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Linalool and -pinene exert their

antidepressant-like activity through the
monoaminergic pathway


Impact Factor: 2.7 DOI: 10.1016/j.lfs.2015.02.021


7 92


Silvia Laura Guzmn Gutirrez Rocio gomez-cansino

Universidad Nacional Autnoma de Mxico Universidad Nacional Autnoma de Mxico


Ricardo Reyes-Chilpa
Universidad Nacional Autnoma de Mxico


All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Ricardo Reyes-Chilpa
letting you access and read them immediately. Retrieved on: 23 February 2016
Life Sciences 128 (2015) 2429

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Life Sciences

journal homepage: www.elsevier.com/locate/lifescie

Linalool and -pinene exert their antidepressant-like activity through the

monoaminergic pathway
Silvia Laura Guzmn-Gutirrez a,c,d, Herlinda Bonilla-Jaime a, Roco Gmez-Cansino b, Ricardo Reyes-Chilpa b,
Laboratorio de Farmacologa Conductual, Dpto. Biologa de la Reproduccin, D.C.B.S. Universidad Autnoma Metropolitana Iztapalapa, 09340, Iztapalapa, Mxico D.F., Mxico
Departamento de Productos Naturales, Instituto de Qumica, Universidad Nacional Autnoma de Mxico, Ciudad Universitaria, 04510 Coyoacn, Mxico D.F., Mxico
Departamento de Inmunologa, Instituto de Investigaciones Biomdicas, Universidad Nacional Autnoma de Mxico, Ciudad Universitaria, 04510 Coyoacn, Mxico D.F., Mxico
Ctedra CONACYT, Mxico

a r t i c l e i n f o a b s t r a c t

Article history: Aims: Linalool and -pinene are two volatile monoterpenes that possess antidepressant-like activity. These are
Received 2 December 2014 components of many aromatic plants used in folk medicine around the world to relieve anxiety and depression.
Received in revised form 14 January 2015 In this contribution, we focused on examining the mechanism of action of these compounds.
Accepted 12 February 2015 Main methods: We used mice in the forced swimming test (FST) and antagonist drugs (i.p.) to receptors related to
Available online 11 March 2015
the depression process such as 5-HT1A. To assess the possible contribution of the serotoninergic system, animals
were pre-treated with WAY 100635 (a 5-HT1A receptor antagonist) and PCPA (a serotonin synthesis inhibitor).
To assess the participation of the noradrenergic system, the animals were pre-treated with yohimbine (an 2 re-
-Pinene ceptor antagonist), propranolol (a receptor antagonist) and neurotoxin DSP-4 (a noradrenergic neurotoxin). In
Antidepressant the dopaminergic system, we used SCH23390 (a D1 receptor antagonist).
Monoterpenes Key ndings: WAY 100635 blocked the antidepressant-like effect of linalool and -pinene. In contrast, pretreat-
Aromatic compounds ment of mice with PCPA did not modify reductions in the immobility time elicited by the two monoterpenes.
The yohimbine modied the effect of linalool on immobility time. Propranolol and neurotoxin DSP-4 reversed
the anti-immobility effect of -pinene; also, SCH23390 blocked the antidepressant-like effect of -pinene.
Signicance: Our results indicate that linalool and -pinene produce an antidepressant-like effect through inter-
action with the monoaminergic system.
2015 Elsevier Inc. All rights reserved.

1. Introduction nervous system, diarrhea, vomiting, pain in the bones, colic in children,
as well as postpartum baths [2]. Our group previously determined that
Although several treatment options are available for depressive dis- the essential oil of L. glaucescens shows antidepressant activity in mice
orders, there is a need for new drugs with improved tolerability and ef- subjected to the forced swimming test (FST). The main active com-
cacy. There are several reports describing the antidepressant activity of pounds were identied as linalool and -pinene [3]. Recently, the anti-
different plant species, and in some cases, the active components have depressant activity of linalool was conrmed using the tail suspension
been identied. The most notable example is Hypericum perforatum test (TST) in mice [4]. However, its mechanism of action remains
(St. John's Wort), which contains the active components hypericin and unknown.
hyperforin [1]. Experimental and clinical evidence support the monoaminergic hy-
Litsea glaucescens (Lauraceae) is a shrub species native to Mexico pothesis of depression, which postulates that the main neurochemical
and Central America. It is known as laurel, its leaves are commonly process in this disorder is impairment of monoaminergic neurotrans-
used as food condiment, replacing the European species Laurus nobilis mission with a concomitant decrease in extracellular concentrations of
(Lauraceae), but laurel is also used in traditional medicine. An infusion noradrenaline and/or serotonin [5]. For this reason, the receptors, trans-
of leaves of L. glaucescens is used to treat illnesses related to the central porters or enzymes that participate in monoaminergic transmission
were explored as targets of substances with potential antidepressant ac-
tivity. This study was designed to explore the mechanism of action of
linalool and -pinene. To achieve this objective, we used antagonist
Corresponding author at: Instituto de Qumica, Departamento de Productos Naturales,
Universidad Nacional Autnoma de Mxico, Ciudad Universitaria, Coyoacn 04510,
drugs on some serotonergic, dopaminergic and noradrenergic receptors
Mxico D.F., Mxico. Tel.: +52 55 56224512; fax: +52 55 56162203. that participate in pathways modied by some antidepressant drugs,
E-mail address: chilpa@unam.mx (R. Reyes-Chilpa). such as uoxetine.

0024-3205/ 2015 Elsevier Inc. All rights reserved.
S.L. Guzmn-Gutirrez et al. / Life Sciences 128 (2015) 2429 25

Fig. 1. Effect of the pre-treatment with WAY 100635 (1 mg/kg, i.p.) or PCPA (100 mg/kg, i.p.) on the immobility time induced by linalool (100 mg/kg, i.p.; panels A and B, respectively) or -
pinene (100 mg/kg, i.p.; panels C and D, respectively) in the FST in mice. Each column represents the mean SEM (n = 810). ANOVA followed by a Tukey's test, p b 0.05 with the ex-
ception of panel C (ANOVA KruskalWallis followed by Dunn's test). Signicant effect compared to the control group (a), and to the monoterpene group (b).

2. Materials and methods laboratory animals. All experiments were performed in a room isolated
from external noise.
2.1. Animals
2.2. Drugs
All the experiments were performed with adult male ICR
mice (2733 g) obtained from the bioterium of Universidad All compounds were purchased from the Aldrich Co. (St. Louis, MO):
Autnoma Metropolitana in Mexico City. Mice were maintained Imipramine hydrochloride (tricyclic antidepressant), linalool, (1S)-()-
under a 12-h light/dark cycle (22 1 C) with free access to -pinene, WAY 100635 (a 5-HT1A receptor antagonist), yohimbine (a
food and water. Procedures involving animal care were approved 2 receptor antagonist), prazosin (a 1 receptor antagonist), proprano-
by the Ethics Committee and conducted in conformity with the Mexican lol (a non-selective receptor antagonist), SCH23390 (a D1 receptor
Ofcial Norm for Animal Care and Handling (NOM-062-ZOO-1999), antagonist), PCPA (a serotonin synthesis blocker), and DSP-4 (a norad-
and in compliance with international rules on the care and use of renergic neurotoxin). -Pinene, linalool, yohimbine, PCPA, prazosin,
26 S.L. Guzmn-Gutirrez et al. / Life Sciences 128 (2015) 2429

Fig. 2. Effect of the pre-treatment with yohimbine (1 mg/kg, i.p.), propanolol (2 mg/kg, i.p.) or DSP-4 (50 mg/kg, i.p.) on the immobility time induced by linalool (100 mg/kg, i.p.; panels A, C
and E, respectively) or -pinene (100 mg/kg, i.p.; panels B, D and F, respectively) in the FST in mice. Each column represents the mean SEM (n = 812). ANOVA followed by a Tukey's
test, p b 0.05 with exception of panel F (ANOVA KruskalWallis) followed by Dunn's test. Signicant effect compared to the control group (a), and to the monoterpene group (b).
S.L. Guzmn-Gutirrez et al. / Life Sciences 128 (2015) 2429 27

and WAY 100635 were suspended in 0.5% Tween 80 in saline solution monoterpenes, previous administration of WAY 100635 (a 5-HT1A re-
(0.9%). Propranolol, SCH23390, imipramine hydrochloride, and DSP-4 ceptor antagonist) blocked the antidepressant-like effect of both linalo-
were dissolved in saline solution (0.9%). Treatments were injected in- ol (F4,35 = 53.13, p b 0.05) and -pinene (F4,35 = 42.06, p b 0.05). In
traperitoneally (i.p.) at a volume of 0.1 mL/10 g of body weight. Control contrast, pretreatment of mice with PCPA (tryptophan hydroxylase in-
animals received the same volume of the vehicle. hibitor) did not modify the reduction in immobility time elicited by lin-
alool (Fig. 1C) or -pinene (Fig. 1D).
2.3. Treatments
3.2. Involvement of the noradrenergic and dopaminergic systems
For all experiments we use imipramine hydrochloride (30 mg/kg),
linalool (100 mg/kg 3) and (1S)-()--pinene (100 mg/kg 3) [3]. In relation to noradrenergic and dopaminergic pathways, Fig. 2A
To assess the possible contribution of the serotoninergic system over (F4,55 = 89.09, p b 0.05), C (F4,35 = 41.71, p b 0.05) and E (F4,55 =
linalool and -pinene action, mice were pre-treated with PCPA 23.84, p b 0.05) show that linalool and imipramine decreased the immo-
(100 mg/kg 4), WAY 100635 (0.1 mg/kg), or vehicle. For the FST, bility time of mice compared to control. Similarly, Fig. 2B (F4,35 = 41.71,
WAY 100635 was administered three times, always 15 min before ad- p b 0.05), D (F4,35 = 40.79, p b 0.05) and F (H(4) = 32.93, p b 0.05) show
ministration of linalool or -pinene. PCPA was administered once a that -pinene and imipramine decreased immobility time. Concerning
day for four consecutive days before the FST [6]. the mechanism of action, pre-treatment with yohimbine (an 2 recep-
We also tested the inuence of the noradrenergic, adrenergic and tor antagonist) modied the effect of linalool (F3,41 = 11.07, p b 0.05)
dopaminergic systems on the antidepressant-like effect of monoter- (Fig. 2A), but not -pinene (Fig. 2B).
penes. In this case, the animals were pre-treated with yohimbine Regarding -pinene, Fig. 2D (F4,35 = 40.79, p b 0.05) and F (H(4) =
(1 mg/kg), prazosin (1 mg/kg), DSP-4 (50 mg/kg), propranolol 32.93, p b 0.05), show that propranolol and neurotoxin DSP-4, respec-
(2 mg/kg), SCH23390 (0.01 mg/kg) or vehicle. For the FST, each drug tively, were able to prevent its anti-immobility effect; whereas linalool
was administered three times, always 15 min before administration of was not affected by the administration of either treatment (Fig. 2C
linalool or -pinene, except for DSP-4, which was administered only and E). Prazosin had no effect on the activity of either monoterpene.
once, 7 days before the swimming test [7]. Fig. 3 (F4,45 = 61.49, p b 0.05) shows that -pinene and imipramine
decreased the immobility time of mice with respect to control. Pre-
2.4. Forced swimming test (FST) treatment with SCH23390 (a D1 receptor antagonist) blocked the
antidepressant-like effect of -pinene.
The FST method used to assess antidepressant activity was similar to
that described by Herrera-Ruiz and Martnez-Vzquez [89]. The appa- 4. Discussion
ratus consisted of a glass vessel (25 cm height 12 cm diameter) lled
with water to a depth of 15 cm (24 1 C). In the pre-test session, each Although current antidepressants offer both short- and long-term
animal was placed individually in the vessel for 15 min, 24 h prior to the benets, important problems persist, such as tolerance, delayed thera-
5-min swimming test. Each drug was administered three times: imme- peutic onset, limited efcacy of common treatments in milder and resis-
diately after the initial pre-test, and at 18 h and 1 h 15 min prior to the tant depression [10]. For these reasons, patients need new therapeutic
FST, while linalool or -pinene was administered 15 min after each ap- alternatives that could be provided by medicinal plants and natural
plication of the drugs, except for PCPA and DSP-4 (see the Treatments products.
section). All test sessions were video-recorded and analyzed after the Linalool is a monoterpene that acts on the central nervous system; for
experiment to register the immobility time (in seconds) for each ani- example, it has shown anticonvulsive and sedative effects in animals, and
mal. Mice were considered to be immobile when they made no further humans [1113]. It is present in several aromatic plants, such as Lavandula
attempt to escape, only moving the minimum necessary to keep their augustifolia, Melissa ofcinalis and L. glaucescens [3,1415]. Previously we
heads above the water. A decrease in the duration of immobility time have demonstrated that linalool produces antidepressant activity. Re-
in the test group compared to controls indicated an antidepressant ef- garding -pinene, a common constituent of several essential plant oils,
fect of the substance tested. Each experimental group consisted of 8 its antidepressant activity has also been reported in FST on mice [3].
10 animals [8]. In the current work, imipramine, linalool and -pinene decreased the
immobility time of mice when compared with control on the FST. These
2.5. Statistical analysis results are in agreement with a previous report [3]. Concerning the mech-
anism of action, the serotoninergic pathway is implicated, since WAY
The data were analyzed by a one-way ANOVA followed by a Tukey's 100635 reversed the antidepressant effect of linalool and -pinene,
test, unless otherwise stated. Differences were considered signicant if these data suggest that the 5-HT1A receptors are involved in the mecha-
p b 0.05. Data were expressed as mean standard error of the mean nism of action of monoterpenes. Preceding studies have shown that 5-
(SEM). HT1A receptor agonists, such as buspirone and gepirone, have antidepres-
sant activity, and these drugs act on presynaptic and postsynaptic recep-
3. Results tors [16]. However, PCPA did not reverse the antidepressant activity of
monoterpenes, this suggests that they could act through postsynaptic
In this study, the antidepressant mechanism of the monoterpenes type receptors [17]. A similar effect was observed for 8-hydroxy-2-
linalool and -pinene were examined using antagonist drugs for seroto- (dipropylamino)tetralin (8-OH-DPAT), an 5-HT1A receptor agonist, sug-
nergic, dopaminergic and noradrenergic receptors. gesting that its antidepressant-like effect is exerted through the postsyn-
aptic 5-HT1A receptors [18]. Furthermore, a progressive sensitization of
3.1. Involvement of the serotonergic system postsynaptic 5-HT1A receptors in the dorsal hippocampus, after long-
term treatment with a tricyclic antidepressant has been observed exper-
Regarding the serotonergic pathway, Fig. 1A (F4,35 = 53.13, p b 0.05) imentally [19].
and B (F4,35 = 56.50, p b 0.05) show that linalool and imipramine de- On the other hand, experimental studies indicate that the hypo-
creased the immobility time of mice when compared with control on function of the noradrenergic system is implicated in the pathophysiology
the FST. A similar result is showed for -pinene and imipramine in of depression [20]. There is evidence for the participation of 1 and 2 re-
Fig. 1C (F4,35 = 42.06, p b 0.05) and D (H(4) = 32.56, p b 0.05). ceptors in the mechanism of action of antidepressant agents [21]. The pre-
Concerning the exploration of the mechanism of action of these two treatment of mice with yohimbine reversed the effect of linalool, but not
28 S.L. Guzmn-Gutirrez et al. / Life Sciences 128 (2015) 2429

Fig. 3. Effect of the pre-treatment with SCH23390 (0.01 mg/kg, i.p.) on the immobility time induced by linalool or -pinene (100 mg/kg, i.p.; panels A and panel B, respectively), in the FST
in mice. Each column represents the mean SEM (n = 10). The data were analyzed by ANOVA followed by a Tukey's test, p b 0.05. Signicant effect compared to the control group (a), and
to the monoterpene group (b).

that of -pinene. These results suggest that 2 adrenergic receptors are supports the view that they might indeed be important in the therapeutic
involved in the antidepressant mechanism of linalool. In other studies, effect of these drugs [31].
clonidine, an adrenergic agonist with high afnity for 2 adrenoceptors,
presented antidepressant-like effects on the FST [22], and is proposed 5. Conclusion
that through central alpha 2-adrenoceptors outside the locus coeruleus
and presumably postsynaptically to noradrenaline-containing neurons This study determined that the antidepressant-like effect of linalool
[23], this effect was reversed by yohimbine [24]. O'Neill et al. reported and -pinene occurs through interaction with the serotonergic pathway
that desipramine and reboxetine are successfully used to treat depression through postsynaptic 5-HT1A receptors. In addition both monoterpenes
in clinical medicine by increasing the availability of noradrenaline in the interact with the adrenergic system through different receptors, the 2
synaptic cleft. Their ndings indicate that increasing the stimulation of for linalool, and for -pinene. Furthermore, -pinene interacts with
postsynaptic noradrenergic receptors is associated with relief of depres- the dopaminergic systems through D1 receptors; interestingly the mech-
sive symptoms. Therefore, part of activity of linalool maybe due to the anism of action of some of the most frequently prescribed antidepressant
modulation of adrenergic function, such as clonidine [24]. drugs involves also the monoaminergic system.
On the other hand, propranolol reversed the effect of -pinene, sug-
gesting that the antidepressant activity of -pinene was partly due to its Conict of interest statement
action on receptors. The antidepressant effect exerted by the drug de-
The authors declare no conicts of interest.
sipramine determined in an unpredictable chronic mild stress model in
mice was reversed by propranolol [25]. Furthermore, according to several
studies, -adrenoceptors may be involved in the action of antidepressants Acknowledgments
Regarding dopaminergic pathway, pre-treatment of mice with This work was supported by Universidad Autnoma Metropolitana
SCH23390 blocked the antidepressant-like effect of -pinene. It has and Programa de Apoyo a Proyectos de Investigacin e Innovacin
been documented that dopaminergic neurons originating in the ventral Tecnolgica, Direccin General de Asuntos del Personal Acadmico
tegmental area which project their nerve terminals into different telence- (Project IG 200513), Universidad Nacional Autnoma de Mxico. Dr.
phalic areas, including the prefrontal cortex and the nucleus accumbens, Silvia Laura Guzmn Gutirrez was funded by a post-doctoral fellowship
are involved in the control of reward-related behavior and incentive mo- from the Instituto de Ciencia y Tecnologa del Distrito Federal (ICyTDF)
tivation, both of which are impaired in depression [30]. The published ev- and Consejo Nacional de Ciencia y Tecnologa (CONACyT). The authors
idence supports the hypothesis that chronic antidepressant treatments also thank Antonio Nieto Camacho for the technical assistance and
potentiate dopamine transmission, and that this potentiation results Edgar Antonio Estrella Parra for the animal care.
from an increased sensitivity of the postsynaptic dopamine receptors.
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