adenosine (1 mg/kg, ip) in potentiating the actions of sub-effective doses of MK-801 (0.001 mg/kg, ip, panel A), ketamine (1 mg/kg, ip, panel B) or zinc chloride (5 mg/kg, ip, panel C) in the FST. Values are expressed as the mean ± SEM (n = 6–8). ** p < 0.01 as compared with vehicle pretreated groups and with adenosine/ve- hicle groups. MK-801: [treatment F (1, 22) = 11.59, p < 0.01), pre- treatment (F (1, 22) = 4.89, p < 0.01) and of treatment ´ pretreatment interaction (F (1, 22) = 7.74, p < 0.01). Ketamine: [treatment [F (1, 22)
= 11.65, p < 0.01], pretreatment (F (1, 22) = 6.40, p < 0.05) and of treatment ´ pretreatment interaction (F (1, 22) = 4.46, p < 0.05)]. Zinc chloride: [treatment (F (1, 20) = 16.14, p < 0.01), pretreatment (F (1, 20) = 6.17, p < 0.05) and of treatment ´ pretreatment interaction (F (1, 20) = 5.12, p < 0.05)]
0 100 200 300
400 Vehicle NMDA
** **
# #
Vehicle Adenosine MK-801 A
Immobilitytime(s)
0 100 200 300
400 Vehicle D-serine
** **
# #
Vehicle Adenosine MK-801 B
Immobilitytime(s)
Fig. 2. Effect of pretreatment of mice with NMDA (0.1 pmol/site, icv, panel A) or with D-serine (57 mmol/site, icv, panel B) on the anti- immobility effect of adenosine (10 mg/kg, ip) or MK-801 (0.01 mg/kg, ip, positive control) in the FST. Values are expressed as the mean
± SEM (n = 6–10); ** p < 0.01 as compared with the vehicle-treated control; # p < 0.01 compared with the same group pretreated with ve- hicle. NMDA: [treatment (F(2,35) = 10.36, p < 0.01), pretreatment (F (1, 35) = 24.31, p < 0.01) and of treatment X pretreatment interac- tion (F (2, 35) = 10.82, p < 0.01)]. D-serine: [treatment (F (2, 38) = 12.31, p < 0.01), pretreatment [F (1, 38) = 27.69, p < 0.01] and of treatment X pretreatment interaction (F (2, 38) = 15.12, p < 0.01)]
pramine (15 mg/kg, ip), administered at doses that were previously shown to be active in the FST, alone or in combination, on the immobility time in the FST.
The results depicted in Figure 4B show the effects of CHA (0.1 mg/kg, ip) plus MK-801 (0.01 mg/kg, ip) and imipramine (15 mg/kg, ip), alone or in combina- tion, on the immobility time in the FST. Post-hoc comparisons revealed that the immobility time of mice treated with adenosine or CHA plus MK-801 was not significantly different from that obtained with adenosine, CHA or MK-801 alone; by contrast, ade- nosine or CHA plus imipramine, as well as MK-801 plus imipramine, had a greater effect in the FST than the administration of either drug alone.
Discussion
In the present study, we show that the antidepressant- like effect of adenosine in the FST, which was previ-
ously demonstrated by our group to be dependent on the interaction of adenosine with adenosine A1 and A2 receptors, is also dependent on the inhibition of NMDA receptors. The likely involvement of NMDA receptors in the anti-immobility effect of adenosine is supported by three sets of evidence: (i) the finding that NMDA and D-serine were able to prevent the anti- immobility effect of adenosine in the FST; (ii) the results showing that sub-effective doses of adenosine produced a synergistic antidepressant-like effect with NMDA receptors antagonists; (iii) both adenosine and the adenosine A1 receptor agonist CHA failed to produce an additive effect with MK-801 in the FST, suggesting an overlapping of pharmacological mechanisms in the antidepressant activity of these compounds.
The involvement of NMDA receptors in the antidepressant-like effect of adenosine is supported by the main finding of the present work: both NMDA and D-serine, administered at doses that produce neither convulsions nor excitotoxic damage [23], were able to prevent the anti-immobility effects of both adenosine and MK-801, the latter used as a positive control.
0 100
200 saline/MK-801
adenosine/MK-801 imipramine/saline adenosine/imipramine imipramine/MK-801
Immobilitytim
** **
**
# #
0 100 200
300 saline/saline
CHA/saline saline/MK-801 CHA/MK-801 saline/imipramine CHA/imipramine B
** ** ** **
#Immobilitytime(s)
Fig. 4. Effects of adenosine (10 mg/kg, ip, panel A), CHA (0.1 mg/kg, ip, panel B), MK-801 (0.01 mg/kg, ip) and imipramine (15 mg/kg, ip) alone or in combination on immobility time in the FST. Saline, imipramine, adenosine and CHA were administered 30 min before the test. MK-801 was administered 15 min before the test. Values are expressed as the mean ± SEM (n = 6–7). ** p < 0.01 as compared with the control group (vehi- cle); # p < 0.01 as compared with the groups treated with vehicle or with each drug alone. Fig. 4A: [treatment (F (6, 38) = 20.86, p < 0.01)], Fig. 4B: [treatment [F (5, 30) = 38.46, p < 0.01]
NMDA is a pharmacological agonist of NMDA recep- tors, whereas D-serine functions as an endogenous agonist for the glycine site of NMDA receptors.
D-amino acid oxidase, which degrades D-serine, markedly attenuates NMDA neurotransmission [17].
Recently, the work of Poleszak et al. [19] showed that glycine/NMDA receptor antagonists enhanced the antidepressant-like action of serotonin based antide- pressants.
In addition, we also show that the administration of sub-effective doses of adenosine produced a synergis- tic antidepressant-like effect with sub-effective doses of the NMDA receptor antagonists, MK-801, keta- mine and zinc chloride in the FST. Under these ex- perimental conditions, neither the NMDA receptor an- tagonists nor adenosine alone produced a behavioral response in the mouse FST. In contrast, in combina- tion, these behaviorally inactive treatments provoked a robust reduction in immobility time in this test, in- dicative of an antidepressant behavioral profile. This result indicates that adenosine and NMDA receptor antagonists may act in synergy to produce an antide- pressant effect, which suggests that the inhibition of these receptors by adenosine may be responsible, at least in part, by its effect in the FST. Indeed, MK-801 and ketamine are two well-known noncompetitive NMDA receptor antagonists, and zinc chloride binds to an inhibitory site on the NMDA receptors [3].
Moreover, several studies report that these antagonists exhibit antidepressant-like properties in the FST and TST at doses that do not alter the locomotor activity [7, 15, 16, 19, 22, 26]. MK-801 also mimics the effect of antidepressants in reversing the reduction in su- crose consumption produced by chronic mild stress and is also effective in other animal models such as TST, foot shock-induced fighting behavior in chroni- cally stressed rats and the olfactory bulbectomy model of depression [18]. Ketamine has been shown to be effective in the FST [22]. Interestingly, an acute administration of ketamine was able to ameliorate chronic unpredictable stress-induced anhedonic be- havior in rats [14]. Also, ketamine was reported to cause a significant improvement in depressive symp- toms after infusion in depressed patients, causing a significant reduction in scores on the Hamilton De- pression Rating Scale and is particularly relevant for antidepressant-resistant patients [25].
Another piece of evidence suggesting that the inhi- bition of NMDA receptors may underlie the anti- depressant-like effect of adenosine is given by our re- sults showing the absence of additive effects on im-
mobility time in mice treated with an active dose of MK-801 after prior administration of an active dose of adenosine. These data reinforce the idea that adenosine exerts its antidepressant-like effects by blocking NMDA receptor activation, thus preventing the action of MK-801. This hypothesis is based on the knowledge that MK-801 binds to the activated NMDA receptor complex, interacting with a site lo- cated within the NMDA channel pore. As previously reported by our group and others, the dose of MK-801 used in this set of experiments (0.01 mg/kg, ip) is able to decrease the immobility time of mice in the FST without inducing ataxia, stereotyped behavior or hyperlocomotion [6, 7, 22]. Only doses higher than 0.025 mg/kg were described to induce hyperlocomo- tion in mice [6].
Our data also show that the administration of active doses of adenosine (or MK-801) plus imipramine pro- duced an additive effect with an active dose of MK- 801 in the FST. Indeed, Maj et al. [15] described that the antidepressant-like effect of MK-801 combined with the tryciclic antidepressant imipramine is higher than any of these compounds given alone. Since imi- pramine acts primarily modulating serotonin/nora- drenaline levels in the brain, the additive effect ob- served in this study could be the result of overlapping pharmacological effects of compounds acting by dif- ferent mechanisms (NMDA receptors blockade and serotonin/noradrenaline reuptake inhibition). These results are similar to previous data obtained by our group with GMP, agmatine and zinc chloride, com- pounds that produce antidepressant-like effects in the FST through a mechanism dependent on the blockade of NMDA receptors [7, 22, 26].
The involvement of adenosine A1 receptors in the proposed adenosine-mediated NMDA receptor inhibi- tion was also suggested by the absence of additive ef- fects on immobility time in mice treated with MK-801 after prior administration of the A1 agonist CHA.
These results may be due to the fact that the admini- stration of these agonists blocked the NMDA receptor activation, thus preventing the binding of MK-801 at the NMDA receptor. There are several pieces of evi- dence showing that adenosine A1receptors are able to modulate responses via NMDA receptors. The activa- tion of adenosine A1 receptors, pre- or postsynapti- cally, is well established to decrease glutamate re- lease, hyperpolarize the cell membrane, and thus in- hibit NMDA receptor activation [4, 8].
NMDA receptors in the antidepressant-like effect of adenosine
Manuella P. Kaster et al.
A1 receptors and inhibition of L-arginine-NO-cGMP pathway [11, 12]. It is important to highlight that the NO signalling pathway was also reported to be in- volved in the antidepressant-like effect of MK-801 in the mouse FST [6]. In the brain, NO is produced mainly in postsynaptic structures as a response to the activation of NMDA receptors [5], thus, the inhibition of NMDA receptor activation by adenosine could lead to a consequent inhibition of L-arginine-NO-cGMP pathway. Moreover, K+channels are one of the major downstream targets regulated by the activation of the L-arginine-NO pathway. These results are also in ac- cordance with the interaction between these channels and adenosine, which was shown to produce a syner- gistic antidepressant-like effect with several K+chan- nel blockers [10], an effect that might be a reflection of its action on NMDA receptors as well. The neuro- modulatory effects of adenosine are quite complex and we could not rule out an interaction between NMDA receptor blockade and the potentiation of the serotonergic system in its antidepressant-like effect.
Adenosine interacts with the serotonergic system, es- pecially with 5-HT1Areceptors and potentiates the ef- fect of fluoxetine in the FST [13]. Altogether, the re- sults further reinforce the notion that functional an- tagonists of the NMDA receptor are as effective as antidepressants [18].
Conclusion
In summary, our study extends literature data regard- ing the antidepressant-like action of adenosine pre- senting, for the first time, pharmacological evidence of the involvement of NMDA receptors, dependent on the activation of adenosine A1 receptors, in its anti- depressant-like activity. These results further contrib- ute to the understanding of the mechanism of action of adenosine and reinforce the role of NMDA recep- tors and adenosine A1 receptors in the pathophysiol- ogy of depression.
Acknowledgment:
This study was supported by CNPq and CAPES, Brazil.
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Received: September 28, 2011; in the revised form:
January 31, 2012; accepted: February 14, 2012.
NMDA receptors in the antidepressant-like effect of adenosine
Manuella P. Kaster et al.
