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Possible Involvement of Nitric Oxide (NO) Signaling Pathway in the Anti- Depressant-Like Effect of MK-801(Dizocilpine), a NMDA R

Possible Involvement of Nitric Oxide (NO) Signaling Pathway in the Anti- Depressant-Like Effect of MK-801(Dizocilpine), a NMDA R

Indian Journal of Experimental Biology Vol. 46, March 2008, pp 164-170

Possible involvement of (NO) signaling pathway in the anti- depressant-like effect of MK-801(), a NMDA in mouse forced swim test

Ashish Dhir & SK Kulkarni* Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India

Received 27 November 2007; revised 15 January 2008

L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) is an important signaling pathway involved in depression. With this information, the present study aimed to study the involvement of this signaling pathway in the -like action of MK-801 (dizocilpine; N-methyl-d-aspartate receptor antagonist) in the mouse forced-swim test. Total immobility period was recorded in mouse forced swim test for 6 min. MK-801 (5-25 μg/kg., ip) produced a U- shaped curve in reducing the immobility period. The antidepressant-like effect of MK-801 (10 μg/kg, ip) was prevented by pretreatment with L-arginine (750 mg/kg, ip) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, ip) [a specific neuronal nitric oxide synthase inhibitor] produced potentiation of the action of subeffective dose of MK-801 (5 μg/kg, ip). In addition, treatment of mice with (10 mg/kg, ip) [direct inhibitor of both nitric oxide synthase and soluble guanylate cyclase] potentiated the effect of MK-801 (5 μg/kg, ip) in the forced-swim test. Further, the reduction in the immobility period elicited by MK-801 (10 μg/kg, ip) was also inhibited by pretreatment with sildenafil (5 mg/kg, ip) [phosphodiesterase 5 inhibitor]. The various modulators used in the study and their combination did not produce any changes in locomotor activity per se and in combination with MK-801. MK-801 however, at higher doses (25 μg/kg, ip) produced hyperlocomotion. The results demonstrated the involvement of nitric oxide signaling pathway in the antidepressant-like effect of MK-801 in mouse forced-swim test. Keywords: Cyclic guanosine monophosphate, Forced-swim test, L-arginine, Nitric oxide, MK-801 (dizocilpine), Phosphodiesterase 5 inhibitor

An abnormality in glutamate function has been )4. Also, Berman et al.5 reported the implicated in the neural substrate of depressive first -controlled, double-blind study assessing disorders1,2. Glutamate injected into the nucleus the therapeutic effects of a single infusion dose of accumbens dose-dependently decrease swimming in unipolar depression. time in forced-swim test2. An extensive library of MK-801 [(+)-5-methyl-10, 11-dihydro-5H-dibenzo noncompetitive N-methyl-d-aspartate (NMDA) [a, d] cyclohepten-5, 10-imine maleate)] or antagonists (e.g., MK-801 or dizocilpine, , dizocilpine, a potent, noncompetitive antagonist of the ketamine) that reduce transmission at NMDA receptor6 have been extensively studied for the NMDA receptor have demonstrated use in treatment of diseases with excitotoxic antidepressant-like effects in animal models, components, such as stroke, traumatic brain injury, including forced-swim and tail suspension tests, and neurodegenerative diseases such as Huntington's, inescapable stressors, and in learned helplessness3. An Alzheimer's, and amyotrophic lateral sclerosis. It has acute administration of (novel NMDA shown effectiveness in protecting neurons in cell receptor antagonist) enhanced the antidepressant-like culture and animal models of excitotoxic neuro- effect of ( antidepressant), degeneration7-9. Studies have also demonstrated the fluoxetine (selective reuptake inhibitor), or antidepressant effect of MK-801 in various animal (dual reuptake inhibitor of serotonin and models of despair10. Although the antidepressant-like —————— effect of MK-801 in various animal models of *Correspondent author depression have been reported, little is known Telephone: +91-172-2534114, 2541142 concerning its possible . Fax: +91-172-2541142 L-arginine-nitric oxide (NO)-cyclic guanosine E-mail: [email protected] DHIR & KULKARNI: MK-801 & NITRIC OXIDE MODULATION 165

monophosphate (cGMP) is an important signaling standard laboratory conditions and maintained on pathway that is reported to be involved in natural light and dark cycle, and had free access to depression11. Nitric oxide, a messenger molecule in food and water. Animals were acclimatized to the brain, synthesized from L-arginine by nitric oxide laboratory conditions before the experiment. Each synthase (NOS), have been implicated in animal was used only once. All the experiments were neurotransmission, synaptic plasticity, learning, carried out between 0900 and 1500 hrs. The perception of , aggression and depression12. experimental protocols were approved by the Recent evidences have shown that the reduction of Institutional Animal Ethics Committee (IAEC) and nitric oxide levels within the hippocampus can induce conducted according to the Indian National Science antidepressant-like effects, thus implicating Academy (INSA) Guidelines for the use and care of endogenous hippocampal nitric oxide in the experimental animals. neurobiology of stress and depression13. Several of physiological actions of nitric oxide are mediated Experimental Procedure- through its interaction with the of soluble Forced Swim Test (FST)—The test procedure was guanylate cyclase (sGC), leading to enzyme activation carried out according to the method described by 14 and consequent increase in cGMP . It is proposed Porsolt20 and validated in the laboratory21-25. In brief, that, in response to activation of the NMDA receptor, mice were individually forced to swim inside a nitric oxide is synthesized from L-arginine by rectangular glass jar (25 ×12 × 25 cm3 containing 15 12,15 NOS . Various studies have shown the possibility cm of water maintained at 23˚-25˚ C). After the initial that various NOS inhibitors can be used as a strategy 2-3 min of vigorous activity the animals showed to enhance the antidepressant effect of various drugs period of immobility by floating with minimum including memantine (non-competitive NMDA movements. An animal is considered to be immobile 16 receptor antagonist) . However, none of the studies whenever it remained floating passively in the water have explored the involvement of nitric oxide in a slightly hunched but upright position, its nose signaling pathway in the antidepressant-like effect of above the water surface. The total immobility time for 17 MK-801. In a recent study, Dhir and Kulkarni have the period of 6 min was recorded with the help of demonstrated the involvement of L-arginine-nitric stop-watch23. oxide-cGMP signalling pathway in mediating the Measurement of locomotor activity— antidepressant activity of venlafaxine in mouse Locomotor activity (ambulations) was measured forced-swim test. It was suggested that NOS- by using a computerized actophotometer inhibitors when administered prior to venlafaxine (IMCORP, India). An array of 16 infrared treatment enhances its antidepressant action. emitter, detector pairs measured animal activity Similarly, the importance of nitric oxide signaling along a single axis of motion, the digital data pathway has been elucidated in the antidepressant 18 being displayed on the front panel meters as action of , a reuptake inhibitor ambulatory movements. Mice were allowed to or berberine chloride, an alkaloid obtained from 19 acclimatize to the observation chamber for a Berberis aristata . Since nitric oxide pathway is period of 2 min. Locomotion was expressed in involved in the pathophysiology of depression, the terms of total photobeams counts per 5 min per present study has been undertaken to investigate the animal26,27. participation of the L-arginine-NO-cGMP signaling Drugs and treatment—The following drugs pathway in the antidepressant-like effect of an acute were used: MK-801 (Sigma Chemicals, MO, USA), administration of MK-801 in the mouse forced-swim L-arginine (Loba-Chemie, Mumbai, India), methylene test. blue (S.D.-fine Chem Ltd., Gujarat, India), 7- nitroindazole (7-NI) (Tocris Bioscience, Missouri, Materials and Methods USA), and sildenafil (Panacea Biotec, New Delhi, Animals—Male albino mice (Laca strain) weighing India). All the drugs were dissolved in 0.9% w/v between 22-30 g bred in Central Animal House NaCl except 7-nitroindazole which was (CAH) facility of the Panjab University, Chandigarh, dissolved in few drops of Tween 80 and volume India were used. The animals were housed under was adjusted with distilled water. The doses of 166 INDIAN J EXP BIOL, MARCH 2008

the drugs used and time duration were selected shaped curve in reducing the immobility period in according to the previous studies28 and as reported in mouse FST. MK-801 (5 and 10 μg/kg, ip) did not the literature16,18,21,29. Different doses were alter the locomotor activity in mice (Table 1). administered ip in a fixed volume of 1 ml/100g However, MK-801 at higher dose (25 μg/kg, ip) body weight 30 min before the animals were increased the locomotor activity as evident from subjected to test. The possible participation of the increase in ambulatory movements [F=5.459, P<0.05] L-arginine-NO-cGMP pathway in the antidepressant (Table 1). A dose of 10 μg/kg, ip (dose effective in effect of MK-801 was investigated. Mice were forced-swim test and not affecting locomotor activity) pretreated with L-arginine, a precursor of nitric oxide or 5 μg/kg, ip (dose ineffective in forced-swim test (750 mg/kg, ip, a dose that does not affect the and also not affecting locomotor activity) was chosen immobility period as compared to vehicle treatment for carrying out drug interaction studies. group), or vehicle. After 30 min, L-arginine, MK-801 Effect of pretreatment with various nitric oxide (10 μg/kg, ip, a dose active in the forced-swim test modulators on the antidepressant-like activity of MK- and having no effect on the locomotor activity) or 801—Pretreatment with a subeffective dose of L- vehicle was injected and 30 min later animals were arginine (750 mg/kg, ip, NO precursor) reversed the subjected to forced-swim test. In another set of antidepressant action of MK-801 (10 μg/kg, ip) as experiments, the synergistic effect of MK-801 (5 shown by an increase in immobility period compared μg/kg, ip, a subeffective dose) was investigated with a to MK-801 (10 μg/kg, ip) per se group (Fig. 2A). A subeffective dose of 7-nitroindazole (25 mg/kg ip, a two-way ANOVA revealed significant differences of specific neuronal nitric oxide synthase inhibitor) or pretreatment [F (1, 20) = 67.89, P < 0.001], treatment methylene blue (10 mg/kg, ip, an inhibitor of NOS [F (1, 20) = 86.41, P < 0.001] and of pretreatment × synthase and an inhibitor of sGC). These modulators treatment interaction [F (1, 20) = 176.09, P < 0.001] were administered 30 min before MK-801 or vehicle on immobility period in the forced swim test. Post hoc and 30 min later challenged with forced-swim test. analyses indicated that the antidepressant-like effect Further in another set, mice received an injection of of MK-801 (10 μg/kg, ip) was prevented by sildenafil (5 mg/kg, ip, phosphodiesterase 5 inhibitor) pretreatment of animals with L-arginine. or vehicle 30 min before MK-801 (10μg/kg, ip). After In contrast, 7-nitroindazole (25 mg/kg, ip, a 30 min of MK-801 administration, the animals were specific nNOS inhibitor) enhanced the antidepressant subjected to forced-swim test. The same drug Table 1—Effect of MK-801 and its interaction with L-arginine, treatment schedule was followed while measuring the 7-nitroindazole, methylene blue or sildenafil on the mean locomotor activity in mice. Different group of animals ambulatory movements in mice were taken for both tests. Statistical analysis—Results are expressed as mean (sec.) ± S.E and the data were analyzed using One- Way or Two-Way Analysis of Variance (ANOVA) where appropriate. If any statistically significant change was found, post-hoc comparisons were performed using a Dunnett’s test. P<0.05 was considered statistically significant.

Results Effect of pretreatment of MK-801 in mouse Forced Swim test—MK-801, in a dose range of 10 and 25

μg/kg, ip, produced a decrease in immobility period with respect to vehicle control group in forced-swim Fig. 1—Effect of different doses of MK-801 (5, 10, 25 μg/kg, ip) test (Fig. 1) [F=31.681, P<0.001]. However, the effect on the mean immobility period in mouse forced-swim test (FST). was not dose dependent. MK-801 at the lower dose (5 The values are expressed as mean ± SE (n = 6–8). Data were analyzed by One Way Analysis of Variance (ANOVA) followed μg/kg, ip) was ineffective in decreasing the by Dunnett’s test. P* values: < 0.001 compared with the vehicle- immobility period in mice in forced-swim test treated control. a < 0.01 compared with the MK-801 (10 μg/kg, ip) (Fig. 1). MK-801 (5-25 μg/kg, ip) produced a U- group. DHIR & KULKARNI: MK-801 & NITRIC OXIDE MODULATION 167

[Values are mean±SE] revealed significant differences of pretreatment [F (1, 20) = 6.13, P < 0.05], treatment [F (1, 20) = 6.13, P < S. Treatment Dose Mean 0.05] and of pretreatment × treatment interaction [F No. (mg/kg, ip) ambulatory movement (1, 20) = 6.55, P < 0.05] on immobility period in the forced swim test. Post hoc analyses indicated that the 1 Vehicle — 215 ± 20.3 antidepressant-like effect of MK-801 (5 μg/kg., ip) 2 MK-801 5 μg/kg 235.5 ± 33.5 was enhanced by pretreatment of animals with 7- 10 μg/kg 245 ± 7.07 nitroindazole. Methylene blue (10 mg/kg ip, direct inhibitor of 25 μg/kg 327 ± 13.7* both NOS and sGC) did not affect the immobility 3 L-arginine 750 226 ± 11.8 period per se. However, methylene blue significantly 4 L-arginine 750 + 218± 28.8 enhanced the antidepressant effect of subeffective + MK-801 10μ g/kg dose of MK-801 (5 μg/kg., ip) [F= 41.522, P<0.001] 5 7-nitroindazole 25 248 ± 10.0 (Fig. ). A two-way ANOVA revealed significant 6 7-nitroindazole 25 + 5 μg/kg 249 ± 23.1 differences of pretreatment [F (1, 20) = 79.96, P < + MK-801 0.001], treatment [F (1, 20) = 57.92, P < 0.001] and of 7 Methylene blue 10 238.3 ± 15.4 pretreatment × treatment interaction [F (1, 20) = 8 Methylene blue + 10 + 5 μg/kg 219.9 ± 13.6 60.72, P < 0.001] on immobility period in the forced MK-801 swim test. Post hoc analyses indicated that the 9 Sildenafil 5 229.6 ± 19.9 antidepressant-like effect of MK-801 (5 μg/kg, ip) was enhanced by pretreatment of animals with 10 Sildenafil + MK-801 5 + 10 μg/kg 230.6 ± 33.6 methylene blue. *P < 0.001 compared with the vehicle-treated control (One way Figure 2 D shows the effect of pretreatment with ANOVA followed by Dunnett’s test) sildenafil (5 mg/kg, ip, a PDE5 inhibitor). Sildenafil effect of subeffective dose of MK-801 (5 μg/kg, ip) did not affect immobility period per se, but [F=5.111, P<0.05] (Fig. 2B). A two-way ANOVA pretreatment with sildenafil reversed the

Fig. 2—Effect of MK-801 (5 or 10 μg/kg, ip) and its modulation by (A) L-arginine (750 mg/kg, ip), (B) 7-nitroindazole (25 mg/kg, ip), (C) methylene blue (10 mg/kg, ip), (D) sildenafil (5 mg/kg, ip) on the immobility period (sec) induced by FST. The values are mean ± SE (n = 6–8). Data were analyzed by One Way Analysis of Variance (ANOVA) followed by Dunnett’s test. Various and antagonists were administered 30 min before MK-801 and after 30 min of MK-801 injection, mice were challenged to FST. (A) P* values: < 0.001 compared with the vehicle-treated control; ** < 0.001 compared with the same group pretreated with vehicle (B) ** < 0.05 compared to 7-NI per se group (C) ** < 0.001 compared to methylene blue per se group (D) * < 0.001 compared to sildenafil per se group. ** < 0.001 compared with the same group pretreated with vehicle. 168 INDIAN J EXP BIOL, MARCH 2008

antidepressant effect of MK-801 (10 μg/kg, ip) dose causing statistically significant reduction, and [F=53.701, P<0.001]. A two-way ANOVA revealed higher doses causing no alteration in the immobility significant differences of pretreatment [F (1, 20) = time respectively33. The dose of L-arginine (750 48.45, P < 0.001], treatment [F (1, 20) = 15.24, P < mg/kg, ip) was chosen as it did not affect the 0.001] and of pretreatment × treatment interaction [F immobility period in the forced swim session and also (1, 20) = 14.52, P < 0.001] on immobility period in did not alter the locomotor activity. the forced swim test. Post hoc analyses indicated that The fluoxetine suppressed the dependence and the antidepressant-like effect of MK-801 (10 μg/kg, development of tolerance to the antinociceptive effect ip) was prevented by pretreatment of animals with of morphine34. Fluoxetine-induced suppression was sildenafil. potentiated by N (G)-nitro-L-arginine methyl ester (L- Combination of all the nitric oxide modulators with NAME) and accentuated by L-arginine, thus MK-801 did not affect the locomotor activity of mice demonstrating NO modulation of drug effects34. 7- (Table 1). nitroindazole, a specific neuronal NOS inhibitor and methylene blue, a direct inhibitor of both NOS and Discussion soluble guanylate cyclase (sGC), reduces the L-arginine- nitric oxide (NO)-cyclic guanosine immobility time in FST28. The effect is comparable to monophosphate (cGMP) is an important signaling standard antidepressant like imipramine35, 36. These pathway that has been recently implicated in studies argue for the possibility of inhibition of NO depression. In the present study, the antidepressant- synthase could be a strategy to enhance the clinical like effect of MK-801 was attenuated by pretreatment efficacy of . The involvement of nitric with L-arginine and the action of subeffective dose of oxide signaling pathway has been demonstrated in the MK-801 was potentiated by various NOS inhibitors. antidepressant activity of venlafaxine, a dual reuptake Another important observation of the study was the inhibitor of serotonin and norepinephrine17, reversal of antidepressant-like action of MK-801 by bupropion, a dopamine reuptake inhibitor18 and sildenafil (phosphodiesterase 5 inhibitor). The present berberine chloride, an alkaloid obtained from Berberis study for the first time demonstrated the involvement aristata21. of L-arginine-NO-cGMP pathway in the In the present study, it was observed that MK-801 antidepressant-like effect of an acute administration of produced reduction in immobility period in FST in MK-801 in the forced-swim test (FST). mice. The dose response curve obtained was infact U- Nitric oxide (NO) plays a significant neuro- shaped, lower doses (10 μg/kg) decreasing the modulatory role in the central nervous system (CNS). immobility period more as compared to higher doses Any pharmacological manipulation of NO pathway (25 μg/kg). MK -801 at lower doses (5 and 10 μg/kg) may be considered as a novel therapeutic approach for did not produce any alterations in the locomotor the management of CNS disorders, more so for activity while at higher doses (25 μg/kg), it produced mental depression30. Several in vivo studies have hyperlocomotion. However, for further interaction shown a modulatory role of NO in the extracellular studies, higher dose of MK 801 (25 μg/kg, ip) was levels of serotonin (5-HT) re-uptake mechanism in the discarded and instead lower doses (5 and 10 μg/kg, CNS31. Further, it was proposed that, in response to ip) were used. This biphasic response obtained is in activation of the NMDA receptor, NO is synthesized accordance with the results obtained by Belozertsava from L-arginine by nitric oxide synthase (NOS) and et al.37, who have demonstrated similarly the biphasic elicits depressive episodes. On the contrary, various response with 3-ethyl-2-methyl-quinolin-6-yl) - (4 - NOS inhibitors and NMDA receptor antagonists have methoxy - cyclohexyl) - methanone methane- been reported to possess antidepressant-like sulfonate, metabotropic antagonist, behavioral properties16,32. These effects are dose- in mouse FST. From this, it can be argued that the dependent and stereoselective and can be reversed by antidepressant-like effect is not dependent on any co-treatment with the NO precursor, L-arginine16. L- alterations in the locomotor activity. Pretreatment of arginine is reported to exert a U-shape effect in the L-arginine resulted in the reversal of the forced swim test, doses ranging from 30, 100 to 1000 antidepressant action of MK-801 as shown by mg/kg with lower dose causing no alteration, middle increased in immobility period. On the contrary, various nitric oxide synthase inhibitors enhanced the DHIR & KULKARNI: MK-801 & NITRIC OXIDE MODULATION 169

antidepressant action of MK-801 in mouse forced- stress and death after 4-aminopyridine-induced epilepsy, Eur swim test. J Neurosci, 22 (2005) 3067. Thus, these results indicate that the inhibition of 8 Kocaeli H, Korfali E, Ozturk H, Kahveci N & Yilmazlar S, MK-801 improves neurological and histological outcomes NO synthesis may underlie the reduction in the after spinal cord ischemia induced by transient aortic cross- immobility time in the FST elicited by MK-801. clipping in rats, Surgical Neurology, 64 (2005) S22. Another interesting observation of the present 9 Mukhin A G, Ivanova S A, Knoblach S M & Faden A I, New study was the reversal of the antidepressant-like effect in vitro model of traumatic neuronal injury: Evaluation of of MK-801 by sildenafil, a PDE5 inhibitor38. This secondary injury and glutamate receptor-mediated neurotoxicity, Neurotrauma, 14 (1997) 651. indicates that MK-801 exerts its effect in the FST 10 Maj J, Rogoz Z & Skuza G, The effects of combined probably by decreasing cGMP levels. The treatment with MK-801 and antidepressant drugs in the intracellular cGMP concentrations are regulated not forced swimming test in rats, Polish Pharmacol, 44 (1992) only by sGC, but also by PDE5, which catalyses the 217. hydrolysis of the second messengers cAMP and 11 Mantovani M, Pertile R, Calixto J B, Santos A R & cGMP to yield AMP and GMP, respectively39. The Rodrigues A L, exerts an antidepressant-like effect in the tail suspension test in mice: evidence for duration and magnitude of NO-induced cGMP signal involvement of N-methyl-D-aspartate receptors and the L- is determined by the activity of PDE5. PDE5 is arginine-nitric oxide pathway, Neurosci Lett, 343 (2003) 1. expressed in several brain areas, particularly in the 12 Esplugues J V, NO as a signalling molecule in the nervous neurons of the Purkinje cell layer in the cerebellum system, Brit J Pharmacol, 135 (2002) 1079. and in the pyramidal neurons of the hippocampus40. 13 Joca S R & Guimaraes F S, Inhibition of neuronal nitric Taken together, the present study concluded the oxide synthase in the rat hippocampus induces antidepressant-like effects, Psychopharmacology (Berl), 185 involvement of L-arginine-nitric oxide (NO)- cyclic (2006) 298. GMP (cGMP) signaling pathway in the 14 Kaster M P, Ferreira P K, Santos A R S & Rodrigues A L S, antidepressant-like effect of MK-801, a NMDA Effect of potassium channel inhibitors in the forced receptor antagonist in the forced swimming test in swimming test: Possible involvement of L-arginine-nitric mice. Moreover, these findings support the notion that oxide-soluble guanylate cyclase pathway, Behavioural Brain Res, 165 (2005) 204. the inhibition of nitric oxide production in the brain 15 Contestabile A, Roles of NMDA receptor activity and nitric may be critical to the action of antidepressants. oxide production in brain development, Brain Res Rev, 32 (2000) 476. References 16 Almeida R C, Felisbino C S, Lopez M G, Rodrigues A L S 1 Paul I A & Skolnick P, Glutamate and Depression, Ann NY & Gabilan N H, Evidence for the involvement of L-arginine- Acad Sci, 1003 (2003) 250. nitric oxide-cyclic guanosine monophosphate pathway in the 2 Rada P, Moreno S A, Tucci S, Gonzalez I E, Harrison T, antidepressant-like effect of memantine in mice, Behavioural Chau D T, Hoebel B G & Hernandez L, Glutamate release in Brain Res, 168 (2006) 318 the nucleus accumbens is involved in behavioral depression 17 Dhir A & Kulkarni S K, Involvement of L-arginine-nitric during the porsolt swim test, Neuroscience, 119 (2003) 557. oxide-cyclic guanosine monophosphate pathway in the 3 Papp M & Moryl E, Antidepressant activity of non- antidepressant-like effect of venlafaxine in mice, Prog competitive and competitive NMDA receptor antagonists in Neuropsychopharmacology Biological Psychiatry, 31 (2007) a chronic mild stress model of depression, Eur J Pharmacol , 921. 263 (1994) 1. 18 Dhir A & Kulkarni S K, Involvement of nitric oxide (NO) 4 Kos T, Legutko B, Danysz W, Samoriski G & Popik P, signaling pathway in the antidepressant action of bupropion Enhancement of antidepressant-like effects but not brain- a dopamine reuptake inhibitor, Eur Pharmacol, 568 (2007) derived neurotrophic factor mRNA expression by the novel 177. N-methyl-D-aspartate receptor antagonist neramexane in 19 Dhir A & Kulkarni S K, Involvement of Dopamine mice, J Pharmacol Exp Ther, 318 (2006) 1128. (DA)/serotonin (5-HT)/ Sigma (σ) receptor modulation in 5 Berman R M, Cappiello A, Anand A, Oren D A, Heninger G mediating the antidepressant action of R, Charney D S & Krystal J H, Antidepressant effects of hydrochloride a D2/D3 dopamine receptor , Brain ketamine in depressed patients, Biol Psychiatry, 47 (2000) Research Bulletin, 74 (2007) 58. 351. 20 Porsolt R D, Anton G, Blavet N & Jalfre M, Behavioural

6 Wong E H, Kemp J A, Priestley T, Knight A R, Woodruff G despair in rats: a new model sensitive to antidepressant N, Iversen L L, The MK-801 is a potent N- treatments, Eur Pharmacol, 47 (1978) 379. methyl-D-aspartate antagonist, Proc Natl Acad Sci USA, 83 21 Kulkarni S K & Dhir A, Possible involvement of L- (1986) 7104. Arginine-nitric oxide (NO)-cyclic guanosine monophosphate

7 Ayala G X & Tapia R, N-methyl-D-aspartate receptor (cGMP) signaling pathway in the antidepressant activity of blockade rescues hippocampal neurons from excitotoxic berberine chloride, Eur Pharmacol, 569 (2007) 77. 170 INDIAN J EXP BIOL, MARCH 2008

22 Kulkarni S K & Dhir A, Effect of various classes of (2003) 616. antidepressants in behavioural paradigms of despair, Prog 32 Wegener G, Volke V, Harvey B H & Rosenberg R, Local Neuropsychopharmacology Biological Psychiatry, 31 (2007) but not systemic administration of serotonergic 1248. antidepressants decreases hippocampal nitric oxide synthase 23 Kulkarni S K & Mehta A K, Purine nucleoside-mediated activity, Brain Res, 959 (2003) 128. immobility in mice: reversal by antidepressants, 33 Ergun Y & Ergun U G, Prevention of pro-depressant effect Psychopharmacology (Berl) 85 (1985) 460. of l-arginine in the forced swim test by N(G)-nitro-l-arginine 24 Parale M P & Kulkarni S K, Clonidine-induced behavioural and [1H-[124]Oxadiazole[43-a]quinoxalin-1-one], Eur despair in mice: Reversal by antidepressants, Pharmacol, 554 (2007)150. Psychopharmacology, 89 (1986) 171. 34 Singh V P, Jain N K & Kulkarni S K, Fluoxetine suppresses 25 Reddy DS, Kaur G & Kulkarni SK, Sigma (sigma1) receptor tolerance and dependence: modulation of NO- mediated anti-depressant-like effects of neurosteroids in the cGMP/DA/serotoninergic pathways, Methods Find Exp Clin Porsolt forced swim test, Neuroreport, 9 (1998) 3069-3073. Pharmacol, 25 (2003) 273. 26 Dhir A & Kulkarni S K, Involvement of sigma (σ ) receptors 1 35 Volke V, Wegener G, Bourin M & Vasar E, Antidepressant- in modulating the antidepressant effect of neurosteroids and anxiolytic-like effects of selective neuronal NOS ( or pregnenolone) in mouse tail- inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice, suspension test, Psychopharmacol, (In Press). Behav Brain Res, 140 (2003) 141. 27 Dhir A, Naidu P S & Kulkarni S K, Protective effect of 36 Eroglu L & Caglayan B, Anxiolytic and antidepressant cyclooxygenase-2 (COX-2) inhibitors but not non-selective properties of methylene blue in animal models, Pharmacol cyclooxygenase (COX)-inhibitors on withdrawal- Res 36 (1997) 381. induced behavioral changes, Biology, 10 (2005) 329. 37 Belozertseva I V, Kos T, Popik P, Danysz W & Bespalov A 28 Patil C S, Singh V P & Kulkarni S K, Peripheral and central Y, Antidepressant-like effects of mGluR1 and mGluR5 activation of nitric oxide-cyclic GMP pathway by sildenafil, antagonists in the rat forced swim and the mouse tail Inflammopharmacology, 13 (2005) 467. suspension tests, Eur Neuropsychopharmacol, 17 (2007) 29 Harkin A, Connor T J, Burns M P & Kelly J P, Nitric oxide 172. inhibitors augment the effects of serotonin re-uptake 38 Kulkarni S K & Patil C S, Phosphodiesterase 5 enzyme and inhibitors in the forced swimming test, Eur its inhibitors: update on pharmacological and therapeutical Neuropsychopharmacol, 14 (2004) 274. aspects, Methods Find Exp Clin Pharmacol, 26 (2004) 789. 30 Heiberg I L, Wegener G & Rosenberg R, Reduction of 39 Denninger J W & Marletta M A, Guanylate cyclase and the cGMP and nitric oxide has antidepressant-like effects in the NO/cGMP signaling pathway, Biochim Biophys Acta, 1411 forced swimming test in rats, Behavioural Brain Res, 134 (1999) 334. (2002) 479. 40 Bender A T & Beavo J A, Specific localized expression of 31 Harkin A, Connor T J, Walsh M, St John N & Kelley J P, cGMP PDEs in Purkinje neurons and macrophages, Serotonergic mediation of the antidepressant-like effects of Neurochemistry International, 45 (2004) 853. nitric oxide synthase inhibitors, Neuropharmacology, 44

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