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Year : 2018  |  Volume : 50  |  Issue : 5  |  Page : 227--235

Effect of Vaccinium macrocarpon on MK-801-induced psychosis in mice

Disha Shukla1, Rajesh A Maheshwari1, Kirti Patel2, R Balaraman1, Ashim Kumar Sen1,  
1 Department of Pharmacy, Sumandeep Vidyapeeth, Piparia, Vadodara, Gujarat, India
2 Faculty of Pharmacy, The M. S. University of Baroda, Vadodara, Gujarat, India

Correspondence Address:
Ms. Disha Shukla
Department of Pharmacy, Sumandeep Vidyapeeth, Piparia, Vadodara - 391 760, Gujarat


OBJECTIVES: This study was aimed to investigate the effect of aqueous cranberry extract (ACE) on MK-801-induced psychosis in mice. MATERIALS AND METHODS: MK-801-treated mice were administered ACE (1 and 2 g/kg, p.o.) for 14 days. Various behavioral parameters and neurochemical estimations such as dopamine (DA), 5-hydroxytryptamine (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA), glutamate, and glycine as well as markers of oxidative stress such as nitrite levels were measured. RESULTS: Psychosis-induced mice showed a significant elevation of immobility time in forced swim test, locomotor activity, and reduction in time of permanency in rota-rod test, escape latency time in Cook's pole test while treatment with ACE showed a significant alteration in above-mentioned behavioral parameters in MK-801-induced psychosis. Moreover, MK-801-induced psychosis in the mice showed a significant increase in DA, 5-HT, and NA levels and decrease in GABA, glutamate, and glycine levels in the brain. In contrast, treatment with ACE at both doses remarkably altered the neurochemical parameters. In addition, ACE-treated mice showed a substantial reduction in acetylcholinesterase, D-amino acid oxidase enzyme activity, and nitrite levels which were elevated by the administration of MK-801. CONCLUSIONS: Treatment with ACE once for 14 days (1 and 2 g/kg) significantly ameliorated the behavioral symptoms in experimentally induced psychosis by virtue of neuromodulation and decreased oxidative stress.

How to cite this article:
Shukla D, Maheshwari RA, Patel K, Balaraman R, Sen AK. Effect of Vaccinium macrocarpon on MK-801-induced psychosis in mice.Indian J Pharmacol 2018;50:227-235

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Shukla D, Maheshwari RA, Patel K, Balaraman R, Sen AK. Effect of Vaccinium macrocarpon on MK-801-induced psychosis in mice. Indian J Pharmacol [serial online] 2018 [cited 2019 Jan 19 ];50:227-235
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Worldwide, approximately 1% of the total population is affected by the psychiatric disorder, schizophrenia. It is the seventh most costly medical illness of the society.[1] Various environmental and developmental vulnerabilities support it to be a polygenetic disorder.[2] It is a highly complex disorder characterized by positive, negative, and disorganized symptoms.[3]

These symptoms are believed to be arising due to the defects in the dopaminergic,[4] glutamatergic,[5] and serotonergic pathways,[6] and a link between the hyperdopaminergic pathway and the hypoglutamatergic pathway[7] confirms the cause of this disease. Most of the antipsychotic agents produce several undesirable side effects such as extrapyramidal syndrome, weight gain, hyperglycemia, and dyslipidemia. Thus, these drawbacks of the synthetic molecule forced us to work in the line of herbal remedies, which are easily available in daily life and are able to decrease the symptoms related to the disorder with minimal or no side effects.

Cranberry (Vaccinium macrocarpon) is a plant of North American native with its fruits and juice to exhibit different health benefits. Reports have shown that it is effective in peptic ulcer and Escherichia coli induced urinary tract infections. Cranberry along with the protection against lipid peroxidation has also shown in vitro anticancer activity, owing to the effects to the phenolic compounds of the fruit. The amount of phenolic content in cranberry per serving was found to be the highest by weight along with the antioxidant content among 20 fruits analyzed. Of these, some of them are proanthocyanidins, flavonoids, anthocyanidins, condensed tannins, and phenolic acids of low molecular weight. The potential antioxidant compounds, flavonoids and anthocyanins, prevent the oxidative damage due to reactive oxygen species, thus preventing diseases of the cardiovascular system and also some cancers. Flavonoids accounted for 75% of phenolic compounds in comparison to 25% of phenolic and hydroxybenzoic acids when berries were screened for flavonoids and phenolic acids.[8]

Till now, there has been no report on the antipsychotic potential of cranberry. Thus, the proposed research work was planned to study the effects of cranberry on MK-801-induced psychosis in Swiss Albino female mice.

 Materials and Methods

Drugs and chemicals

MK-801 was procured from Sigma Aldrich (USA). Cranberry was obtained from Indu NutriIngredients Pvt. Ltd., Ahmedabad, India. Analytical grade reagents and chemicals were used throughout the study and were purchased from different places.

Saline was used to dissolve MK-801 to get the stock solution of 0.35 mg/ml. Drug solutions were prepared every day by suspending the drug in distilled water. Aqueous cranberry extract (ACE) was prepared in stock solutions of 1 and 2 g/kg, respectively.

Experimental animals

Psychosis was induced by MK-801 using female Swiss Albino mice with a weight of 25-30 g. Animals were procured from Ahmedabad (India) based Zydus Research Centre. All the animals were housed in polymer cages (not more than three animals per cage) with paddy husk as bedding with constant temperature of 25°C ± 2°C and a fixed 12-h light-dark cycle. Animals were kept on standard chow diet and had free access to water ad libitum. The mice were adapted to the laboratory condition 5 days prior to behavioral study. The behavioral studies were carried out between 9.00 and 18.00 h in a noise proof dark laboratory.

The protocol of the experiment (MSU/IAEC/2014-15/1417) was approved by “Institutional Animal Ethical Committee” as per the guidance of the Committee for the Purpose of Control and Supervision of Experiments on Animals, Ministry of Social Justice and Empowerment, Government of India.

Acute toxicity study

Based on OECD guideline no. 423, the magnitude of oral toxicity of ACE was performed in female Swiss Albino mice weighing 25– 30 g at various doses (100, 200, 500, 1000, 2000, 2500, and 5000 mg/kg, p.o.) in three mice. Signs and indications were seen after 0, 30, 60, 120, 180, and 240 min and pursued by once per day for two weeks.[9]

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay

Cell viability assay was performed on SH-SY5Y neuroblastoma cell line which is a commonly used cell line in in vitro evaluation of cytotoxicity study of various chemical compounds.[10] Cells were pretreated with MK-801 at a concentration of 20 nM. The neuroprotective effect of ACE was tested on these pretreated cells at concentrations of 10, 100, 300, 600, and 1000 μg/ml. All the drug dilutions were made in Dulbecco's modified Eagle's medium with fetal bovine serum (10 %) and antibiotic (0.1 %).

The resulting 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) formazan was extracted with 200 μl dimethyl sulfoxide and microtiter plate reader was used to measure the absorbance at 570 nm. GraphPad Prism 5.0 (GraphPad Software, Inc., La Jolla, CA 92037 USA) was used to calculate cell viability by taking 100% cell viability of blank wells containing only media.

Treatment schedule

After acclimatization, all mice were divided randomly into five groups (n = 6 in each group).

Group 1: Normal control (saline 10 ml/kg, i.p.)Group 2: Positive control (MK-801, 0.3 mg/kg, i.p.)[11]Group 3: Clozapine (1 mg/kg, p.o.)[12] + MK-801 (0.3 mg/kg, i.p.)Group 4: ACE (1 g/kg, p.o.)[13] + MK-801 (0.3 mg/kg, i.p.)Group 5: ACE (2 g/kg, p.o.) + MK-801 (0.3 mg/kg, i.p.).

All the previously mentioned medications were administered every day to particular groups for two weeks.

Positive parameter, i.e., locomotor activity, was assessed using photoactometer,[14] negative parameters were assessed using forced swim test[15] and rota-rod apparatus,[16] and cognitive functions were assessed using Cooke's pole apparatus[17] on the 1st, 7th, 14th, and 15th days of the drug treatments.

Estimation of tissue nitrite content

Nitrite estimation was conducted colorimetrically utilizing Griess reagent and supernatant of brain homogenate free from protein.[18] Protein-free supernatant of brain homogenate and Griess reagent (sulfanilamide 1% w/v, naphthyl ethylenediamine dihydrochloride 0.1% w/v, and orthophosphoric acid 2.5% v/v) were blended in equivalent volumes and kept at room temperature for 10 min. Measurement of absorbance was carried out at 540 nm and then was compared with absorbance of sodium nitrite standard.

Estimation of brain acetylcholinesterase activity

In vivo acetylcholinesterase (AChE) activity in the brain was measured by Ellman's assay with slight modifications.[19] Animals were sacrificed, and whole brains were dissected out in ice-cold 0.1 M phosphate-buffered saline (pH 8.0). Homogenization of tissues were performed in ice-cold 0.1 M phosphate-buffered saline (pH 8.0) using homogenizer and subjected to centrifugation at 1000 ×g for 10 min at 4°C. The supernatant was gathered and utilized as a source of enzyme in AChE assay. Acetylthiocholine (30 μL) iodide solution and buffered Ellman's reagent (160 μL) were allowed to react at room temperature for 10 min. Immediately after adding 60 μL supernatant to the reaction mixtures, absorbance was taken at 412 nm using Bioradmicroplate Reader 680XR. The results of positive control group were compared with other groups for AChE inhibitory activity.

Estimation of D-amino acid oxidase activity

D-amino acid oxidase (DAO) activity was estimated colorimetrically according to the reported method.[20] Brain tissue was homogenized in 7 mM pyrophosphate buffer (pH 8.3). Centrifugation of Homogenates were carried out at 550 × g for 5 min followed by estimation of supernatant. The reaction mixture consisted of 0.3 ml of 0.133 M pyrophosphate buffer (pH 8.3) with 700 IU/ml of catalase, 0.3 ml of 0.1 M D-alanine, 0.2 ml of 0.1 mM flavin adenine dinucleotide, and 0.1 ml of 70% (v/v) methanol. Reaction was initiated by adding 0.1 ml of supernatant solution into reaction mixture at 37°C up to 60 min based on the sample activity. Thereafter, termination of the reaction was aided by the addition 1 ml of 10% v/v trichloroacetic acid (TCA). TCA added to the reaction mixture before the commencement of enzyme reaction was taken as blank. The supernatant was collected after centrifugation at 700 × g for 20 min. To 0.5 ml of the supernatant, 0.5 ml of 5 N KOH and 0.5 ml of 0.5% 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole in 0.5 N HCl were included. The mixture was kept at room temperature for 15 min and then added 0.5 of 0.75% w/v KIO4 in 0.2 N KOH to it with intense shaking. Absorbance was measured at 550 nm.

The DAO activity was calculated using the given formula:

Activity (μmol/min) =2.584 A/t.

where, A = differential absorbance at 550 nm between the sample and blank and t = duration of reaction (min).

Neurochemical estimation

Brain was weighed and 10% w/v 0.17 M perchloric acid was used for homogenization for 30 s using an electric homogenizer. Centrifugation was done at 1000 rpm and the supernatant was separated and analyzed for neurotransmitters immediately or kept at −70°C until assayed. RP-HPLC coupled with electrochemical detector (Waters Corporation, Milford, USA) was utilized to estimate the concentration of different neurotransmitters. Estimation was directed by a few adjustments in technique. A Sunfire® C18 column was utilized, and mobile phase involving methanol (15% v/v) in an solution containing (pH 4.2) 32 mM citric acid, 12.5 mM disodium hydrogen orthophosphate, 0.5 mM octyl sodium sulfate, 0.5 mM EDTA, and 2 mM KCl was utilized for separation and the flow rate employed was 1.2 ml/min at 3000 psi operating pressure. The operating potential on electrochemical detector was kept at 0.61 V. The standards were prepared by spiking pre-determined amount of standard (dopamine [DA], norepinephrine [NE], 5-hydroxytryptamine [5-HT], gamma-aminobutyric acid [GABA], glycine, and glutamate) in 1 ml of pooled supernatant. The levels of endogenous neurotransmitters such as glycine, GABA, glutamate, DA, NE, and 5-HT in the aliquots of the brain homogenates were estimated.[21],[22]

Statistical analysis

All the data were demostrated as mean ± standard error of the mean. The outcomes were compared using a computer-based fitting program GraphPad Prism 5.0 (GraphPad Software, Inc., La Jolla, CA 92037 USA). Analysis of statistical difference among the mean of the various groups was analyzed using one-way analysis of variance followed by Dunnet's post hoc test with P 0.05.


Acute toxicity study

There were no any signs of morbidity and mortality observed with the dose of 5000 mg/kg, p.o of ACE in Swiss Albino mice. Therefore, it was confirmed that above mentioned oral dose was safe. The Proposed protocol was followed using 1 and 2 g/kg dose.

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetr azolium assay

In vitro cell viability test for aqueous cranberry extract at different concentrations with the cytotoxic agent MK-801

The exposure of different concentrations of ACE (10, 100, 300, 600, and 1000 μg/ml) in the presence of MK-801 (20 nM) for 24 h possessed significant (P < 0.05) neuroprotective activity in a dose-dependent manner when compared with MK-801-treated human neuroblastoma SHSY5Y cells. The IC50 value of ACE was found to be 69.01 μg/ml [Figure 1].{Figure 1}

Effect of aqueous cranberry extract on time of immobility in forced swim test

On day 1, the immobility duration in positive control mice was not significantly different from normal control mice. MK-801 resulted in a significant (P < 0.001) increase in immobility duration from day 7 to day 15 in comparison to normal control. However, the treatment with clozapine and ACE (1 and 2 g/kg) showed a significant (P < 0.001) decrease in duration of immobility from day 7 to day 15 as compared to positive control animals [Table 1].{Table 1}

Effect of aqueous cranberry extract on rotarod test

The time of permanency in positive control mice was not significantly (P < 0.001) different from normal control on day 1. In positive control mice, there was a significant (P < 0.001) decrease in time of permanency as compared to normal control mice on day 14 and 15 but did not show any significant change on day 7. In contrast, the treatment with ACE (1 and 2 g/kg) showed a marked (P < 0.001) increase in time of permanency on day 14 and 15 as compared to positive control mice [Table 2].{Table 2}

Effect of aqueous cranberry extract on escape latency test

There was a significant (P < 0.001) decrease in the duration of escape latency of positive control mice from day 7 to day 15 as compared to normal control animals. Moreover, ACE (1 and 2 g/kg)-treated mice showed a marked (P < 0.001) increase in escape latency duration from day 7 to day 15 as compared to positive control animals [Table 3].{Table 3}

Effect of aqueous cranberry extract on locomotor activity

There was a significant (P < 0.001) increase in locomotor activity of positive control mice from day 7 to day 15 in comparison to normal control animals. ACE (1 and 2 g/kg)-treated mice caused a significant (P < 0.001) decrease in the locomotor activity on day 14 and 15 as compared to the positive control animals [Table 4].{Table 4}

Effect of aqueous cranberry extract on nitrite levels and D-amino acid oxidase activity

There was a significant (P < 0.001) elevation of brain nitrite levels and DAO activity in positive control animals in comparison to the normal control group. The treatment with ACE (1 and 2 g/kg) showed a significant (P < 0.001) reduction in brain nitrite levels and the DAO activity when compared with positive control animals [Table 5].{Table 5}

Effect of aqueous cranberry extract on inhibition of acetylcholine esterase levels in the brain

The % fold change to normal control in positive control group (42%) was significantly (P < 0.001) reduced in comparison to the normal control animals (100%). The treatment with ACE (1 and 2 g/kg) showed a significant (P < 0.001) increase in % fold change (62.78% and 82.99%, respectively) as compared to the positive control group [Table 5].

Effect of aqueous cranberry extract on NE levels in mice brain

Positive control animals showed a significant (P < 0.001) rise in brain norepinephrine (NA) levels as compared to normal control mice. However, when treated with clozapine, a significant (P < 0.001) reduction in brain NA levels was seen in comparison to positive control group. In addition, mice treated with ACE (1 and 2 g/kg) caused a significant (P < 0.001) decrease in brain NA levels in comparison to positive control animals [Figure 2]a.{Figure 2}

Effect of aqueous cranberry extract on dopamine levels in mice brain

DA levels in mice brain were significantly (P < 0.001) elevated in positive control animals than normal control animals. However, when animals were treated with ACE (1 and 2 g/kg), they caused a marked (P < 0.05; P < 0.01) decrease in brain DA levels in comparison to positive control animals [Figure 2]b.

Effect of aqueous cranberry extract on 5-hydroxytryptamine levels in mice brain

5-HT level was markedly (P < 0.001) elevated in positive control mice than the normal control mice. However, mice treated with ACE (1 and 2 g/kg) caused a significant (P < 0.01 and P < 0.001) reduction in brain 5-HT levels as compared to positive control animals [Figure 2]c.

Effect of aqueous cranberry extract on glycine levels in mice brain

Positive control mice showed a significant (P < 0.001) reduction in brain glycine levels when compared to the normal control group. Clozapine significantly (P < 0.01) prevented this decrease in brain glycine levels induced by MK-801. Treatment with ACE (1 and 2 g/kg) also significantly (P < 0.05 and P < 0.001) increased brain glycine levels when compared against positive control animals [Figure 3]a.{Figure 3}

Effect of aqueous cranberry extract on glutamate levels in mice brain

Positive control animals showed a significant (P < 0.001) decrease in brain glutamate levels when compared to normal control animals. On the contrary, treatment with ACE (1 and 2 g/kg) caused a marked (P < 0.01) elevation of brain glutamate levels in comparison to positive control animals [Figure 3]b.

Effect of aqueous cranberry extract on gamma-aminobutyric acid levels in the brain

Brain GABA level was significantly (P < 0.001) decreased in MK-801-treated mice against the normal control group. However, treatment with ACE (1 and 2 g/kg) caused a marked (P < 0.05 and P < 0.01) increase in brain GABA level when compared to positive control animals [Figure 3]c.


Since synthetic antipsychotics are producing several adverse effects, there is a need for alternative therapy to control the psychotic symptoms in human beings. Medicinal plants have been important sources of unknown chemical constituents with potential therapeutic activity.

Therefore, it was decided to select the herbal plant which is reported to have some effect on the dopaminergic system. In this study, the effect of ACE against MK-801-induced psychosis was evaluated. Administration of MK-801 for 14 days produced psychosis which was characterized by various behavioral symptoms and neurochemical abnormalities.

To assess the safety of the test drug ACE, in vitro activity of this extract on human neuroblastoma SHSY5Y cell line was tested. Evaluation of the efficacy of the test drug extract was conducted by the MTT assay wherein the cell line was previously toxified with MK-801 (20 nM) and then treated with different concentrations of ACE. ACE at different concentrations showed a significant increase in cell viability against the MK-801-toxified cells. It was shown that ACE was safe to be used as a neuroprotective agent.

The increase in the duration of immobility after the administration of N-methyl-D-aspartic acid (NMDA) antagonist has been used as a model for the assessment of negative symptoms of psychosis, e.g., flattening of affect and avolition. In addition, NMDA receptor antagonist-induced behavioral anomalies have been prevented by antipsychotic drugs.[23] Immobility time in the forced swim test was significantly increased upon repeated treatment with MK-801. On the contrary, the test drug at both the therapeutic doses was shown to decrease the immobility time significantly whin MK-801 treated mice.

Administration of MK-801 in animals has impaired performance on tasks that seem to depend on hippocampal or amygdalar function. With these findings, the effect of both the doses of ACE on the pole climbing task in mice was evaluated. ACE at both the therapeutic doses showed a significant increase in the escape latency time tested by Cooke's pole apparatus in comparison to the positive control mice. The test drug delayed the time of pole climbing against the positive control mice.

In addition, according to previous studies, MK-801 produced hyperlocomotion, ataxia, impaired social interactions, and stereotypy in animals,[24] which were due to the interaction of the dopaminergic pathway. Treatment with ACE at the doses of 1 and 2 g/kg showed a correction of motor incoordination by increasing the time of permanency tested by rota-rod apparatus as compared to positive control group.

NMDA antagonists when administered chronically caused hyperactivity and increased the locomotion in animals.[25] Thus, a hyperlocomotor state was observed in the animals of positive control group which was reverted on treatment with ACE at both the doses in the treatment groups.

Excess nitric oxide (NO) is considered to be neurotoxic owing to the formation of peroxynitrite, a very reactive anion formed by protonation.[26] To assess the outcome of MK-801 administration on NO metabolism, the estimation of the nitrite levels as a measure of NO concentration was performed. The nitrite level was significantly elevated in positive control group. The groups treated with ACE at both the therapeutic doses showed a significant decrease in the brain nitrite levels when compared to the positive control groups. A decrease in the nitrite level might be due to the antioxidant potential of ACE through the neuronal nitric oxide synthase activation.

Acetylcholine (ACh) in the cortex has been found responsible for mediating detection, selection and processing of stimuli. Varying concentration levels of acetylcholine have been associated with visual hallucination or reality distortion. Reports have also stated that the metabolism of Ach to be involved in cognitive functions. Hence, estimation of the inhibition of AChE activity was conducted. In the present study, it was seen that treatment with ACE decreased the brain AChE activity significantly as compared to the positive control animals.

D-serine is metabolized by the enzyme DAO. Recent studies show that this enzyme is linked with vulnerability to schizophrenia.[27] Co-administration of D-serine with the conventional neuroleptics showed a significant improvement in negative, positive and cognitive symptoms in schizophrenic subjects. This serves the purpose of the selection of cranberry as a treatment option for the psychosis model. Supporting evidence also states that cranberry contains benzoic acid, a potent DAO inhibitor. Thus, ACE was found to inhibit the activity of DAO enzyme and decrease the enzyme levels in the mice brain significantly as compared to the model control animals.

Several studies have shown that MK-801 administration modifies expression of few proteins in the hypothalamus. Moreover, MK-801 treatment hoists presynaptic dopaminergic neuron action and in an indirect way stimulates DA discharge in the brain.[28] Based on these findings, various neurotransmitter levels were estimated in the mice brain homogenate. It was found that MK-801-treated group showed a significant increase in the DA, 5-HT, and NE levels as compared to that of normal control group at the end of the study. The treatment ACE at both the therapeutic doses was seen to decrease the brain concentrations of DA, NE, and 5-HT significantly as compared to positive control group which was elevated as a result of induced psychosis.

Studies have shown that provision of GABA is responsible for the amelioration of the cognitive symptoms of schizophrenia and lessens the extrapyramidal side effects that occur due to DA blockade. Anatomic, histochemical, biochemical, and hereditary examinations of schizophrenia have affirmed that there are both morphologic changes in interneurons and their associations with pyramidal cells, and also variations from the norm in the GABA metabolism, including diminished levels of GABA alongside the diminished movement of an isoform of glutamic acid decarboxylase, the rate-limiting enzyme in the transformation of glutamate to GABA.[29] Reports have also suggested that a plummeting glutamatergic pathway anticipating from cortical pyramidal neurons to the ventral tegmental region through GABA interneurons hinders DA discharge from mesolimbic DA pathway.[30] Thus, the present neurochemical study has shown that ACE at both the doses caused a significant reduction of the DA, 5-HT, and NA levels in the mice brain against the positive control group.

In 1980, it was discovered that glutamate is reduced in the cerebrospinal fluid of schizophrenic patients, demonstrating the involvement of this major excitatory neurotransmitter in schizophrenia pathology. On this basis, the effect of ACE on the concentrations of GABA, glutamate, and glycine neurotransmitters in mice brain was studied. Interestingly, ACE increased the brain concentrations of these neurotransmitters significantly as compared to MK-801-treated mice.


ACE (1 and 2 g/kg, p.o.) once daily for 14 days significantly ameliorated the behavioral symptoms in experimentally induced psychosis, caused neuromodulation, and decreased oxidative stress.


We are thankful to the Faculty of Pharmacy, The M.S. University of Baroda and Department of Pharmacy, Sumandeep Vidyapeeth, Vadodara, for providing all the facilities for carrying out the work.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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