{"id":60634,"date":"2024-09-30T11:24:04","date_gmt":"2024-09-30T11:24:04","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=60634"},"modified":"2024-10-09T18:06:40","modified_gmt":"2024-10-09T18:06:40","slug":"study-the-effect-of-drakshasava-on-dopamine-serotonin-and-cortisol-levels-and-behavioural-changes-in-acute-and-chronic-stress-model-in-wistar-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no3\/study-the-effect-of-drakshasava-on-dopamine-serotonin-and-cortisol-levels-and-behavioural-changes-in-acute-and-chronic-stress-model-in-wistar-rats\/","title":{"rendered":"Study the Effect of Drakshasava on Dopamine, Serotonin and Cortisol Levels and Behavioural Changes in Acute and Chronic Stress Model in Wistar Rats"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Both major depression and mania are serious health\nproblems that can profoundly affect an individual’s quality of life if not\ntreated promptly. The modalities used to address these conditions include\nmedication, psychotherapy, and lifestyle modifications, all aimed at managing\nsymptoms and improving overall quality of life. Characteristic symptoms the patient\npresents with like sad mood, loss of interest in self and surrounding and\nreduced pleasure in doing the things, reduced initiative and tiredness,\nworthlessness, guilt, psychomotor retardation or agitation, reduced appetite\nand sleep, melancholia and suicidal tendency 1<\/sup>. Depression is also associated\nwith substantial impairment of cognitive function, Individuals\nwith depression often experience difficulties with both short-term and\nlong-term memory. They may have trouble recalling recent events or retaining\nnew information. Episodic memory, which is the ability to remember specific\nevents and experiences, is particularly affected.2,3<\/sup>  Mechanism of depression is thought to be an\ninterplay between the three important biochemical substances like Dopamine,\nSerotonin and cortisol4<\/sup>. Exact mechanism is still uncertain as per recent\nadvances some factors are considered to be responsible for depression are like disturbances\nin serotonin and norepinephrine neurotransmission. There is interplay between\nthe neurotransmitters norepinephrine, serotonin and dopamine at the nucleus accumbens\n5, 6<\/sup> where decrease in serotonin levels plays a greater role in the\noccurrence of depression7<\/sup>.<\/p>\n\n\n\n

 Many mechanisms contributing for the\nantidepressant effect of the drugs used such as blockade of receptors other\nthan dopamine, monoamine transporters, sleep pattern normalisation, decrease in\ncortisol levels and increase in neurotrophic growth factors8<\/sup> At\npresent Antidepressant drugs of first choice are selective serotonin reuptake\ninhibitors (SSRI), such as fluoxetine, paroxetine, fluvoxamine, citalopram, and\nsertraline 9<\/sup>. There are many adverse effects but attention required\ntowards the suicidal behaviour and symptoms observed after stopping the drug10,11<\/sup>.\nThe relation between depression and increased cortisol levels is very well understood\n12<\/sup>. Currently available drugs like SSRI, Citalopram,\nFluoxetine, Fluvoxamine, paroxetine\nreported to decrease cortisol levels along with having effect on serotonin and\ndopamine 13<\/sup>. <\/p>\n\n\n\n

Drakshasava is\nprepared from the multiple ingredients, draksha is main along with kumara,\ndhatkipushpa, kankol, chavak, ranuk, nagpushpa, trijat, lavang, marich, piper,\nchitrak jatiphal,  pipalimoola sugar etc.\n14<\/sup> Our previous research work we evaluated  the antidepressant effect of Drakshasava in\nwistar rats and got very promising results in the unpredictable chronic mild\nstress model15<\/sup>.Hence, in this study efforts were made to explore the\nmechanism of action of Drakshasava responsible for reducing the symptoms of\ndepression. <\/p>\n\n\n\n

Aim<\/strong><\/p>\n\n\n\n

To investigate the effects of Drakshasava on dopamine, serotonin, and cortisol levels, as well as the associated behavioral changes in Wistar rats under both acute and chronic stress models.<\/p>\n\n\n\n

Objectives<\/strong><\/p>\n\n\n\n

To measure the changes in dopamine, serotonin and cortisol levels in Wistar rats subjected to acute and chronic stress after the administration of Drakshasava.<\/p>\n\n\n\n

To observe and record behavioral changes in Wistar rats subjected to acute and chronic stress, with and without Drakshasava treatment.<\/p>\n\n\n\n

To Investigate the potential mechanisms by which Drakshasava modulates neurotransmitter levels and stress-related behaviors.<\/p>\n\n\n\n

Material and Methods<\/strong><\/p>\n\n\n\n

Study was started\nafter obtaining IAEC approval. Wistar rats of weighing 150 – 200 g of both the\nsex were used for the study. As per the CCSEA guidelines rats were housed in standard\ncages, temperature and humidity maintained. Food in the form of pellets and aqua\nguard purified water was given ad libitum. Time for performing the experimental\npart was maintained same throughout the study. <\/p>\n\n\n\n

Six groups of\nanimals were prepared consisting of eight rats in each group. Group 1 was control\ngroup treated with saline, Group 2 was disease control exposed to the stress\nand received saline only, Group 3 &4 were test drug groups received Drakshasava\n(Low dose) i.e.2ml\/kg and (High dose)- 4ml\/kg, <\/p>\n\n\n\n

Group 5 was\nstandard drug treatment group received Fluoxetine (10 mg\/kg) and Group 6 was\nunpredictable chronic mild stress group received (High dose) – 4ml\/kg. All the\ndrugs given orally.<\/p>\n\n\n\n

Following tests were carried out for evaluation of antidepressant activity\nof Drakshasava-<\/p>\n\n\n\n

Acute Model of Stress<\/strong><\/p>\n\n\n\n

Forced swim test & Sucrose preference test were done at baseline. Animals received drug treatment as per the groups for 7 days to all the animals of group 3-5, group 1 was control and group 2 was disease control treated with saline. On the day 8 animals were exposed to Forced swim test & Sucrose preference test and blood withdrawal was done for checking the levels of DA, Serotonin & Cortisol.<\/p>\n\n\n\n

Sucrose preference was calculated according to the formula: <\/p>\n\n\n\n

Sucrose preference = [sucrose intake\/ (sucrose\nintake + water\nintake)] \u00d7 100.\n<\/p>\n\n\n\n

 Decrease\nin the sucrose consumption when given a choice between water and sucrose due to\ndepression and antidepressants reduce anhedonia.<\/p>\n\n\n\n

Chronic model of stress<\/strong><\/p>\n\n\n\n

Forced swim test & Sucrose preference test was done at baseline. Animals were exposed to the stress with UCMS for 15 days from group 6. Different stressors were used every day randomly for 3 weeks like: No food for 20 h; No water for 20 h; 24 h crowd (6 rats in one cage) housing, 24 h isolation in separate cages, 45\u00b0 cage tilt for 17 h, soiled base of the cage for 12 h, constant bright light for 24 h, applying tail clamp for 1 min; and shock from which animal cannot escape. After exposure to every stress rats were returned to the normal conditions until the next stressor was given.<\/p>\n\n\n\n

Forced swim test & Sucrose\npreference test was done on day 15, for next 7 days\u2019 drug treatment given with\nUCMS. On day 22, animals were exposed to Forced swim test & Sucrose preference\ntest and blood withdrawal was done to estimate dopamine, serotonin & cortisol\nlevels. Blood withdrawal was done after forced\nswim test by retro orbital method under ketamine anaesthesia for estimation of\nDopamine, Serotonin and cortisol levels.<\/p>\n\n\n\n

Statistical Analysis<\/strong><\/p>\n\n\n\n

Data collected was analysed with software\nGraph Pad Prism 6. Results were expressed as mean \u00b1 standard error of mean. One-way ANOVA\nwas used to compare the groups followed by post-hoc\nTukey\u2019s test was used. P < 0.05\nwas considered as statistical significance.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Plasma\nlevels of Dopamine, Serotonin and cortisol were estimated in rats of acute and\nchronic depression. Comparison between the means of serum Dopamine, Serotonin\nand cortisol levels was done in control, disease control and drug treated rats.<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Effect of Drakshasava on serum dopamine levels in acute stress<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

DS- Disease, DKS LD- Drakshasava low dose, DKS HD- Drakshasava high dose, Fluox- Fluoxetine. Values are represented in the form of mean \u00b1 SEM, &<\/sup> p<0.05 data compared with control group findings. *p<0.05 & **p<0.01 in comparison with disease control group.<\/p>\n\n\n\n

Dopamine levels were significantly (p<0.05) low in disease control\ngroup as compared to control group. In the drug treated groups, dopamine levels\nwere significantly high in DKS LD (p<0.05), DKS HD (p<0.05) as well as\nFluoxetine treated group (p<0.01) in comparison with disease control group.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Effect of Drakshasava on serum serotonin levels in acute stress<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

DS- Disease, DKS LD- Drakshasava low dose, DKS HD- Drakshasava high dose, Fluox- Fluoxetine. Values are represented in the form of mean \u00b1 SEM, &<\/sup> p<0.05 data compared with control group findings. *p<0.05 & **p<0.01 in comparison with disease control group.<\/p>\n\n\n\n

Serotonin levels in the disease control group were significantly\n(p<0.01) low in when compared to control group. Increase in serotonin levels\nwas observed in DKS LD (p<0.05) and DKS HD (p<0.01) in comparison with\ndisease control group. Fluoxetine group also showed significant increase (p<0.05)\nin serotonin level similar to the low dose Drakshasava.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 3: Effect of Drakshasava on serum cortisol levels in acute stress<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

DS- Disease, DKS LD- Drakshasava low dose, DKS HD- Drakshasava high dose, Fluox- Fluoxetine. Values are represented in the form of mean \u00b1 SEM, &<\/sup> p<0.05 data compared with control group findings. *p<0.05 & **p<0.01 in comparison with disease control group.<\/p>\n\n\n\n

Significant increase in cortisol levels (p<0.01) was seen in\ndisease control in comparison with control group. Cortisol levels were\nsignificantly reduced in comparison in DKS HD (p<0.05). Low dose also showed\ndecrease in the cortisol levels, but it was not statistically significant. Fluoxetine\ntreated group showed (P<0.01) decrease in cortisol levels.<\/p>\n\n\n\n

Table 1: Effect of Drakshasava on Immobility Period in Forced Swim Test<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

 <\/strong><\/p>\n<\/td>\n

\n

Group<\/strong><\/p>\n<\/td>\n

\n

Dose<\/strong><\/p>\n<\/td>\n

\n

Baseline-Immobility Period (in sec)<\/strong><\/p>\n<\/td>\n

\n

Post treatment- Immobility Period (in sec)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

No stress<\/p>\n<\/td>\n

\n

0.5 ml<\/p>\n<\/td>\n

\n

51.12 \u00b1 2.08<\/p>\n<\/td>\n

\n

74.87 \u00b12.29<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

Acute Stress +Saline<\/p>\n<\/td>\n

\n

0.5 ml<\/p>\n<\/td>\n

\n

50.12 \u00b1 2.75<\/p>\n<\/td>\n

\n

182.87\u00b1 3.02&&&<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

Acute Stress+ DKS LD<\/p>\n<\/td>\n

\n

2ml\/kg<\/p>\n<\/td>\n

\n

49.00 \u00b11.73<\/p>\n<\/td>\n

\n

96.00 \u00b1 5.24***<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Acute Stress+ DKS HD<\/p>\n<\/td>\n

\n

4 ml\/kg<\/p>\n<\/td>\n

\n

48.25 \u00b1 2.61<\/p>\n<\/td>\n

\n

88.37 \u00b1 3.58***<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Acute Stress+ Fluoxetine<\/p>\n<\/td>\n

\n

10 mg\/kg<\/p>\n<\/td>\n

\n

49.50 \u00b1 2.11<\/p>\n<\/td>\n

\n

92.62 \u00b1 2.78***<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

UCMS (15 d)+ DKS HD<\/p>\n

with UCMS (7d)<\/p>\n<\/td>\n

\n

4 ml\/kg<\/p>\n<\/td>\n

\n

147.0 \u00b1 4.99***<\/p>\n<\/td>\n

\n

86.87 \u00b1 3.18***<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

DS- Disease, DKS LD- Drakshasava low dose, DKS HD- Drakshasava high dose, Fluox- Fluoxetine.<\/p>\n

Values are represented in the form of mean \u00b1 SEM, &&&<\/sup> p<0.001 data compared with control group findings. ***p<0.001  in comparison with disease control group.<\/p>\n\n\n

Significant increase in immobility time (p<0.001) was seen in disease control in comparison with control group. Immobility time was significantly reduced in comparison with disease control in all the drug treated groups. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 4: Effect of Drakshasava on sucrose preference in acute and chronic stress<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

DS- Disease, DKS LD- Drakshasava low dose, DKS HD- Drakshasava high dose, Fluox- Fluoxetine. Values are represented in the form of mean \u00b1 SEM, &&&<\/sup> p<0.001 data compared with control group findings. ***p<0.001 in comparison with disease control group.<\/p>\n\n\n\n

Significant decrease in sucrose preference (p<0.001) was seen in\ndisease control in comparison with control group. Sucrose preference was\nsignificantly increased in comparison with disease control in all the drug\ntreated groups. <\/p>\n\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Many factors are contributing in the\npathophysiology of depression like neurotransmitters disturbances and neuroendocrine\nalterations, genetic factor, real life events 16<\/sup>. Recent research highlights\nthe cause of depression as disturbances in serotonin, dopamine and Norepinephrine\nneurotransmission17<\/sup>. Dopamine (DA) is found to be\ninvolved in the major physiological\nfunctions like motivation, psychomotor speed,\nconcentration, and the ability to experience pleasure 18,19<\/sup> impairment\nand disturbance of these functions of dopamine is the main features of\ndepression.\n<\/p>\n\n\n\n

Stress in the day to day life in all\nthe age groups has shown the raised levels of blood cortisol and reduces memory\nand cognitive performance20<\/sup>. Increased levels of cortisol for long duration increases the\nrisk of depression 21<\/sup>. Stress increases corticosteroid levels in\ncirculations and these increased corticosteroids\nlower the serotonin levels ultimately resulting in depression,\naggression and other psychological conditions 22<\/sup>. Interaction between serotonin, dopamine and\ncortisol is complex, serotonin increases levels of dopamine and reduces cortisol\nlevels showing the beneficial effects23<\/sup> Cortisol is considered as a\nculprit resulting increasing in stressful situations and ultimately negatively\naffecting immune function. Cortisol is a crucial hormone for managing acute\nstress, but its chronic elevation can have harmful effects, particularly on the\nimmune system. By suppressing immune function and disrupting inflammation\nregulation, high cortisol levels can increase vulnerability to infections, slow\ndown healing, and contribute to the development of chronic diseases. <\/p>\n\n\n\n

There are various models, have been developed to test the\nantidepressant activity of a new molecule. In our study, to test antidepressant\nactivity, Forced Swim Test that imparts acute stress in animals, and to observe\nthe effect on unpredictable chronic mild stress model of depression was used. Observation\nshowed that there was decrease in the immobility time in forced swim test (Table\n1) and sucrose preference was improved significantly (Figure 4) in all drug\ntreated animals proving its efficacy as an antidepressant. The UCMS model\nencompasses subjecting rodents to a variety of recurrent unpredictable\nstressors, such as foot shocks, exposure to low temperatures, crowded housing\nand deprivation of water and food. Stimulate stressful situations to induce behavioural\nchanges in rodents also associated with neuro-inflammation24<\/sup>.Gradual\nincrease in the stress and resultant depression mimics the depression in the\nhuman being. Rodents have a natural tendency to\ndrink the weakly sweet solutions of sucrose 25<\/sup>. Animals given\nsucrose and water in two different bottle and they have choice of selection.\nControl rats showed a preference for drinking sucrose containing sweet water,\nbut stressed rats lost interest in drinking sucrose water. All drug treated\nanimals showed improved preference to sucrose water. These findings are\nsuggestive of the positive impact of Drakshasava in depression through\ndifferent mechanism. Here we have showed that it increases the serotonin and\ndopamine and the cortisol levels are reduced. \nSince it is a polyherbal preparation consist of various ingredients\nwhich may have contributed in reducing stress and ultimately the disturbances\nin neurotransmitters.<\/p>\n\n\n\n

Increase in levels of serotonin and\ndopamine (Figure-1 & 2) in the drug treated groups, may have resulted in\nthe reduction of immobility time. Drakshasava has different ingredients, few of them have been\nstudied for their use in depression and have been shown to increase the\ndopamine and serotonin levels. Cardamom oil reduced symptoms of depression\nin reserpine-injected rats model indicating the positive effect on forced\nswimming test by reducing immobility and increasing locomotor activities. 26<\/sup> Linalool present\nin cardimum\nwhich interacts with the monoaminergic system including serotonergic and non-adrenergic\nsystem 27<\/sup>. Another ingredient is cinnamon\n(Cinnamomum burmanii)-cinnamon bark extract improved clinical depression this effect was due to reduction in\nexpression of TNF-alpha in the hippocampus which the viability of serotonin\nneuronal cells remained optimal and increase in serotonin levels28,29<\/sup>.\nFST mimics the human symptoms of\ndepression in the form of immobility despair-based behaviour or a stress coping\nbehaviour. <\/p>\n\n\n\n

Treatment with Drakshasava decreased cortisol levels\nsignificantly (Figure-3) this finding is consistent with our previous study as\nalso by many other studies which report decrease in the cortisol levels with different\ningredients of this herbal preparation. Honey is one of the ingredient of\nDrakshasava and it has been reported in the various studies when honey is used as\na vehicle in various preparations it reduces cortisol and ultimately the stress\neffects, Integrating honey into herbal preparations like Drakshasava may offer\na holistic approach to managing stress and promoting overall well-being. 30,31<\/sup>.\nSimilarly, clove ( Syzygium aromaticum ) powder\nhave shown promising antidepressant\neffects in preclinical studies, and there is emerging evidence suggesting their\npotential to lower cortisol levels. The antioxidant, anti-inflammatory, and neuroprotective\nproperties of clove compounds, along with their aromatherapeutic effects, may\ncontribute to these beneficial effects. 32,33<\/sup> and Cardimum also\nreduces the cortisol levels34<\/sup>.<\/p>\n\n\n\n

Considering\ndepression as major health issue and the treatment available is producing\ninsufficient impact due to no response or suboptimal response, sometimes slow\nresponse, usually over several weeks of chronic drug treatment; need for new\ntreatment options remains. Due to the resistant depression and limitations of the\npresent drugs, depression research has moved towards the compounds that target\nnon-monoaminergic molecular structures 35<\/sup>. So, in this study, Drakshasava\nwhich has shown its efficacy in the experimental models as well as on the\nbiochemical parameters, can prove to be one such promising add on drug in the\ntreatment of depression.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Drakshasava increased serum\ndopamine, Serotonin levels and decreased cortisol in both the animal models of\ndepression. The biochemical findings show the correlation with the test\nresults. Which was comparable with the standard drug fluoxetine. Drakshasava,\nthrough its modulation of key neurotransmitters and reduction of cortisol\nlevels, shows promise in managing stress and its associated symptoms. By increasing\nserum levels of serotonin, dopamine and decreasing cortisol, Drakshasava may\nhelp to alleviate anxiety and depression, improve cognitive function, and\nenhance overall well-being.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

Authors are grateful to theBharati Vidyapeeth (DU) Medical College, Pune for providing infrastructure and the help of the animal house staff for this research work.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The author(s) received no financial support for the research, authorship, and\/or publication of this article.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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