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Limonene inhibits methamphetamine-induced locomotor activity via regulation of 5-HT neuronal function and dopamine release.


Methamphetamine is a psychomotor stimulant that produces hyperlocomotion in rodents. Limonene (a cyclic terpene from citrus essential oils) has been reported to induce sedative effects. In this study, we demonstrated that limonene administration significantly inhibited serotonin (5-hydroxytryptamine, 5-HT)-induced head twitch response in mice. In rats, pretreatment with limonene decreased hyperlocomotion induced by methamphetamine injection. In addition, limonene reversed the increase in dopamine levels in the nucleus accumbens of rats given methamphetamine. These results suggest that limonene may inhibit stimulant-induced behavioral changes via regulating dopamine levels and 5-HT receptor function.

Key words:



Drug addiction




Acute administration of abused drugs such as cocaine, morphine, and methamphetamine (METH) induces hyperlocomotion, whereas repeated administration results in a progressive, enhanced locomotor activity (Filip et al., 2006; Fukushima et al., 2007; Shimosato and Ohkuma, 2000) in rodents. This phenomenon is also known as context-dependent behavioral sensitization and may have a role in the development of compulsive drug-seeking behaviors (Hooks et al., 1993; Mattingly et al., 2000; Shen et al., 2006). It has been suggested that enhanced mesolimbic dopaminergic neuronal transmission is responsible for the enhancement of behavioral changes to a stimulant (Bello et al., 2011; Pak et al., 2006). Limonene is a common terpene from the genus Citrus and has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects (de Almeida et al., 2012; do Amaral et al., 2007; Lima et al., 2013; Zhou et al., 2009). However, the effect of limonene on stimulant-induced behavioral changes is largely unknown. In this study, we investigated the effect of limonene on METH-induced locomotor activity in rats. Furthermore, to elucidate the possible mechanism of limonene in METH-induced hyperlocomotion, we performed behavioral pharmacological experiments, including head twitch response (HTR), to evaluate the effect of limonene on serotonergic (5-hydroxytryptaminergic, 5-HTergic) neuronal activity in mice. In addition, we tested whether limonene has a role in modulating METH-induced dopamine concentration changes in the nucleus accumbens of rat.

Materials and methods

Animals and drugs

Male Sprague-Dawley rats (male, 180-220g) and ICR mice (male, 25-35 g) obtained from the Ministry of Food and Drug Safety (MFDS, Osong, Korea) were housed in groups of 4-5 rats and 5 mice, in a temperature-controlled room at 22 [+ or -] 2[degrees]C with a 12 h light/dark cycle (light on 08:00 to 20:00 h) and were given a solid diet and tap water ad libitum. The following agents were used; METH HC1, (R)-(+)-limonene (LIM), ketamine-HCl/xylazine-HCl solution, and 5-HT were obtained from Sigma chemical Co. (St. Louis, MO, USA). All drugs were dissolved in 0.9% saline (containing Tween 80, 5%) and injected (i.p.) with a volume of 1 ml/kg (rats) and 10 ml/kg (mice).

Head twitch response (HTR) in mice

According to the method which was described elsewhere (Kim et al., 2000), intracerebroventricular (i.c.v.) injections were made by insertion of a Hamilton injection needle (3/8,27 gauges) perpendicularly through the soft bone 1.5 mm to the right of the bregma on the coronal suture. The needle was attached to a Hamilton microsyringe and was inserted through a stainless-steel tube that acted as a stopper. Animals were divided into six groups (n = 10) as following: (1) Vehicle/Saline, (2) LIM (600)/saline, (3) Vehicle/5-HT, (4) LIM (200)/5-HT, (5) LIM (400)/5-HT, and (6) LIM (600)/5-HT. The mice were placed into transparent Plexiglas cylinders (20 cm diameter: 25 cm height). The mice were pretreated with limonene (200, 400, and 600 mg/kg, [micro]p) 40 min before the injection of 5-HT or saline. The HTR frequency was scored for 2 min at 10 min after the injection of 5-HT (60 [micro]g/10 [micro]l/mouse) by an observer who was blind to the drug treatment. Successful injection of 5-HT was verified via co-administration of India ink (1 [micro]l, proper distribution of the ink in the cerebroventricular system) with 5-HT, and data from animals with unsuccessful injection were excluded.

METH-induced hyperactivity in rats

METH-induced hyperactivity using a dose of 1 mg/kg of METH was investigated. The locomotor activity of the rats was measured with a photobeam (infrared) activity chamber (ENV-515, Med Associates Inc., St. Albans, VT, USA). Animals were divided into four groups (n = 8) as following: (1) Vehicle/Saline, (2) Vehicle/METH, (3) LIM (200)/METH, and (4) LIM (400)/METH. Each rat was placed in an activity chamber (43.2 cm x 43.2 cm x 30.5 cm) and after an adaptation period of 10 min, 1 mg/kg of METH was administered (i.p.). The rats were pretreated with limonene (200 and 400 mg/kg, which have no effect on motility, proven by climbing behavior test according to previous report (Yun et al., 2001), data not shown, i.p.) 40 min before the injection of METH. The locomotor activity was measured every 10 min for 1 h after the administration of METH.

Microdialysis measurements of METH-induced dopamine release in the nucleus accumbens of rats

According to previous report (Yun et al., 2005) microdialysis was performed with modification. Animals were divided into two groups (n = 4) as following: (1) Vehicle/METH, (2) LIM (400)/METH. Rats were anesthetized with ketamine (80 mg/kg i.p.) and xylazine (11 mg/kg i.p.) and mounted in a stereotaxic apparatus. A stainless steel guide cannula (EICOM, Kyoto, Japan) was implanted into the right nucleus accumbens: the stereotaxic coordinates were 1.5 mm anterior to bregma, 1.5 mm lateral to the sagittal suture, and 6.5 mm ventral to the brain surface according to the atlas of Paxinos and Watson (1998). The cannula was fixed with dental cement and screw onto the skull. All animals were allowed a 3-4 day recovery period with a dummy probe inserted into the guide cannula until the brain microdialysis experiment. A microdialysis probe with active membrane (EICOM) was inserted into the guide cannula. Artificial cerebrospinal fluid (8.6g NaCl, 0.3 g KC1, 0.25 g Ca[Cl.sub.2]/l) was then perfused through the probe at a rate of 2.3 [micro]l/min for 2 h followed by METH treatment and additional perfusion for 4h. Limonene or vehicle was administered 40 min before the injection of METH. Dialysate was collected every 20 min (ca. 46 [micro]l) and added to 5 [micro]l of 0.1 M perchloric acid. All dialysate samples were stored at 4[degrees]C until required for analysis. Dialysate samples were analyzed using the Waters Alliance HPLC system (Waters 2690) with an Eicom electrochemical detector (ECD 300) using a EICOMPAK SC-50DS column (EICOM, 2.1 mmx 150 mm). The graphite working electrode of the electrochemical detector was set at 0.75 V with respect to an Ag/AgCl reference electrode. The mobile phase consisted of 0.1 M acetate-citrate buffer (pH 3.9) containing 140 mg/1 of 1-octanesulfonic acid, 5 mg/1 of [Na.sub.2] EDTA, and 17% methanol (v/v). The amount of dopamine present in dialysate was calculated using the Millennium computerized integrating system (version 3.01).

Statistical analysis

One-way analysis of variance (ANOVA) followed by Dunnett's test and two-way repeated measures ANOVA with Bonferroni's test was used for multigroup comparisons.


Effect of limonene on 5-HT-induced HTR

To elucidate the effect of limonene on serotonergic neuronal activity in vivo, we examined if limonene could reduce HTR induced by 5-HT in mice. As previously reported, a single injection of 5-HT (60 [micro]g/10 [micro]l/mouse) induced HTR (Kim et al., 2000). Compared to pretreatment with vehicle, pretreatment with limonene (200,400, and 600 mg/kg, intraperitoneal (i.p.)) 40 min before 5-HT administration inhibited the effect of the 5-HT in a dose-dependent manner (Fig. 1). However, limonene had no effect on HTR by itself. These results demonstrate that limonene has anti-serotonergic activity.

Effects of limonene on the METH-induced locomotor activity

To explore the effect of limonene on METH-induced hyperlocomotion, we pretreated rats with limonene (200 and 400 mg/kg, i.p.) before METH injection. Limonene treatment (400 mg/kg) inhibited hyperactivity induced by a single METH (Fig. 2). Doses of limonene in current study have no effect on overall motility by itself in climbing behavior experiment as mentioned above. These results suggest that limonene inhibits METH-induced hyperactivity.

Effect of limonene on METH-induced increase in extracellular dopamine levels

To investigate a possible mechanism underlying the effect of limonene on locomotor activity induced by METH, the extracellular levels of dopamine in the nucleus accumbens of rats was measured. Compared to baseline (mean value for 60 min prior to vehicle or limonene injection) animals treated with METH have increased dopamine levels in the nucleus accumbens at 20 min and 40 min after METH administration. Pretreatment with limonene (400 mg/kg, i.p.) inhibited this increase of dopamine levels at 40 min after METH administration (Fig. 3). Meanwhile, no effect of limonene itself on dopamine concentration was evident by no significant difference between limonene and vehicle treatment group (for 40 min after vehicle and limonene injection).


Stimulants-induced hyperactivity is associated with an increase in mesolimbic dopaminergic neurotransmission (Bello et al., 2011; Pak et al., 2006). In this study, it is demonstrated that limonene inhibited METH-induced hyperactivity in rats. Limonene also reversed the METH-induced elevated dopamine levels in the nucleus accumbens of rats. Therefore, it is suggested that an inhibitory effect of limonene on the enhancement of dopamine release induced by METH is implicated in reversal of the hyperlocomotion. In addition to dopamine release, dopamine D1 and D2 receptors are also necessary for the expression of hyperlocomotion induced by an administration of METH (Kelly et al., 2008). It has been reported that dopamine D2 receptor null mutant (Drd2-/-) are deficient in basal and methamphetamine-induced locomotor activation (Kelly et al., 2008; Neve et al., 2013). However, effect of limonene on activation of dopamine D1 and D2 receptors is possibly not related with reduced hyperlocomotion because limonene at doses used in the current experiment had no effect on overall movement in climbing behavior induced by vehicle or apomorphine (dopamine D1 and D2 agonist) injection as mentioned in material and methods section, a useful animal behavior to investigate dopaminergic neuronal activity and to screen candidate dopamine receptor agonists or antagonists (Protais et al., 1976). It has been reported that there is no LIM-related toxicity at dose <1650mg/kg daily in rats and mice (National Toxicology, 1990; Whysner and Williams, 1996). According to dose translation from animal to human (Reagan-Shaw et al., 2008), dosages (200,400, and 600mg/kg) in present study give 972 mg, 1945 mg, and 2918 mg of LIM for a 60 kg person, respectively. The maximum tolerated dose was 8g/[m.sup.2] per day (15g/day) in cancer patients (Vigushin et al., 1998). At a dose of 100mg/kg of LIM caused no gradable toxicity in healthy volunteers (Crowell et al., 1994). Oral administration of LIM is rapidly and almost completely absorbed in the gastrointestinal tract in humans as well as animals (Crowell et al., 1992; Igimi et al., 1974; Kodama et al., 1976; Vigushin et al., 1998). Therefore, dosages in this study are considered to have no toxicity in human as well as animals, which is accompanied with previous report (Sun, 2007). The mechanism behind limonene-mediated reversal of the increased extracellular dopamine levels of nucleus accumbens is not clear. Zhou et al. (Zhou et al., 2009) demonstrated that limonene administration significantly increased brain 7-aminobutyricacid (GABA) levels in rats. Pharmacologic increases in brain GABA levels or activation of GABA B receptors, but not activation of GABA A receptors, blocked the increase in dopamine levels elicited by morphine or cocaine injection (Klitenick et al., 1992; Morgan and Dewey, 1998). Therefore, limonene may increase GABA levels (activate GABA B receptors) and consequently reduce the elevated extracellular dopamine levels induced by METH.

In addition, this study has identified the additional pharmacological targets of limonene in stimulant-induced behavioral changes. We asked if limonene inhibited 5-HT-induced HTR, which is a unique behavior induced by several hallucinogens including R(-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane(DOM) and 2,5-dimethoxy-4-iodoamphetamine (DOI) (Canal and Morgan, 2012; Fantegrossi et al., 2005). Components of the 5-HT system may provide novel targets for the development of pharmacological treatments for psychostimulant dependence is associated with significant aberrations in dopamine neurotransmission (Bubar and Cunningham, 2008). Limonene pretreatment significantly inhibited 5-HT-induced HTR and had no effect on its own. It is generally considered that HTR is induced by 5-[HT.sub.2A] receptor activation (Willins and Meltzer, 1997). To my knowledge, there is no report indicating that limonene can affect 5-[HT.sub.2A] receptor; however, limonene induces 5-HT release in vitro and in vivo (Fukumoto et al., 2006; Zhou et al., 2009). HTR mediated by 5-[HT.sub.2A] could be modulated by activation of 5-[HT.sub.2C] receptor (Canal et al., 2010; Fantegrossi et al., 2010). These results suggest that limonene-induced increases in serotonin levels may potentiate the action of injected 5-HT (i.c.v.) on 5-[HT.sub.2C] receptor. In addition, LIM has antioxidant effects (Grassmann, 2005). It was reported that antioxidants reduced 5-[HT.sub.2A] signal in vitro (Greene et al., 2000). Antioxidants protect against 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity which is associated with 5-HT receptor stimulation (Capela et al., 2007). Therefore, LIM may reduce 5-[HT.sub.2A] receptor activity via antioxidant property and consequently inhibit 5-HT-induced HTR in mice. In conclusion, these results suggest that limonene may inhibit METH-induced hyperlocomotion through regulation of dopamine release and serotonergic neuronal activity.


Article history:

Received 29 September 2013

Received in revised form 15 October 2013

Accepted 20 December 2013


This study was supported by Ministry of Food and Drug Safety of Republic of Korea.


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Jaesuk Yun *

Pharmaceutical Standardization Research and Testing Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Republic of Korea

* Correspondence to: Osong Health Technology Administration Complex, 187 Osongsaengmyeong 2(i)-ro, Osong-eup, Cheongwon-gun, Chungcheongbuk-do 363-700, Republic of Korea. Tel.: +82 43 719 4607; fax: +82 43 719 4600.

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Author:Yun, Jaesuk
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:May 15, 2014
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