Content uploaded by Vijayapandi Pandy
Author content
All content in this area was uploaded by Vijayapandi Pandy on Sep 21, 2020
Content may be subject to copyright.
Journal of
Research in Pharmacy
Research Article
www.jrespharm.com
How to cite this article: Khan Y, Pandy V. Morinda citrifolia Linn. (Noni) fruit extract attenuates ethanol seeking behavior in mouse runway
paradigm. J Res Pharm. 2020; 24(5): 632-639.
© 2020 Marmara University Press
ISSN: 2630-6344
https://doi.org/10.35333/jrp.2020.218
632
Morinda citrifolia Linn. (Noni) fruit extract attenuates
ethanol seeking behavior in mouse runway paradigm
Yasmin KHAN 1, 2 *
İD
, Vijayapandi PANDY 1, 3 *
İD
1 Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
2 Department of Pharmacy, Benazir Shaheed University Lyari, Karachi, Pakistan.
3 Department of Pharmacology, Chalapathi Institute of Pharmaceutical Sciences, Chalapathi Nagar, Lam, Guntur-
522034, Andhra Pradesh, India.
* Corresponding Authors. E-mail: yasminkhanmpharm@gmail.com (Y.K.); Tel. +92-302-220 25 62. E-mail:
pandiphd@gmail.com (V.P.); Tel. +91-863-252 41 24.
Received: 27 April 2020 / Revised: 28 June 2020 / Accepted: 21 August 2020
ABSTRACT: In this study, we used methanolic extract of Morinda citrifolia Linn. fruit (MMC) in order to find its effect
against ethanol seeking behavior in a modified mouse runway paradigm. During conditioning/acquisition animals
were treated with accelerated doses of ethanol (0.5-4 g/kg, i.p.) for 5 days (Day 1- Day 5). Then, ethanol seeking
behavior was assessed on Day 6 (postconditioning test). Ethanol seeking behavior was confirmed in ethanol control
group in which the run time to reach the target box was significantly decreased. The test drug MMC (1, 3, and 5 g/kg,
p.o.) caused a significant reversal of the ethanol seeking behavior by increasing the run time to reach the goal box as
seen with the reference drug acamprosate (ACAM; 300 mg/kg, p.o.) in mice. After postconditioning test, non-
rewarded abolishment assays were performed for a period of five days (Day 7 –Day 11). After 5 days of abolishment
(abstinence), a priming dose of ethanol (the highest dose at 1/5th portion applied in control (i.e. 0.8 g/kg, i.p.)) in
house cage significantly reinstated the ethanol-seeking behavior. Interestingly, MMC at a higher dose (5 g/kg, p.o.)
showed significant halt on ethanol-induced reinstatement in mice as shown with the reference drug ACAM (300
mg/kg, p.o.). The outcome of this study reveals that MMC alleviated ethanol seeking behaviour in modified mouse
runway paradigm and it could be effectively used to treat alcohol dependence.
KEYWORDS: Alcohol dependence; acamprosate; Morinda citrifolia Linn; mouse runway paradigm; self-
administration.
1. INTRODUCTION
The motivational effects of numerous consummatory reinforcers including food, water and drugs of
abuse have been extensively studied using a test on alley running performance in rodents [1]. Traditional
runway models of operant drug reward have been restricted by systematization aspects related to the
requirement to ensure medicament delivery to the animal over heavy distances beside intervening with the
runway behavior of rats [2]. Ideally, one would want a system with precise motivational and confounding
factors that should not affect animal behavior. Recently, we developed a novel runway model of drug self-
administration using mice without compromising a great active long-term analysis of runway efficient
performance for drug reward [3].
Morinda citrifolia Linn. (Noni) has been utilized as diet source, medicine, and fabric dyes by Polynesian
people [4]. Traditionally, M. citrifolia has been widely used as prophylaxis and treatment of many CNS
disorders such as anxiety, depression, psychosis and drug dependence. In earlier study by our research
group, MMC was reported for anxiolytic and antidepressant-like activity [5] anti-psychotic-like activity [6]
and anticraving effect in opposition to heroin, ethanol and methamphetamine dependence using
conditioned place preference test in rats and mice [7-10]. The current investigation was designed to test the
activity of MMC against ethanol seeking behavior in mice by employing modified runway paradigm of self-
administration of drug.
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
633
2. RESULTS
2.1. Inhibitory effect of MMC and ACAM against ethanol seeking in mice by employing the modified
runway paradigm of drug self-administration
Figure 1 narrates the operating period of pre- as well as post-conditioning of the different treatment
groups. The two-way ANOVA manifested the effect of treatment [F (5, 84) = 10.81; P < 0.0001] and
Treatment×Time interaction [F (5, 84) = 16.94; P < 0.0001] in a significant manner. However, a non-significant
effect of Time [F (1, 84) = 3.754; P = 0.0561] was observed. The Post doc Bonferroni's multiple comparisons
test revealed that there was no significant difference between all treatment groups on pre-conditioning run
times. However, the post conditioning run times were significantly different between groups (P<0.0001 for
Ethanol control versus Saline control; P<0.05 for MMC 1g versus Ethanol control; P<0.0001 for MMC 3g and
MMC 5g versus Ethanol control; P<0.001 for ACAM versus Ethanol control). This results demonstrated a go
down in runtime (s) (P<0.0001) for ethanol control when compared with saline control group which one
assumes the ethanol seeking behaviour in ethanol-conditioned mice. Interestingly, the MMC (1, 3 and 5
g/kg, p.o.) treated groups presented a significant (P<0.05) reversal of the ethanol seeking behaviour in mice
as is seen with the reference drug acamprosate (300 mg/kg, p.o.) treated mice (Figure 1).
Figure 1. Effect of MMC and ACAM on expression of ethanol run times (mean ± SEM; n = 7- 9) in mice
using a runway paradigm. Significant differences were observed at ####p<0.0001 when compared with
the saline control group; *p<0.05, ***p<0.001 and ****p<0.0001 when compared with the ethanol control
group; when not indicated, the differences were not statistically significant.
Furthermore, the motivation of the test group to approach the desired box during termination
attempts (Ext 1 to Ext 5) from Day 7 to Day 11 were compared between different treatment groups (saline
control, ethanol control, MMC (1, 3, and 5 g/kg, p.o.) along with ACAM (300 mg/kg, p.o.)) as shown in
(Figure 2). The repeated measures ANOVA revealed a significant effect of treatment [F (5, 210) = 54.69; P <
0.0001] and Treatment×Time interaction [F (20, 210) = 2.711; P = 0.0002] on runtime. Post hoc analyses on
extinction runtime (s) data demonstrated a significant (p<0.05) decrease in runtime (s) over 5-day extinction
trials for ethanol control group when related with the saline control group that assumes the ethanol seeking
behaviour in ethanol-extinct animals upto 5 days. The MMC (3 and 5 g/kg, p.o.) treated groups significantly
(P<0.001) reversed the ethanol seeking behaviour in ethanol-extinct mice as is seen with the reference drug
acamprosate (300 mg/kg, p.o.) treated mice. Albeit, MMC at a concentration of 1 g/kg, p.o. failed to
attenuate the ethanol seeking motivation in ethanol-extinct animals (Figure 2).
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
634
Figure 2. Effect of MMC and ACAM on extinction of ethanol run times (mean ± SEM; n = 7- 9) in mice
using a runway paradigm. Significant differences were noted at #p<0.05 and ####p<0.0001 when
compared with saline control group; ***p<0.001 and ****p<0.0001 when compared with the ethanol control
group; when not indicated, the differences were not statistically significant.
On reinstatement day (Day 13), the two-way ANOVA results indicated a significant change due to
Treatment [F (5, 84) = 27.65; P < 0.0001], Time [F (1, 84) = 26.78; P < 0.0001] and Treatment×Time interaction
[F (5, 84) = 12.50; P < 0.0001]. The Post doc Bonferroni's multiple comparisons test revealed that the ethanol at
a low dose (priming dose 0.8 g/kg, i.p.) reinstated the ethanol seeking behavior by exhibiting a quicker run
time in the ethanol control group (Figure 3). MMC at a higher dose (5g/kg, p.o.) exhibited a significant
reversal of the priming ethanol-induced reinstatement in mice that was comparable with the reference drug,
acamprosate (300 mg/kg, p.o.). However, MMC at tested doses of 1 and 3 g/kg, p.o. failed to reverse the
priming ethanol-induced reinstatement in mice.
Figure 3. Effect of MMC and ACAM on reinstatement of ethanol run times (mean ± SEM; n = 7- 9) in mice
using a Runway paradigm. Significant differences were noted at ####p<0.0001 when compared with
saline control group; ****p<0.0001 when compared with the ethanol control group; when not indicated, the
differences were not statistically significant.
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
635
3. DISCUSSION
Issell et al., (2008) performed a pharmacokinetic study of Morinda citrifolia Linn. (noni) fruit extract in
healthy human volunteers. In this study, scopoletin was used as a biomarker for M. citrifolia fruit extract and
its plasma concentration were noted in a range of (0.5 to 5 ng/mL; upto 8h) after ingestion of M. citrifolia
fruit extract capsules (1.5, 2 and 2.5g). This study highlighted scopoletin can be used as a biomarker for
pharmacokinetic studies of noni products [11]. Similarly in a preclinical study, Noni puree (1 ml/100 g b.wt,
p.o) was given to female rats and plasma scopoletin level was monitered. This results revealed a peak level
of scopoletin was reached in 2 h and reduced to 50% in 4 h [12]. Moreover, in an in vitro study by Yang et al.,
2015, twelve coumarins including scopoletin was investigated for its ability to penetrate the blood brain
barrier (BBB) using MDCK-pHaMDR cell monolayer BBB model. In this study, Papp value was determined
and compared between different coumarins. In general, if Papp value of a drug is more than 1 × 10−5 cm/s,
the drug is expected to have good penetration through BBB. The Papp AP-BL value of scopoletin was found
to be 37.10 ± 1.97 × 10−6 cm/s that was comparable with the reference drug caffeine (43.58 ± 4.86 × 10−6
cm/s). This study clearly indicated the high penetrating nature of scopoletin through BBB [13].
Zulissetiana and Susilawati (2013) demonstrated that methanolic extract of M. citrifolia fruit (50-800
mg/kg, p.o.) significantly increased the Brain-derived neurotrophic factor (BDNF) level in the
immobilization stressed (2 h immobilization for 21 days) male swiss webster mice [14]. Muralidharan et al.
(2010) reported that ethyl acetate extract of M. citrifolia fruit (200, 400 mg/kg, for 21 days, p.o.) showed a
memory enhancing activity in beta-amyloid (25-35) peptide-induced amnestic mice using step-down
inhibitory avoidance, Morris water maze and Y maze tests [15]. Moreover, this study highlighted the
inhibitory effect of ethyl acetate extract of M. citrifolia fruit on acetylcholine esterase (AchE) and monoamine
oxidase-A (MAO-A) enzymes activity in the brain [15]. Meanwhile, the antioxidant enzymes such as
superoxide dismutase (SOD), glutathione reductase (GSHr) and glutathione peroxidase (GSHx) in the
mouse brain was significantly reduced in beta-amyloid (25-35) peptide-induced amnestic mice and these
enzymes levels were restored in M. citrifolia fruit extract treated mice [15]. All these preclinical study
evidences confirm that the biactive principles of M. citrifolia fruit extract could penetrate the BBB and can
exhibit various CNS activities.
Conditioning with intensifying concentrations of ethanol, (0.5, 1, 2, 4 and 4 g/kg, i.p.) from 1 to 5 days
revealed ethanol seeking behavior on postconditioning day (Day 6) by declining the runtime to reach the
goal box is explained in Figure 1. This result demonstrated the strong rewarding properties of ethanol that
can activate the brain’s reward pathways thereby execute motivational ethanol seeking behavior [16].
Interestingly, Figure 1 also demonstrated that the test groups who were treated with (1, 3 and 5 g/kg, p.o.)
doses of MMC and (300 mg/kg, p.o.) of ACAM implied the inhibitory activity against ethanol seeking in a
modified straight alley runway model. As per literature, dopamine is inferred in certain effective
physiological and pharmacological actions including the motivational reward [17]. The dopaminergic
neuronal system involving certain brain part for example, the amygdala, the ventral tegmentum and nucleus
accumbens, are associated with positive reinforcement, craving of drug and sensitive to recur of ethanol and
also some abusable drugs [18,19]. The research team of this study earlier reported antidopaminergic activity
of MMC following both in vivo and ex vivo investigations [20,6]. Interestingly, our research team also
demonstrated the biphasic effect of ethyl acetate fraction of the methanolic extract of unripe noni (M. citrifolia
Linn.) fruit (EAMMC) on the dopaminergic system in mice [21]. EAMMC at lower doses (< 25 mg/kg, p.o.)
was found to attenuate a dopamine receptor agonist apomorphine-induced cage climbing and
methamphetamne-induced stereotypy in mice. On converse, EAMMC at a higher dose (3000 mg/kg, p.o.)
inhibited a dopamine D2 receptor antagonist haloperidol (0.5 mg/kg, i.p.)-induced catalepsy in mice. This
study postulated the blockade of postsynaptic dopaminergic D2 receptors at lower doses of EA-MMC and
blockade of presynaptic autodopaminergic D2 receptors (attenuating negative feedback mechanism) at
higher doses of EA-MMC could be responsible for the biphasic effect of noni fruit extract [21]
Moreover, it has been proposed the inclusion of phytochemicals of M. citrifolia fruit, rutin and
scopoletin for its antidopaminergic property [21,22]. Thus, we postulate that the anti-motivational property
of MMC against ethanol self-administration in the mouse modified runway paradigm may stem from its
antidopaminergic activity. The phytochemicals of noni, rutin and scopoletin might be responsible to have
anti-motivational property of MMC against ethanol self-administration. Currently in our laboratory, we
directed our investigation applying rutin and scopoletin per se against ethanol seeking behavior in mouse
behavioral models.
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
636
Reinforcing/motivational properties of drugs of abuse can be affected by conditioned sensitization of
drugs of abuse. In this scenario, the animals might run fast over trials due to formation of conditioned
sensitization [23]. However, the notion that conditioned sensitization can be influenced by other parameters
like locomotion and cognitive function. Interestingly, MMC was found not to alter spontaneous locomotor
activity and also to facilitate learning and memory in mice [9]. Therefore, it is unlikely that the effect of MMC
in reversing ethanol self-administration is reponsible for drug-triggered variations in the test animal motoric
activity.
In the current protocol, no saline injections were administered in place of the ethanol injections during
extinction period since, doing so would undoubtedly have required many more extinction trials to weaken
the runway behavior (i.e. the injection itself would be expected to serve as a form of conditioned
reinforcement due to its pairing with the administration of the drug). Numerous reports following this
protocol have been published in the literature [24-26]. The anti-motivational property of MMC (3 and 5
g/kg, p.o.) against ethanol seeking was also observed during the extinction period proposing its efficacy
during ethanol abstinence.
In the present study, a small dose ethanol (0.8 g/kg, i.p.) administration (priming) following
extinction trials significantly reinstated the motivation of subjects to reach the goal box. This result is in
agreement with a previous study for "relapse" drinking in a two-bottle and in a four-bottle oral ethanol self-
administration paradigm[27]. According to the current analysis, (5 g/kg, p.o.) of MMC and (300 mg/kg,
p.o.) of the reference drug acamprosate were identified to be effective in turning back or relieving ethanol-
induced restoration of runway behavior, which implies that MMC is likely to be effective only at (5 g/kg,
p.o.) in treating relapse of ethanol self-administration.
4. CONCLUSION
Overall, the current experimental data results reveal the anti-motivational properties of M. citrifolia
fruit in subjects traversing the modified runway for self-administration of ethanol thereby suggesting the
therapeutic potential of M. citrifolia fruit against alcohol dependence. Additional clinical investigations are
required to confirm these preclinical findings.
5. MATERIALS AND METHODS
5.1. Unripe M. citrifolia fruit extract
Methanolic extract of M. citrifolia (MMC) was standardized first and then used for the present study
and its preparation and phytochemical characterization was demonstrated in our earlier publications [6,20].
5.2. Animals
All animals were weighed 25-30 g bw. Animals were housed and fed for 7 days earlier the initiation of
the study. All the experiments were conducted as per guidelines set of University of Malaya (Approval No.
2013-12-03/PHAR/R/VP) to meet the standards of the National Research Council of the Academies of the
USA.
5.3. Drugs
Ethanol (10% v/v) solution was acquired from ethanol (95% v/v) (Copens Scientific, Malaysia) in
sterile water for injection and injected into peritonium. MMC and ACAM suspension was prepared in 1%
w/v sodium carboxymethyl cellulose. In order to prepare MMC and ACAM suspensions 1% w/v sodium
carboxymethyl cellulose was used and given by oral route in a constant amount of 1 ml/100 g body weight
of the animal 1h prior to postconditioning, extinction, and reinstatement tests.
5.4. Modified Straight Alley Runway Paradigm of Ethanol Self-Administration in mice
5.4.1. Apparatus
The Composite Aluminium was used to make this apparatus as described in our earlier publication
[3]. The mice tracement using this apparatus was noted in real time with the help of a Logitech webcam
(C270) mounted above the apparatus and also attached with a computer. Using a digital stopwatch, the run
time (seconds) was assessed manually.
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
637
5.4.2. Procedure
After 3 days of each 15 min habituation to the runway device (except the target box), the experimental
data collection was initiated. On a given trial, every mouse was kept for testing in the initiation (start) box,
and then permitted to traverse the alley and enter the goal box, the time required to do so (run time) was
recorded on every trial and constituted the primary dependent measure. Following 3-day habituation, a
baseline runtime was recorded which was served as preconditioning runtime. Conditioning/acquisition
trials were then initiated for the next 5 days (Day 1-Day 5) during which each animal received ethanol
(raising doses 0.5, 1, 2, 4 and 4 g/kg, i.p.) or saline upon entry into the goal box and conditioned for half an
hour in the target (goal) box from Day 1 to Day 5 as described previously [3]. The Post-conditioning test was
performed 24 h after the last conditioning (on Day 6) during which no saline or ethanol doses were given
upon target box entry. From Day 7 to Day 11, animals were subjected to extinction trials during which
animals did not receive ethanol or saline upon goal box entry. On Day 12 no procedures were performed,
then on Day 13, the animals underwent reinstatement testing in which animals got a small dose of ethanol
0.8 g/kg, i.p. (1/5th of the maximum dose of ethanol used in conditioning) to reinstate the subjects’
motivation to receive ethanol in the goal box.
5.4.3. Effect of MMC and ACAM on ethanol seeking behavior in mouse runway paradigm of self-administration
Mice were randomly selected and divided into six groups such as: Group 1- Saline control group;
Group 2- Ethanol control group; Group 3, 4, 5- MMC (1, 3, and 5 g/kg, p.o.)-treated groups respectively;
Group 6- a reference drug, acamprosate (ACAM) (300 mg/kg, p.o.)-treated group. During the conditioning
stage, the saline-control group (Group 1) was administered with saline whereas Groups (2, 3, 4, 5, and 6)
received ethanol upon goal box entry as depicted in Figure 4. The test groups served with MMC (1, 3, and 5
g/kg, p.o.) and ACAM (300 mg/kg, p.o.), 1 h prior to postconditioning, extinction, and reinstatement
testing.
Data are expressed as mean ± S.E.M. The results were analysed using two-way ANOVA with post hoc
Bonferroni's multiple comparisons test for post conditioning and reinstatement results. A repeated measures
analysis of variance (ANOVA) using one ―between-subject’s variable ―Group and a ―within-subject’s
variable ―Trial was performed for the extinction trial results. Statistical significance was set as p < 0.05.
Figure 4. Study design of mouse runway paradigm of drug self-administration.
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
638
Acknowledgements: The author V.P extend his sincere appreciation to Science & Engineering Research Board (SERB),
India for the core research grant (CRG/2018/000813).
Author contributions: Concept – Y.K., V.P.; Design – Y.K., V.P.; Resources – Y.K., V.P.; Materials – Y.K., V.P.; Data
Collection and/or Processing – Y.K., V.P.; Analysis and/or Interpretation – Y.K., V.P.; Literature Search – Y.K., V.P.;
Writing – Y.K., V.P.; Critical Reviews – Y.K., V.P.
Conflict of interest statement: The authors declare that they have no competing interests.
Ethics committee approval: This study was approved by FOM Institutional Animal Care and Use Committee,
University of Malaya (FOM IACUC) with approval number 2013-12-03/PHAR/R/VP on December 18, 2013.
REFERENCES
[1] Ettenberg A. The runway model of drug self-administration. Pharmacol Biochem Behav. 2009; 91: 271–277.
[CrossRef]
[2] Geist TD, Ettenberg A. A simple method for studying intravenous drug reinforcement in a runway. Pharmacol
Biochem Behav. 1990; 36: 703–706. [CrossRef]
[3] Pandy V, Khan Y. Design and development of a modified runway model of mouse drug self-administration. Sci
Rep. 2016; 6, 21944. [CrossRef]
[4] Dixon AR, McMillen H, Etkin NL. Ferment this: the transformation of Noni, a traditional Polynesian medicine
(Morinda citrifolia, Rubiaceae). Econ Bot. 1999; 53(1): 51–68. [CrossRef]
[5] Narasingam M, Vijeepallam K, Mohamed Z, Pandy V. Anxiolytic- and antidepressant-like activities of a methanolic
extract of Morinda citrifolia Linn. (noni) fruit in mice: Involvement of benzodiazepine-GABAAergic, serotonergic
and adrenergic systems. Biomed Pharmacother. 2017; 96: 944-952. [CrossRef]
[6] Pandy V, Narasingam M, Mohamed Z. Antipsychotic-like activity of Noni (Morinda citrifolia Linn.) in mice.
BMC Complement Altern Med. 2012; 12(1): 186. [CrossRef]
[7] Narasingam M, Pandy V, Mohamed Z. Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of
heroin in conditioned place preference but not withdrawal in rodents. Exp Anim. 2016; 65(2): 157–164. [CrossRef]
[8] Khan Y, Pandy V. Methanolic Extract of Morinda citrifolia L. (Noni) Unripe Fruit Attenuates Ethanol-Induced
Conditioned Place Preferences in Mice. Front Pharmacol. 2016; 7: 352. [CrossRef]
[9] Pandy V, Wai YC, Roslan NFA, Sajat A, Jallb AHA, Vijeepallam K. Methanolic extract of Morinda citrifolia Linn.
unripe fruit attenuates methamphetamine-induced conditioned place preferences in mice. Biomed Pharmacother.
2018; 107: 368-373. [CrossRef]
[10] Pandy V, Khan Y. Noni (Morinda citrifolia Linn.) fruit juice attenuates the rewarding effect of ethanol in
conditioned place preference in mice. Exp Anim. 2016; 65(4): 437–445. [CrossRef]
[11] Issell BF, Franke A, Fielding RM. Pharmacokinetic study of Noni fruit extract. J Diet Suppl. 2008; 5: 373–382.
[CrossRef]
[12] Wang MY, West BJ, Jensen CJ, Nowicki D, Su C, Palu AK, Anderson G. Morinda citrifolia (Noni): a literature
review and recent advances in Noni research. Acta Pharmacol. Sin. 2002; 23: 1127–1141.
[13] Yang YF, Wei Xu, Song W, Ye M, Yang XW. Transport of Twelve Coumarins From Angelicae Pubescentis Radix
Across a MDCK-pHaMDR Cell Monolayer-An in Vitro Model for Blood-Brain Barrier Permeability. Molecules.
2015; 25: 20(7): 11719-32. [CrossRef]
[14] Zulissetiana KF, Susilawati. The Efficacy of Noni Fruit Methanol Extract (Morinda citrofolia) to Brain Derived
Neurotrophic Factor (BDNF) on Male Swiss Webster Mice Induced By Immobilization Stress. Journal of Physics:
Conf. Series 1095. 2018; 012013.
[15] Muralidharan P, Srikanth J. Anti epileptic activity of Morinda citrifolia Linn fruit extract. J Chem. 2010; 7: 612–616.
[CrossRef]
[16] Schulte T, Oberlin BG, Kareken DA, Marinkovic K, Müller‐Oehring EM, eyerhoff DJ, Tapert S. How acute and
chronic alcohol consumption affects brain networks: insights from multimodal neuroimaging. Alcohol Clin Exp
Res. 2012; 36(12): 2017–2027. [CrossRef]
[17] Luo SX, Huang EJ. Dopaminergic neurons and brain reward pathways: from neurogenesis to circuit assembly. Am
J Clin Pathol. 2016; 186(3): 478–488. [CrossRef]
Khan and Pandy
Noni fruit attenuates ethanol seeking in mice
Journal of Research in Pharmacy
Research Article
https://doi.org/10.35333/jrp.2020.218
J Res Pharm 2020; 24(5): 632-639
639
[18] Aguilar MA, Manzanedo C, Do Couto BR, Rodríguez-Arias M, Miñarro J. Memantine blocks sensitization to the
rewarding effects of morphine. Brain Res. 2009; 1288: 95–104. [CrossRef]
[19] Davis M, Myers KM. The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications
for exposure therapy. Biol Psychiatry. 2002; 52(10): 998–1007. [CrossRef]
[20] Pandy V, Narasingam M, Kunasegaran T, Murugan DD, Mohamed Z. Effect of noni (Morinda citrifolia Linn.) fruit
and its bioactive principles scopoletin and rutin on rat vas deferens contractility: an ex vivo study.
ScientificWorldJournal. 2014; 2014: 909586. [CrossRef]
[21] Pandy V, Narasingam M, Vijeepallam K, Mohan S, Mani V, Mohamed Z. The Ethyl Acetate Fraction of a
Methanolic Extract of Unripe Noni (Morinda Citrifolia Linn.) Fruit Exhibits a Biphasic Effect on the Dopaminergic
System in Mice. Exp Anim.2017; 5: 66(3): 283-291. [CrossRef]
[22] Pandy V, Vijeepallam K. Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of
schizophrenia in mouse models. Exp Anim. 2017; 66 (4): 417-423. [CrossRef]
[23] Bevins RA, Besheer J, Pickett KS. Nicotine-conditioned locomotor activity in rats: dopaminergic and gabaergic
influences on conditioned expression. Pharmacol Biochem Behav. 2001; 68: 135-145. [CrossRef]
[24] Kuzmin A, Sandin J, Terenius L, Ogren SO. Acquisition, expression, and reinstatement of ethanol-induced
conditioned place preference in mice: effects of opioid receptor-like 1 receptor agonists and naloxone. J Pharmacol
Exp Ther. 2003; 304(1): 310–318. [CrossRef]
[25] Mattioli L, Titomanlio F, Perfumi M. Effects of a Rhodiola rosea L. extract on the acquisition, expression, extinction,
and reinstatement of morphine- induced conditioned place preference in mice. Psychopharmacology (Berl). 2012;
221(2): 183-193. [CrossRef]
[26] Mueller D, Stewart J. Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine
after extinction. Behav Brain Res. 2000; 115(1): 39–47. [CrossRef]
[27] Spanagel R, Hölter SM, Allingham K, Landgraf R, Zieglgänsberger W. Acamprosate and alcohol: I. Effects on
alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol. 1996; 305 (1–3): 39–44. [CrossRef]
This is an open access article which is publicly available on our journal’s website under Institutional Repository at http://dspace.marmara.edu.tr.
