Citrus aurantium for mental alertness -
Flumazenil, a competitive antagonist of benzodiazepine binding, and the selective 5-HT 1A receptor antagonist WAY were used in the experimental procedures to determine the mechanism of action of the EO.
To exclude false positive results due to motor impairment, the mice were submitted to the rotarod test. Acute treatment with the EO showed no activity in the forced swim test, which is sensitive to antidepressants.
A neurochemical evaluation showed no alterations in neurotransmitter levels in the cortex, the striatum, the pons, and the hypothalamus. Furthermore, no locomotor impairment or signs of toxicity or biochemical changes, except a reduction in cholesterol levels, were observed after treatment with the EO.
reported that pregnant women with sleep disturbances have poor physical function [ 9 ] and social health, and physical pain and limitations of daily activity increase in these individuals [ 10 ]. Anxiety is a natural and adaptive reaction to the experience of unsafe or threatened feeling.
It is common during pregnancy; the risk factors are a history of high anxiety or depression, perfectionism, history of miscarriage s , high-risk pregnancy, and major life stressors [ 11 ]. Anxiety during pregnancy may adversely affect fetal development [ 12 ]. At current, a group of antidepressants and sedatives and antipsychotics is at the first line of pharmacological treatment of sleep disturbances during pregnancy, which is limited information on the safe use of these medications in pregnancy [ 13 ].
Cognitive—behavioral therapy CBT is a combination of cognitive and behavioral approaches. CBT reduces cognitive, physical, and behavioral symptoms through the use of specific methods including relaxation, regular desensitization, cognitive reconstruction, response prevention, problem-solving, activity listing, and training of interpersonal skills [ 14 ].
The content of therapy includes identifying thoughts and beliefs, reviewing evidence, and examining cognitions and thoughts that are related to mood and behavior [ 15 ].
Cognitive—behavioral therapy for insomnia CBT-I is a structured program to identify and replace thoughts and behaviors that cause or worsen sleep disturbances with practices that promote proper sleep. The five main components of CBT-I are cognitive restructuring, sleep consolidation, stimulus control, sleep hygiene, and relaxation techniques [ 16 ].
Herbal medicines have been used widely since old days in ancient civilizations [ 17 ]. Aromatherapy is one of the treatments that have grown increasingly in recent years compared to complementary medicine treatments [ 18 ]. According to a recent systematic review, various essential oils, such as lavender, bergamot, and chamomile, have improved sleep quality and reduced stress, pain, anxiety, depression, and fatigue [ 19 ].
These oils help individuals to relax their bodies and minds, leading to better sleep quality. Also, some aromas may increase slow-wave sleep SWS and subjective sleep quality [ 20 ]. One of the essential oils used in aromatherapy is Citrus aurantium.
This essential oil is an amber-colored liquid that turns red in the presence of light. Its smell is strong, very fragrant and its taste is bitter [ 21 ]. Citrus aurantium has central nervous system stimulating and mood-enhancing effects, as well as sedative, antispasmodic, anti-inflammatory, anti-flatulence, digestive, antihypertensive and diuretic effects [ 22 ].
Based on the literature review, limited studies have been found about the effect of Citrus aurantium on sleep quality, anxiety, and quality of life of pregnant women. In a recent study, this essential oil was effective in reducing the anxiety of women at risk of preterm labor [ 24 ]; it was also effective in reducing anxiety during labor in another study [ 25 ].
No study has been conducted with the integration of CBT and aromatherapy. Considering that poor sleep quality has detrimental effects on mood, psychological function and overall well-being [ 26 ] and given the various studies have reported the sedative and anxiolytic effects of Citrus aurantium [ 22 ], and also CBT helps the patient to recognize and change distorted thought patterns and dysfunctional behaviors [ 14 ].
Thus, the present study aimed to evaluate the effect of cognitive—behavioral counseling with and without Citrus aurantium on sleep quality primary outcome , anxiety and quality of life secondary outcomes in pregnant women.
This randomized controlled trial was conducted on 75 pregnant women referring to health centers in Tabriz, Iran from July to February The inclusion criteria included pregnant women with a gestational age of 20—24 weeks, women with poor sleep quality based on the Pittsburgh Sleep Quality Index PSQI score above 5 , having a minimum degree of secondary school, living in Tabriz, having a medical record in the health center integrated health system , lack of olfactory problems and allergy to herbal medicines by examination by the researcher, obtaining a depression score of 12 and lower according to the Edinburgh Pregnancy Depression Scale EPDS.
The exclusion criteria included pregnant women with mental illness and a history of hospitalization in a psychiatric hospital or the use of any psychiatric medication, addiction to drugs and smoking, high-risk pregnancies including diabetes, hypertension, chronic diseases, such as cardiovascular, lung, etc.
The sample size in this study was calculated using G-Power software. According to the results of the study conducted by Effati et al. Sampling began after obtaining the code of ethics from the ethics committee of Tabriz University of Medical Sciences code: IR. Sampling was performed in 6 health centers of Tabriz, Iran.
The researcher referred to health centers in Tabriz, and then briefly explained the goals and methods of the research to women with 20—24 gestational ages. If women were willing to participate in the study, they were examined in terms of inclusion and exclusion criteria and eligible individuals were selected.
Then, the PSQI and the EPDS were completed through interview with participants by the researcher and participants who scored sleep quality score higher than 5 and a depression score 12 and less, and met other inclusion criteria were included in the study after obtaining informed written consent and then the socio-demographic characteristics questionnaire, Pregnancy-Specific Anxiety Scale PSAS and Pregnancy-Specific Quality of life Questionnaire QOL-GRAV were completed through interview with participants by the researcher.
Participants were randomly allocated to three groups including the first intervention group receiving cognitive—behavioral counseling with aromatherapy with Citrus aurantium essential oil , the second intervention group receiving cognitive—behavioral counseling and placebo , and control group using the block randomization method with the block sizes of 6 and 9 and an allocation ratio of The type of intervention was written on paper and placed in opaque and sealed envelopes that numbered sequentially to conceal the allocation sequence.
The envelopes were opened in the order in which the participants entered the study and the type of group of individuals was determined. Envelopes were prepared by a person not involved in sampling, data collection and analysis.
Similar glasses of Citrus aurantium essential oil or placebo were prepared and coded with letters of A and B. The Citrus aurantium essential oil and placebo had exactly the same appearance smell, color, and shape.
The intervention groups received a glass of drug or placebo in addition to counseling. The researcher and participants of intervention groups were blinded to the type of drug received.
The first and second intervention groups received 8 sessions of cognitive—behavioral counseling held in the health center in groups of 5—7 people.
The mean duration of counseling sessions was 60—90 min. Cognitive—behavioral counseling sessions were by the first author Master of Counseling in Midwifery under the supervision of the project clinical psychologist in health centers held as 2 sessions per week and lasted for 4 weeks.
The content of the counseling included explaining the goals of training and acquaintance with the members, conducting a pre-test, explaining the importance of treatment, assessing the insomnia, perception of sleep and insomnia, evaluating thoughts, training relaxation, sleep health and new sleep schedules, restriction of sleep, prevention of daily naps, problem-solving skills, summarizing thoughts, reality of sleep, introducing the cycle of thought and feeling and behavior, and training thought blocking.
Due to COVID disease, the last two sessions were held online in the Zoom program due to unwillingness of pregnant women to attend the health center. The content of the counseling sessions was as follows:.
Session 1: Explaining the goals of training and acquaintance with members, conducting a pre-test, teaching how to monitor the baseline of sleep with a sleep report table, reminding the importance of treatment tasks, a complete assessment of the nature of insomnia.
Session 2: Presenting the principles and logic of treatment, teaching the mechanism of sleep and its stages, sleep—wake cycles and underlying factors, maintenance and continuation of insomnia, relaxation training.
Session 3: Reviewing the previous session of treatment, reviewing the findings of the sleep report form, sleep hygiene training, and review the relaxation and new sleep schedule.
Session 4: Restricting sleep, preventing daily naps, evaluating thoughts and teaching how to record thoughts related to insomnia and reviewing the assignments of previous sessions sleep report form and homework schedule. Session 5: Summarizing thoughts, problem-solving skills, reviewing the sleep report form and homework and troubleshooting.
Session 6: Introducing the cycle of thinking, feeling and behavior, reviewing relaxation and training not to try fall asleep and apply all the instructions of the previous sessions and reviewing the homework of the previous sessions sleep report form and homework table.
Session 7: Training thought blocking, mental imaging, troubleshooting cognitive-behavioral therapy plan, reviewing patient homework. Session 8: Reviewing and troubleshooting the cognitive—behavioral treatment plan, noting the progress of treatment according to the sleep calendar to the patients.
The participants in the first intervention group, in addition to cognitive—behavioral counseling sessions, received aromatherapy with Citrus aurantium essential oil, so that they placed 2 drops of Citrus aurantium aromatic distillate on a tissue and inhaled it through normal breathing for 15—20 min before bedtime.
The Citrus aurantium essential oil required for the study was purchased from Bu Ali Sina Medical Company of Iran and after determining the concentration by gravimetric method was used by the Faculty of Pharmacy of Tabriz University of Medical Sciences.
The safe dosage was 8 mg of Citrus aurantium essential oil in ml of distilled water. Based on the evaluations made by the pharmacist, the minimum number of drops was considered for pregnant women.
The second intervention group received a placebo with the same prescription. The content of the placebo were distilled water. A kind of aroma was used to make the placebo smell similar to Citrus aurantium essential oil when opening the lid of container; however, it didn't have the potential to stimulate the nervous system.
The control group received only routine prenatal care. Data collection tools included the socio-demographic and obstetric characteristics questionnaire, PSAS, PSQI, and QOL-GRAV, which were completed before and after the intervention through interview with participants.
The PSQI is a self-report tool scored from 0 to 21 and developed by Buysse et al. This questionnaire has seven components that include subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, and sleep disturbances, the use of sleeping medication, and daytime dysfunction.
A score above 5 indicates insomnia and poor sleep quality [ 29 ]. In a study conducted on pregnant women in Tabriz, Iran, the reliability of this tool was reported 0. A modified PSAS was used to measure pregnancy anxiety. Its short version contains 11 questions.
The answer to each question varies from not at all score 1 to very relevant score 5. Higher scores indicate a higher level of anxiety and there is no cut-off point. In a study conducted in Tabriz, Iran, Cronbach's alpha coefficient was obtained at 0.
The QOL-GRAV has 9 questions to assess the level of personal experiences of quality of life during pregnancy.
Each item is scored based on the Likert scale ranging from not at all score zero and completely score five. In this questionnaire, the first six questions are scored in reverse. Persian version of QOL-GRAV has good validity and reliability, so this tool can be used to assess the quality of life of pregnant women [ 31 ].
Data were analyzed by SPSS software. The Kolmogorov—Smirnov test was used to assess the normality of quantitative data and all variables had normal distribution. Chi-square, Chi-square for trend, and Fisher's exact and independent t tests were used to evaluate the homogeneity of groups in terms of sociodemographic and obstetric characteristics.
One-way analysis of variance was used to compare the mean scores of quality of life and anxiety among the intervention groups before the intervention and ANCOVA test was used after the intervention by adjusting the baseline score and the age variable.
Figure 1 shows the study flow diagram. The socio-demographic and obstetric characteristics of the participants are presented in Table 1.
There was no statistically significant difference among the groups in terms of all socio-demographic characteristics except age variable, the effect of which was controlled by ANCOVA test. After the intervention, the quality of life score in the intervention group 1 AMD: 2.
The results of this study showed that cognitive—behavioral counseling reduced anxiety and improved quality of life but had no effect on sleep quality. The results of studies conducted by Edinger and Sampson [ 32 ] on patients at Durham Medical Center showed that cognitive—behavioral therapies improve sleep quality.
Also, the results of a study conducted by Reybarczyk [ 33 ] on older adults show that CBT is effective in reducing sleep onset time and improving sleep quality.
In another study by Querstret et al. Thus, the results are controversial. Cognitive—behavioral counseling with or without Citrus aurantium essential oil did not have an effect on quality sleep, which is probably due to differences in participants, the virtual holding of some sessions due to COVID disease, as well as the lack of regular and correct exercise at home.
Along with primary insomnia and physical conditions, pregnancy-specific sleep problems may impede treatment. It seems that CBT may not be sufficient for women with high PSQI scores. Also, observing sleep restrictions and scheduling might be difficult during pregnancy. There is a need to perform high-quality trials for sleep-related interventions during pregnancy and implement effective programs in standard prenatal care [ 35 ].
Citrus aurantium essential oil did not have an effect on sleep quality in our study. Based on the literature review, the effect of Citrus aurantium on sleep quality has been less studied than other essential oils, such as lavender, bergamot, and chamomile [ 36 ].
In comparison with the previous studies, the results may be due to the pregnancy-specific conditions and socio-demographic differences of the participants [ 37 , 38 ].
It is recommended that future studies focus more on the above-mentioned items. The results showed that cognitive—behavioral counseling had a positive effect on pregnancy anxiety.
Many studies confirm the role of psychological therapies as a way to reduce anxiety and choose natural childbirth in pregnant women. For example, the results of a study showed that CBT methods reduce anxiety in nulliparous women [ 39 ]. Firouzbakht et al. Another study revealed that psychological education in nulliparous women with severe fear of childbirth reduces the choice of cesarean section and increases satisfaction with the experience of childbirth [ 42 ].
Cognitive reconstruction, also known as rational empiricism, helps people identify the flow of anxious thoughts using logical reasoning for practical testing the content of their anxious thoughts against the reality of their life experiences.
In other words, they test the probability of occurring that something that will happen in reality [ 43 ]. Thus, cognitive assessment of events affects the response to those events and will pave the way for changing cognitive activity [ 44 ].
The results of this study showed that cognitive—behavioral counseling has a positive effect on quality of life. In explaining these results, it can be stated that pregnancy is associated with stress, which can affect the quality of life of pregnant women.
Thus, cognitive—behavioral counseling helps pregnant women manage stress, identify stressful situations, and then teach strategies to cope with these situations.
CBT equips participants with a variety of integrated techniques that they can use to reduce stress and improve quality of life [ 45 ]. Through training muscle relaxation and diaphragmatic breathing, people are taught to control their daily stress, and through negative thinking and thinking power, people are taught to recognize and control their negative cognitive symptoms [ 46 ].
The effect of cognitive—behavioral counseling with aromatherapy on sleep quality in pregnant women was examined for the first time. In this regard, standard and valid questionnaires were used to assess the consequences and the native language of pregnant women was used during counseling sessions to communicate more with women and these cases can be considered as the study strengths.
All women participating in this study were literate, so this can affect the generalizability of results in illiterate women. Also, we only included pregnant women with a gestational age of 20—24 weeks. The future studies should be conducted on women in the first and third trimesters of pregnancy. It is recommended to hold several sessions of cognitive—behavioral counseling for those who support these women husbands and other family members.
Also, the effect of CBT-I should be also assessed in future studies. It is also recommended to investigate the effect of cognitive—behavioral counseling on other populations such as women of childbearing age.
Based on the findings of the study, it is concluded that cognitive—behavioral counseling with or without aromatherapy with Citrus aurantium essential oil can reduce anxiety and improve quality of life during pregnancy, but had no effect on the quality of sleep of pregnant women and its subdomains.
Further studies are required to develop a protocol to guide pregnant women with sleep problems. Arman Arab, Nahid Rafie, … Fatemeh Shirani.
Gholami Fatemeh, Moradi Sajjad, … Mirzaei Khadijeh. VandenBerg KA. State systems development in high-risk newborns in the neonatal intensive care unit: identification and management of sleep, alertness, and crying.
J Perinat Neonatal Nurs. Article PubMed Google Scholar. Boulpaep EL, Boron WF. Medical physiology e-book. New York: Elsevier; Google Scholar. Dewald JF, Meijer AM, Oort FJ, Kerkhof GA, Bögels SM. The influence of sleep quality, sleep duration and sleepiness on school performance in children and adolescents: a meta-analytic review.
Sleep Med Rev. Administered orally, the EO derived from the petals and stamens of C. aurantium reduced the preoperative anxiety of patients scheduled for elective minor surgery [ 19 ].
More recently, preparations from Citrus species have also been investigated for antidepressant activity in both rodents and humans. EO preparations made from the leaves of C. maxima [ 20 ] and C. limon [ 21 ] decreased the immobility time of mice in the forced swim and tail suspension tests, strengthening the suggestion that citrus fragrance can reduce the dose of antidepressants required to treat depressive subjects [ 22 ].
Our group found similar effects in experiments investigating the oral treatment of mice with the EOs obtained from the peels of C. aurantium [ 23 , 24 ], C. latifolia or C. reticulate [ 25 ].
Thus, the activity profile observed for EOs from Citrus species denotes a wide spectrum of action given that the EOs were active in experimental models sensitive to both anxiolytic and antidepressant drugs.
Considering this background, the aim of the present work was to investigate the putative mechanism of the anxiolytic-like effect and identify any neurochemical changes in specific cerebral areas that result from acute treatment with C.
aurantium EO. To better characterize their activity, the EO was also evaluated in anxiety tests after a repeated day oral treatment, where changes in body weight, the integrity of the locomotor system and serum biochemical parameters were monitored.
Finally, the EO was evaluated in experimental procedures related to depressive disorders after oral or inhaled treatment.
aurantium Rutaceae ripe fruits were harvested between April and June of from adult plants in an orchard at the Department of Botany, Institute of Biosciences, UNESP, Botucatu. The plant was identified in the BOTU Herbarium of the Department of Botany, UNESP, where a voucher specimen had been deposited.
Immediately after harvesting the fruits were peeled and the fresh peels were processed with a Clevenger apparatus, and the EO was obtained through hydrodistillation while protected from light and heat.
The EO was then stored until use in the behavioral assays. Afterwards, an aliquot was separated, and the EO was analyzed by gas chromatography coupled with mass spectrometry as previously described [ 24 ].
All of the experiments were conducted in accordance with the Ethical Principles in Animal Research adopted by the Brazilian College of Animal Experimentation COBEA and were approved by the Biosciences Institute — Ethics Committee for Animal Research CEEA.
Adult Swiss male mice 30 days old from a colony at the UNESP Central Animal House facility were used in all of the experiments after a one-week acclimation period in the Animal House of the Department of Pharmacology. Thus, the animals used were approximately 40 to 45 days old.
Diazepam DZP, Germed - EMS, Brazil was used as the standard anxiolytic drug, and imipramine hydrochloride IM, Sigma-Aldrich, USA was used as the standard antidepressant drug.
Flumazenil FLU, Flumazil® - Cristália, Brazil was utilized as a competitive antagonist of benzodiazepine binding, buspirone BUSP, Sigma-Aldrich, USA was used as a partial agonist of 5-HT 1A receptors, and WAY WAY, Sigma-Aldrich, USA was used as a highly selective 5-HT 1A antagonist.
For the intraperitoneal injections i. For oral administration p. The digital video was subsequently reviewed, and behaviors were scored by a highly trained observer who had been blinded to the treatment conditions.
In the rotarod test, the behaviors were registered in real time. All of the experimental procedures took place between am and pm. The apparatus used in our lab has previously been described in detail [ 28 ], and our procedure was based on the original protocol proposed by Crawley and Goodwin [ 29 ].
Each animal was individually placed in the center of the light compartment facing the dark compartment and observed for 5 minutes after the first entry into the dark compartment. During this period, we recorded the number of shuttle crossings an activity-exploration index , the number of rearings, and the time spent in the light compartment, which is the most consistent and useful measure for assessing anxiolytic-like activity [ 30 , 31 ].
The LDB test was also used to address a possible contribution from the GABA-benzodiazepine or serotonergic neurotransmission systems in the biological activity of EO. or WAY 0. The LDB procedure was performed 30 min after the last drug treatment.
At the end of the LDB procedure, the mice acutely or repeatedly treated with EO or used to study the EO mechanism of action were immediately placed onto the Rotarod apparatus to verify the integrity of their motor systems.
Each animal was placed on a non-slippery plastic rod 3. To avoid a bias due to an incapacity not related to drug treatment, the mice were assessed in the rotarod test 24 hours before the start of the experimental procedure.
Only those animals that performed satisfactorily in this initial assessment were evaluated in the RRT after the LDB. FST is consistently recognized as a model for assessing antidepressant activity [ 34 — 36 ] and our experimental conditions were previously detailed [ 28 ].
Briefly, each animal underwent a 15 min pre-test swim in a cm column of water 23 ± 2°C in a transparent plastic cylinder The pre-test session was conducted 24 h prior to the 5-min swim tests, in which the immobility time in seconds was determined by a post hoc evaluation of the digital video using the Etholog 2.
Mice treated with oral or inhaled EO were used in the FST. The inhaled treatments were given in an acrylic box with cotton swabs soaked in 2 ml of EO at 0.
Mice were individually placed into the box for 7 min to receive T1, T2, and T3 following the same time schedule described for oral administration. Thirty minutes after the last treatment, the mice were submitted to the LDB and the RRT, both of which are described above. After completion of the behavioral evaluation, blood was collected for biochemical evaluation.
The blood samples were collected in tubes without anticoagulant, which had been kept at room temperature for 30 min, and were centrifuged at 4, rpm for 20 min at 4°C.
The biochemistry parameters measured were aspartate aminotransferase, alkaline phosphatase, urea, albumin, creatinine, total protein, cholesterol, and triglycerides.
The striatum, hypothalamus, pons, and frontal cortices were isolated, weighed, and stored in liquid nitrogen. For the neurochemical analyses, the tissues were homogenized in 0. The levels of neurotransmitters and their metabolites dopamine DA , 3,4-dihydroxyphenylacetic acid DOPAC and homovanillic acid HVA , and serotonin 5HT and 5-hydroxyindoleacetic acid 5HIAA were measured by reversed-phase high performance liquid chromatography HPLC using a system model 6A, Shimadzu, Kyoto, Japan with an electrochemical detector as described elsewhere [ 39 ].
Briefly, μl samples were loaded into a sample injector, and the mobile phase was delivered at a constant rate of 1. The quantitative data from the behavioral procedures were subjected to Kruskal-Wallis non-parametric variance analysis followed by the Mann-Whitney test when appropriate.
All of the statistical analyses was made using GraphPad InStat® version 3. Table 1 shows the results from the gas chromatography coupled with mass spectrometry analysis of the C.
aurantium EO yield: 0. The main EO compound was identified by retention time and the Kovats retention index [ 40 ] as monoterpene limonene The other compounds detected in the EO included β-pinene 0. The LDB was used to access the anxiolytic-like effect of the EO after acute and repeated treatment, as well as to investigate the effect of interference on the GABAergic and serotonergic neurotransmission systems on the anti-anxiety activity of the EO.
was also evaluated after acute treatment and did not modify behavioral parameters in the LDB Figure 1 , central panel. The data are presented as the median and interquartile range Q1-Q3.
The numbers in brackets indicate the number of mice in each group. The results of the GABAergic and serotonergic interference study are presented in Figure 2. A similar approach was used to evaluate interference with the 5HT 1A serotonin receptor. Thus, it appears that the serotonergic system, through 5HT 1A receptor, is linked to the anxiolytic-like action of the EO.
Acute or repeated treatment with the EO had no effect on the ability of the mice to remain on the rotating bar. In the same way, the individual or combined administration of the benzodiazepine or 5HT 1A receptor agonists and antagonists and the EO did not interfere with motor coordination as evaluated by the RRT.
The results of the forced swim test after the oral or inhaled administration of the EO are presented in Table 3. The different doses or routes of EO administration showed no signs of interference with immobility time, which is the main parameter indicating antidepressant activity in this experimental procedure.
The day EO treatment did not induce any observable signs of toxicity; changes in body weight; or abnormalities in the serum levels of aspartate aminotransferase, alkaline phosphatase, urea, albumin, creatinine, total protein, or triglycerides.
Acute treatment with C. aurantium EO did not change the levels of neurotransmitters or their metabolites DA, DOPAC, HVA, 5HT, and 5HIAA in the cortex, the striatum, the pons or the hypothalamus Table 5.
Traditional populations usually consider the leaves and flowers of Citrus species as a useful decoction [ 12 , 14 ] or infusion [ 13 , 15 ] to treat nervous system disturbances. Previously our group demonstrated the sedative and anxiolytic-like effects of C.
aurantium , C. latifolia , and C. reticulata EO in mice [ 23 — 25 ]. The present work not only investigated the mechanism of action underlying the anxiolytic-like effect of C.
aurantium EO but also investigated the antidepressant-like activity of this EO. The major compound present in the EO was limonene, followed by β-myrcene. Both of these compounds are biologically active in the central nervous system, as mice treated with these compounds have shown decreases in spontaneous activity, rearing, and grooming in an open field test, and the compounds increased barbiturate sleeping time [ 43 ].
These results corroborate previous reports [ 43 ] in which limonene was not able to modify the parameters of anxiolytic-like activity evaluated in the elevated plus maze procedure. These findings strengthen the idea that, in herbal preparations, the interactions between compounds often result in biological activity that is greater than the activity of isolated compounds, as noted earlier [ 44 ].
The 5HT system has been implicated in the modulation of anxiety levels, and some components of this system promote anxiety while others reduce its symptoms [ 45 ].
Since the introduction of buspirone as a novel therapeutic agent for the treatment of anxiety, considerable interest in its therapeutic role in anxiety and mood disorders has been generated [ 2 ]. Buspirone is a partial agonist of 5-HT 1A autoreceptors that acts as an antagonist at certain postsynaptic 5-HT 1A receptor sites.
While reports on the effect of the acute administration of buspirone are inconclusive, chronic treatment causes an anxiolytic-like effect [ 4 , 5 ]. As previously reported for EO [ 23 ], the profile of dose-response curve is not monotonic as usually seen in classical pharmacology.
In a monotonic curve, the sign negative or positive of the slope is maintained throughout the entire dose range. Conversely, in nonmonotonic dose-response curve the slope changes sign at some point along the range of doses, resulting in a U- or inverted U-shape.
In more complexes cases, a nonmonotonic curve assumes a multiphasic shape, in which the slope changes the sign in multiple points along the curve.
This phenomenon has puzzled researchers for more than 50 years and recently a comprehensive overview discusses and contributes to its better understanding [ 46 ]. In spite of the main focus under endocrinology field, examples have also emerging in different areas of research such as toxicology, epidemiology and pharmacology [ 46 , 47 ].
Among the several putative mechanisms which produce nonmonotonic responses in cells, tissues, and animals stand out the cytotoxicity, cell-specific and tissue-specific receptors and cofactors, receptor competition, superimposition of monotonic dose responses and other events related with responses of a biological system caused by products that have a complex mixture of substances [ 46 , 48 ], including essential oils.
The anxiolytic-like effects of the acute treatments were not antagonized by FLU, a benzodiazepine antagonist, but these effects were antagonized by the 5-HT 1A specific antagonist WAY. Considering that benzodiazepines are not effective in the LDB after chronic treatment [ 28 ] and the reduction in the anxiolytic-like effect of the EO after WAY administration, we can infer that the EO functions through interactions with the serotonergic system.
However, we cannot discard the possibility that the EO or its metabolites interact with other neurotransmission systems. Increased 5HT and DA synthesis were observed in the prefrontal cortex and hippocampus of mice after the inhalation of lemon oil vapor a species from the Citrus genus , suggesting that lemon oil vapor possibly affects the response to DAnergic activity by modulating the 5HTnergic system [ 49 ].
In our assessment of DA, 5HT, and their metabolites, no alterations in the levels of these neurotransmitters were observed in the cerebral areas evaluated after acute treatment with the EO.
Contradicting our expectations and previous reports [ 20 , 21 ], the EO was unable to modify immobility time in the FST, an experimental model of depression. The use of 5-HT 1A ligands for the treatment of depressive disorders shows inconsistent results [ 50 ].
This inconsistency may be related to differences in the intrinsic activity and potency of 5-HT 1A drugs that appear to depend on the brain region [ 4 ].
Despite the effect observed in a study treating rats with the same concentration used in our procedure [ 16 ], we could not find an anxiolytic-like effect after inhaled exposure to EO. Similarly, no antidepressant-like effect was found in the FST after the inhalation of EO.
Finally, in agreement with a subchronic day toxicity study of C. aurantium extracts in mice [ 51 ], the day repeated EO treatment in this study showed no deleterious consequences. Daily inspection and periodic weighing showed no differences in general aspect, body weight, or the biochemical parameters of the experimental groups, except for a decrease in total cholesterol.
aurantium , to a high fat diet in Wistar rats reversed the diet-induced changes in lipid levels and lipid peroxidation [ 53 ]. aurantium EO possesses a significant anxiolytic-like activity, and the present results strongly suggest the involvement of 5-HT 1A -receptors.
We believe that these results are promising, as EO treatment might be considered a complementary therapy for the treatment of anxiety disorders. However, further studies are necessary to explore the detailed mechanism of EO action on binding sites.
Moreover, the EO appears to be well tolerated, as none of the different doses caused alterations or showed signs of toxicity. López-Muñoz F, Alamo C, García-García P: The Discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs.
J Anx Disord. Google Scholar. Ravindran LN, Stein MB: The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiaty. Article CAS Google Scholar. Uzun S, Kozumplik O, Jakovljević M, Sedić B: Side effects of treatment with benzodiazepines.
Psych Danub.
Background: There Citrus aurantium for mental alertness still no studies mmental the augantium safety of the Citrus aurantium for mental alertness use of Citrus HbAc management in aerobic submaximal exercise. Objective: To foe the effect Cjtrus Better gut health. aurantium supplementation on Thermogenic slimming pills recovery of cardiorespiratory and autonomic parameters following a session of submaximal aerobic exercise. Methods: Twelve healthy male adults achieved a crossover, randomized, double-blind, and placebo-controlled trial. We evaluated systolic blood pressure SBPdiastolic blood pressure DBPpulse pressure PPmean arterial pressure MAPheart rate HR and, HR variability indexes at Rest and during 60 min of recovery from exercise.
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