Effect of Combination of Ketanserin and Escitalopram on Behavioral Anomalies After Olfactory Bulbectomy: Prediction of Quick Onset of Antidepressant Action

Research Article

Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: Prediction of quick onset of antidepressant action

Dilip K. Pandey, Shvetank Bhatt1, Ankur Jindal1, Baldev Gautam1

ABSTRACT

Objectives: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly Department of Pharmacology, prescribed antidepressant drugs. The addition of low dose of 5-hydroxytryptamine Novel Drug Discovery and type 2A enhances the therapeutic effect of SSRIs. The purpose of the present studies Development, Lupin Ltd, Research was to test the effects of combined treatment of a low dose of ketanserin (KET) and Park, Nanded Village, Pune, escitalopram (ESC) on behavioral anomalies occurring after olfactory bulbectomy (OBX). Maharashtra, 1Department of Materials and Methods: Chronic Depression was induced by OBX as shown in Pharmacy, FD-III, Birla Institute of Technology and Science, Pilani, behavioral tests such as Open fi eld, social interaction, and hyperemotionality tests. Rajasthan, India Acute and chronic treatment effect of KET, ESC, and combination was administered to the OBX rats. Received: 21-02-2014 Results: Chronic (14 days) treatment with KET (1 mg/kg) or ESC (10 mg/kg) Revised: 02-09-2014 alleviated the behavioral anomalies of olfactory bulbectomized rats in modifi ed open Accepted: 18-10-2014 fi eld exploration, social interaction, hyperemotionality. When KET treatment was combined with ESC, a short duration regimen (7 days) was suffi cient to reverse the Correspondence to: bulbectomy-induced anomalies. Dr. Dilip K. Pandey, Conclusion: The combination therapy as a likely strategy to achieve an early-onset of E-mail: [email protected] antidepressant action.

KEY WORDS: Antidepressant action, escitalopram, ketanserin, olfactory bulbectomy

Introduction receptors due to prolonged 5-HT exposure. The evidence of neuronal metabotropic 5-hydroxytryptamine type 2A (5-HT ) Antidepressants are the third most frequently prescribed 2A receptors in the assumed correlates of depression, specifically, therapeutic agents worldwide.[1] Selective serotonin re-uptake inhibitor (SSRI) are the most extensively used of all the hippocampus, amygdala, prelimbic prefrontal cortex, striatum, [3,4] antidepressants. Serotonin transporter blockade is the most and olfactory structures has supported the role of these common pharmacological action shared by SSRIs (SSRIs; receptors in rodent’s depression-like behavior and in human depression. Several antidepressants down-regulate 5-HT e.g., citalopram, escitalopram (ESC), fluoxetine, sertraline), 2A adopted for management of mood and anxiety disorders. The receptors after chronic treatment, supporting the role of [5] major shortcomings in treating depression with SSRIs are 5-HT2A receptors in antidepressant action. The paradoxical, that the therapeutic response develops slowly (3-4 week), the antagonist-induced desensitization and down-regulation of [5] side-efiects that often occur and that there is a significant 5-HT2A receptors and the regulatory effects of this receptor percentage (30%) of nonresponders.[2] The mechanism on brain-derived neurotrophic factor pathway[6] are known behind the delay of onset could be the desensitization of to have interesting implications in the depression pathology. Interestingly, it has been shown that SSRIs increase, whereas Access this article online tricyclic antidepressants decrease, binding of ligands to the [7] Quick Response Code: 5-HT2A receptor. More recently, the 5-HT2C receptor has been Website: www.ijp-online.com shown to augment the increase in extracellular 5-HT with SSRIs DOI: 10.4103/0253-7613.144935 in microdialysis, and in 5-HT2C knockout mice, there was an augmented antidepressant effect with the administration of SSRIs as compared to their wild-type counterparts.[8] Surprisingly, despite the numerous rodents models of depression, there are few animal models currently competent

Indian Journal of Pharmacology | December 2014 | Vol 46 | Issue 6 639 Pandey, et al.: Combination effect of Ketanserin and escitalopram on OBX induced behaviour anomalies of detecting a faster onset of antidepressant action over was done after each behavioral ESC based on the treatment another.[9] Along with faster antidepressants, rodent’s schedule [Table 1], The doses of standard antidepressants were model to assess quick antidepressant action is prerequisite. selected from the pilot studies conducted in our laboratory.[12] Henceforth, in the current study, olfactory bulbectomy (OBX) All administrations and behavioral assessments were done in rats has been adopted as the animal model to evaluate between 10 and 15 h and to avoid bias, all observations were the early onset of antidepressant in combination therapy[9] carried out by trained experimenters. using ketanserin (KET) and ESC; as OBX requires chronic Olfactory Bulbectomy antidepressant treatment before a change is detected in the Surgery attenuation of hyperactivity. Bilateral OBX was performed as described by Kelly Materials and Methods et al. and Ramamoorthy et al.[13,14] In brief rats (220-240 g) were anesthetized using combination of xylazine and Animals ketamine (5 and 75 mg/kg, i.p.). The animals were fixed in a Male Wistar rats (180-200 g) were obtained from Hissar stereotactic frame (Inco, India) and the skull was exposed by Agricultural University, Haryana, India. All animals were a midline incision and burr holes (2 mm in diameter) were maintained under standard laboratory conditions (12 h light/ drilled 8 mm anterior to bregma and 2 mm on either side of dark cycle [lights on at 7:00 AM]; temperature 23°C ± 2°C; the midline at a point corresponding to the posterior margin relative humidity; 60% ± 5%) in the Central Animal Facility. of the orbit of the eye. The olfactory bulbs were removed by Rats were given sterilized food (standard pellet chow feed) suction, the holes were then filled with hemostatic sponge in and filtered water ad libitum. Following a quarantine period order to control excessive bleeding, and the scalp was sutured. of 2 weeks, the experiment was started. The experiments Sham-operated rats were treated in a similar manner, including on animal were performed in accordance with the protocol piercing of the dura mater, but their bulbs were left intact. To approved by the Institutional Animal Ethics Committee (IAEC) of avoid postsurgical infection, the animals were given Sulprim Birla Institute of Technology and Science, Pilani, India (Protocol injection (each ml containing 200 and 40 mg of sulphadiazine No. IAEC/RES/12/01). and trimethoprim respectively), intramuscularly (0.2 ml/300 g) Drugs once a day for 2 days, post-surgery. The OBX/Sham animals Escitalopram was procured from Glenmark laboratory as were housed singly in cages. generous gift samples, Mumbai, India. KET tartrate (KET), a Open field behavior [10] preferential 5-HT2A receptor antagonist was purchased from The open field exploration was conducted as described Sigma-Aldrich chemicals private limited, New Delhi. Ketamine by Kelly et al. and Ramamoorthy et al.[13,14] with substantial and Xylazine injection were obtained from Neon Lab and Indian modifications. The apparatus consisted of a circular (90-cm Immunological Mumbai, India, respectively. All the drugs were diameter) arena with 75-cm high aluminum walls and floor dissolved in sterile distilled water and were freshly prepared equally divided into 10 cm squares. A 60 W light bulb was for use. In OBX rat model of depression, KET (1 mg/kg)/Vehicle/ positioned 90 cm above the base of the arena, which was ESC (10 mg/kg) was administered once a day orally for 7 or the only source of illumination in the testing room. Each 14 days to OBX/sham rats, after post-surgical rehabilitation animal was individually placed in the center of the open period (14 days). The surgery, rehabilitation, treatment, and field apparatus, and the following parameters were noted behavioral assessment in the OBX study were done according for 5 min. Ambulation scores (number of squares crossed), to a schedule[11] with slight variation [Table 1], adopted for Thigmotaxis (movement at corner of the apparatus) and our laboratory. The animals were subjected to behavioral the number of rearing episodes were noted as horizontal assessment 20 h after drug/vehicle administration. The drug and vertical activity, respectively. After each experiment, treatment was continued until 23rd/30th day and to avoid the the apparatus was sprayed with dilute alcohol and wiped direct effect of treatment on behavior, drug administration thoroughly to eliminate the residual odor.

Table 1:

Schedule of treatments and behavioral assessments on OBX and sham-operated rats

Day 0 0th-1st day 1st-14th day 15th-21st day 22nd-24th day Behavioral assessments (drug treatment was continued) Surgery Recovery Rehabilitation period Drug/vehicle treatment Modifi ed open fi eld Social interaction Hyper-emotionality from surgery (daily handling and (once a day for 7 days) exploration paradigm behavior (continuous care) observation) Day 0 0th-1st day 1st-14th day 15th-28th day 29th-31st day Behavioral assessments (drug treatment was continued) Surgery Recovery Rehabilitation period Drug/vehicle treatment Modifi ed open fi eld Social interaction Hyper-emotionality from surgery (daily handling and (once a day for 14 days) exploration paradigm behavior (continuous care) observation) OBX = Olfactory bulbectomy

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Rationale: Measurement of Hyperactivity Reflects by the Bonferroni for multiple comparisons. The criterion for a Psychomotor Effect statistically significant difference was fixed to P < 0.05. Social interaction test Results The present protocol was adapted from File and Hyde[15] and performed with slight modification. The apparatus and testing Effects of Escitalopram and Ketanserin on Behavior of environment was similar to that of an open field test except Olfactory Bulbectomy Rats a milder (40 W) illumination. On the day of the test, rat pairs As shown in Table 2, OBX rats exhibited significant increase of the same group housed in different cages were put into two in ambulation (F7,40 = 30.25, P < 0.05), rearing (F7,40 = 45.23, different corners of the open field arena. The social interaction P < 0.05), thigmotaxis (F7,40 = 14.69, P < 0.05), and behavior including the running toward, probing, grooming, defecation (F7,40 = 12.90, P < 0.05) as compared to sham mounting, and crawling under the other rat were recorded for treatment in modified open field paradigm. Chronic (14 days) 10 min after placement of the animals into the apparatus. After treatment with ESC (10 mg/kg) and KET (1 mg/kg) significantly each test, the apparatus was sprayed with dilute alcohol and reduced the ambulation, Thigmotaxis and rearing in OBX rats wiped thoroughly to eliminate the residual odor. as compared to vehicle treated OBX rats. OBX rats treated Rationale: Simulation of Human Social Behavior with ESC (10 mg/kg) and KET (1 mg/kg) exhibited decreased defecation in addition to the decrease in ambulation and Hyperemotionality number of rears. Such an effect was significant when compared The procedure reported in the literature Shibata to lone vehicle, ESC or KET treatments. In the sub-chronic [16] et al. was adopted with slight alterations. Hyperemotionality treatment schedule (7 days), except for the ESC + KET-1, which of rats was measured by scoring the responses to the following significantly decreased the ambulation (F7,40 = 24.82, P < 0.05), stimuli: (1) Bite response: Bite response is scored by a rod rearing (F = 14.52, P < 0.05), Thigmotaxis (F = 8.05, presented 4-5 cm in front of the snout, (2) startle response: 7,40 7,40 P < 0.05and fecal pellets (F7,40 = 8.59, P < 0.05) as compared Startle response to a stream of air directed at the dorsum was to the vehicle treated group and all other treatments fall short scored. The air was delivered using 5-ml syringe, (3) struggle to show any significant reversal of abnormal behavior anomalies response: Struggle response was scored by handling with a in OBX rats [Table 2]. gloved hand (struggle response), and (4) fight response: Fight In the hyper-emotional behavior paradigm assessment, response was scored by the tail pinching with a forceps. The rat it was found that OBX rats showed enhanced emotional tail is gently held from the back of a rat using blunt forceps. The behavior compared to sham treatment [Table 3]. Such an responses were graded as: 0, no reaction; 1, slight; 2, moderate; effect was significantly (F7,40 = 46.52, P < 0.05) reduced by 3, marked; or 4, extreme response. For each emotional response, chronic ESC (10 mg/kg)/KET (1 mg/kg)/ESC + KET treatments audible vocalization were also scored and graded as follows, 0, no compared to vehicle treatment. However, while observing the vocalization; 1, occasional vocalization; or 2, marked vocalization. data from 7 days treatment, it is evident that the combination The vocal score was added to each emotional response score. of ESC + KET significantly (F7,40 = 13.72, P < 0.05) reduced All animals in each group were observed in 1 day. The score for the total hyperemotionality score compared to vehicle-treated each animal in emotional response was given within 5 min. The OBX rats. None of the other treatments significantly changed observers were blind with respect to the drug treatment. 7th day hyperemotionality scores [Table 3]. The drug treatments Statistical Analysis did not conspicuously influence the behavior of sham animals All analysis was performed using Graph Pad Prism 5 for in any of the paradigms mentioned above. windows (GraphPad Software). The results are expressed as Social interaction pattern revealed that OBX rats mean ± standard error of the mean. Statistical differences were spend less time in interaction and display an increased evaluated with a Two-way analysis of variance (ANOVA) followed number of crossings compared to sham treatment. Chronic

Table 2:

Effects of ESC, KET and the combination treatment on open ﬁ eld behavior of OBX and sham-operated rats

Treatment Ambulation Rearing Thigmotaxis Fecal pellets 7th day 14th day 7th day 14th day 7th day 14th day 7th day 14th day Sham Vehicle 109.10±8.36 104.83±7.71 14.33±0.67 15.00±0.52 196.00±10.29 201.55±10.23 3.84±0.48 3.45±0.33 KET (1 mg/kg) 105.50±8.65 108.53±8.86 12.33±0.56 12.15±0.50 194.83±12.60 190.33±11.07 2.83±0.40 2.50±0.52 ESC (10 mg/kg) 135.62±4.35 138.32±6.41 11.33±1.15 11.00±1.74 188.17±7.78 185.17±7.78 2.50±0.50 2.17±0.31 KET (1) + ESC (10 mg/kg) 143.12±7.03* 145.50±7.21* 8.33±0.64* 8.00±0.58* 170.33±6.71* 175.33±5.41* 2.33±0.45 2.00±0.26 OBX Vehicle 207.00±7.19* 234.00±9.36* 26.83±2.20* 33.67±1.87* 250.50±13.95* 271.11±7.75* 5.67±0.49* 7.17±0.60* KET (1 mg/kg) 191.13±12.00 184.30±8.55# 25.80±2.63 27.20±1.89# 236.70±8.44 223.30±9.20# 5.50±0.76 5.20±0.48# ESC (10 mg/kg) 185.80±5.94 172.50±6.15# 25.00±1.83 17.83±1.54# 233.83±8.99 197.33±9.62# 5.33±0.32 3.50±0.43# KET (1) + ESC (10 mg/kg) 166.11±5.70# 150.67±6.33# 17.17±1.63# 11.23±1.80# 190.50±6.89# 168.32±4.47# 2.83±0.45# 2.33±0.56# Values are mean±SEM. n = 6 per group. *P<0.05 compared with vehicle-treated sham-operated rats, #P<0.05 compared with vehicle-treated OBX rats. ESC = Escitalopram, KET = Ketanserin, SEM = Standard error of the mean, OBX = Olfactory bulbectomy

Indian Journal of Pharmacology | December 2014 | Vol 46 | Issue 6 641 Pandey, et al.: Combination effect of Ketanserin and escitalopram on OBX induced behaviour anomalies treatments with ESC (10 mg/kg), KET (1 mg/kg) and approaches based on monoaminergic systems. This ESC (10 mg/kg) + KET (1 mg/kg) significantly increased the encompasses the amalgamation of 5-HT reuptake blockade- interaction time ( F7,40 = 16.59, P < 0.05) and decreased number which represents >80% of all antidepressant treatments of crossing (F7,40 = 58.53, P < 0.05) compared to vehicle on its own (e.g., SSRIs). The current study demonstrates treatment. Combined ESC + KET treatment was most effective the outcome of a combination approach on OBX induced in reversing the OBX induced behavior and the effects were better behavior anomalies. In contrast to other animal models of than the lone ESC (10 mg/kg) or KET (1 mg/kg) treatments. depression, the OBX characterizes a model of chronic agitated In the 7 days treatment schedule, the combination treatment hyposerotonergic depression[17] which is receptive to discover significantly increased the interaction time (F7,40 = 14.35, the antidepressant-like effects of agents affecting the 5-HT [18] P < 0.05) and decreased the crossing (F7,40 = 22.67, P < 0.05) receptor subtypes. OBX necessitates a chronic antidepressant compared to vehicle treatment [Table 4]. treatment before a change is detected is the attenuation of Discussion hyperactivity. Interestingly, this model has been in front as a promising model for detecting a faster onset of antidepressant Till date, successful attempts for early onset of action of effects. Nonetheless it is believed further refinement of the model antidepressants have been depending on pharmacological may be required.[19] The chronic mild stress model has also been proposed as a rodents model for early onset of depression.[20] Table 3: In the current study, OBX rats exhibited a diverse behavioral Effects of ESC, KET and the combination treatment on anomalies, such as (i) ambulation (locomotion), rearing, hyperemotionality scores of OBX and sham-operated rats thigmotaxis, and defecation in modified open field exploration paradigm, (ii) diminished active interaction and increased Treatment Hyperemotionality scores crossing in social interaction paradigm and (iii) enhanced 7th day 14th day hyperemotionality scores as reported earlier. The chronic Sham regime of ESC significantly reversed the bulbectomy-induced Vehicle 5.23±0.48 5.23±0.52 behavior in all the aforementioned paradigms. This result is in KET (1 mg/kg) 4.67±0.63 4.74±0.32 line with previous reports on reversal of bulbectomy induced ESC (10 mg/kg) 4.23±0.36 4.20±0.29 behavior by ESC. In addition, distinguished similarity between KET (1) + ESC (10 mg/kg) 3.96±0.23 3.56±0.85 OBX rat and human depression is the distorted 5-HT2A receptor OBX binding and function.[21] Mianserin and nefazodone restored Vehicle 11.33±1.36* 14.00±2.36* the avoidance learning in bulbectomized rats, and this effect KET (1 mg/kg) 9.63±0.65 10.17±1.99# was correlated with down-regulation of 5-HT2 receptors in the ESC (10 mg/kg) 8.63±0.48 7.17±0.87# frontal cortex.[22] KET (1) + ESC (10 mg/kg) 6.83±0.31# 5.50±0.42# Early onset of action is prerequisite of antidepressant drug Values are mean±SEM. n = 6 per group. *P<0.05 compared with vehicle-treated treatment,[23] and several approaches have been predicted # sham-operated rats, P<0.05 compared with vehicle-treated OBX rats. [24] ESC = Escitalopram, KET = Ketanserin, SEM = Standard error of the mean, to achieve the same. It is a notable finding that the OBX = Olfactory bulbectomy antidepressant-like effects of the co-administration of ESC and KET were evident with a short course of treatment (7 days) in OBX Table 4: rats. KET treatment can possibly lead to a blockade of serotonin type 2A receptors which eventually results in enhanced 5-HT and Effects of ESC, KET and the combination treatment on social norepinephrine neurotransmission.[25] The synaptic serotonin interaction of OBX and sham-operated rats levels are further increased when ESC is co-administered with Treatment Total interaction (s) Number of passive KET, due to the inhibition of serotonin reuptake by ESC. Therefore, interaction a quick-onset of antidepressant-like effect is feasible due to the [5] 7th day 14th day 7th day 14th day involvement of both serotonergic neurotransmission systems and 5-HT blocker.[5] Furthermore, based on clinical observations, Sham 2A it is noted that 5-HT receptor antagonism is a candidate Vehicle 51.50±5.54 54.50±5.45 13.83±0.75 14.50±1.20 2A mechanism for effectual and quick-onset antidepressant KET (1 mg/kg) 48.67±4.20 50.33±4.25 12.33±3.39 11.33±4.24 [3,4] ESC (10 mg/kg) 62.14±5.51 64.33±4.24 10.33±0.86 9.88±1.05 action. In summary, the current study advocates that the KET (1) + ESC 63.00±5.65 68.50±5.95 10.17±0.87 9.02±1.01 blockade of 5-HT2A receptors may complement the antidepressant (10 mg/kg) effects of ESC. Combined administration of ESC with the KET, OBX can be considered as an approach to accomplish an early-onset Vehicle 23.50±3.03* 18.83±1.42* 33.00±3.26* 36.83±2.03* of antidepressant action in humans. Further, more such studies # # KET (1 mg/kg) 26.50±2.28 24.00±2.57 30.12±2.19 28.76±2.03 are warranted, whether selective blockade of 5-HT2A receptors ESC (10 mg/kg) 28.33±2.76 37.50±2.19# 27.50±2.19 21.50±1.15# can also have an additive or synergistic action in the treatment KET (1) + ESC 43.67±2.40# 52.67±5.63# 18.69±2.58# 13.83±1.08# of other diverse neuropsychiatric disorders. (10 mg/kg) Acknowledgments Values are mean±SEM. n = 6 per group. #P<0.05 compared with vehicle-treated sham-operated rats, *P<0.05 compared with vehicle-treated OBX rats. The authors wish to thank Glenmark Research Center, Mumbai for ESC = Escitalopram, KET = Ketanserin, OBX = Olfactory bulbectomy, SEM = Standard error of the mean providing drug sample. Author would also like to thank the Council of Scientific and Industrial Research for partly funding this work.

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References 16. Shibata S, Nakanishi H, Watanabe S, Ueki S. Effects of chronic administration of antidepressants on mouse-killing behavior (muricide) in olfactory bulbectomized 1. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause rats. Pharmacol Biochem Behav 1984;21:225-30. 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-504. 17. Lumia AR, Teicher MH, Salchli F, Ayers E, Possidente B. Olfactory 2. Blier P, de Montigny C. Current advances and trends in the treatment of bulbectomy as a model for agitated hyposerotonergic depression. Brain Res depression. Trends Pharmacol Sci 1994;15:220-6. 1992;587:181-5. 3. Xu T, Pandey SC. Cellular localization of serotonin (2A) (5HT (2A)) receptors in 18. Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. the rat brain. Brain Res Bull 2000;51:499-505. Neurosci Biobehav Rev 2005;29:627-47. 4. McDonald AJ, Mascagni F. Neuronal localization of 5-HT type 2A receptor 19. Cryan JF, McGrath C, Leonard BE, Norman TR. Combining pindolol and immunoreactivity in the rat basolateral amygdala. Neuroscience 2007;146:306-20. paroxetine in an animal model of chronic antidepressant action - can early onset 5. Gray JA, Roth BL. Paradoxical traffi cking and regulation of 5-HT (2A) receptors of action be detected? Eur J Pharmacol 1998;352:23-8. by agonists and antagonists. Brain Res Bull 2001;56:441-51. 20. Willner P. Themesolimbic dopamine system as a target for rapid antidepressant 6. Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A receptor-mediated action. Int Clin Psychopharmacol 1997;12:S7-14. regulation of brain-derived neurotrophic factor mRNA in the hippocampus and 21. Messa C, Colombo C, Moresco RM, Gobbo C, Galli L, Lucignani G, et al. the neocortex. J Neurosci 1997;17:2785-95. 5-HT (2A) receptor binding is reduced in drug-naive and unchanged in 7. Massou JM, Trichard C, Attar-Levy D, Feline A, Corruble E, Beaufi ls B, et al. SSRI-responder depressed patients compared to healthy controls: A PET study. Frontal 5-HT2A receptors studied in depressive patients during chronic Psychopharmacology (Berl) 2003;167:72-8. treatment by selective serotonin reuptake inhibitors. Psychopharmacology (Berl) 22. Gurevich EV, Aleksandrova IA, Otmakhova NA, Katkov YA, Nesterova IV, 1997;133:99-101. Bobkova NV. Effects of bulbectomy and subsequent antidepressant treatment 8. Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mørk A, et al. Inactivation of on brain 5-HT2 and 5-HT1A receptors in mice. Pharmacol Biochem Behav 5-HT (2C) receptors potentiates consequences of serotonin reuptake blockade. 1993;45:65-70. Neuropsychopharmacology 2004;29:1782-9. 23. Artigas F. Limitations to enhancing the speed of onset of antidepressants - Are 9. Horovitz ZP, Ragozzino PW, Leaf RC. Selective block of rat mouse-killing by rapid action antidepressants possible? Hum Psychopharmacol antidepressants. Life Sci 1965;4:1909-12. 2001;16:29-36. 10. Nakamura K, Kurasawa M. Anxiolytic effects of aniracetam in three different mouse 24. Machado-Vieira R, Salvadore G, Luckenbaugh DA, Manji HK, Zarate CA Jr. Rapid models of anxiety and the underlying mechanism. Eur J Pharmacol 2001;420:33-43. onset of antidepressant action: A new paradigm in the research and treatment of 11. Wang D, Noda Y, Tsunekawa H, Zhou Y, Miyazaki M, Senzaki K, et al. Behavioural major depressive disorder. J Clin Psychiatry 2008;69:946-58. and neurochemical features of olfactory bulbectomized rats resembling depression 25. Gobert A, Millan MJ. Serotonin (5-HT) 2A receptor activation enhances dialysate with comorbid anxiety. Behav Brain Res 2007;178:262-73. levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of 12. Pandey DK, Rajkumar R, Mahesh R, Radha R. Depressant-like effects of freely-moving rats. Neuropharmacology 1999;38:315-7. parthenolide in a rodent behavioural antidepressant test battery. J Pharm Pharmacol 2008;60:1643-50. 13. Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of Cite this article as: Pandey DK, Bhatt S, Jindal A, Gautam B. Effect of depression: An update. Pharmacol Ther 1997;74:299-316. combination of ketanserin and escitalopram on behavioral anomalies after 14. Ramamoorthy R, Radhakrishnan M, Borah M. Antidepressant-like effects of olfactory bulbectomy: Prediction of quick onset of antidepressant action. Indian serotonin type-3 antagonist, ondansetron: An investigation in behaviour-based J Pharmacol 2014;46:639-43. rodent models. Behav Pharmacol 2008;19:29-40. 15. File SE, Hyde JR. Can social interaction be used to measure anxiety? Br J Source of Support: Author would also like to thank the Council of Scientifi c Pharmacol 1978;62:19-24. and Industrial Research for partly funding this work, Confl ict of Interest: No.

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