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Sauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice.

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Keywords: Methamphetamine

Sauchinone

CPP

Locomotor activity

ABSTRACT

Sauchinone is a phytochemical known as a nitric oxide (NO) inhibitor. NO is a kind of neurotransmitter and involved in psychotic effect of abuse drug. In present, we carried out a study on the effect of sauchinone on methamphetamine-induced alteration of behavior in mice. Locomotory activity and conditioned place preference (CPP) were used to evaluate behavioral changes. As a result, sauchinone inhibited the methamphetamine-induced hyperlocomotion in dose-dependent manner, whereas sauchinone had no effect on normal locomotory activity. The inhibitory effect of sauchinone on methamphetamine-induced hyperlocomotion was reversed by treatment of molsidomine, a NO donor. Sauchinone also significantly blocked the acquisition and expression of CPP induced by methamphetamine in mouse. However, it did not produce place preference or place aversion, when it was treated alone in animals. Taken together, sauchinone blocked drug reward-related behavior as well as acute hyperlocomotion induced by methamphetamine treatment.

[c] 2013 Elsevier GmbH. All rights reserved.

Introduction

Sauchinone is one of phytochemicals containing lignan structures. It shows various biological activities such as antioxidant. Specially, sauchinone has been reported to suppress nitric oxide (NO) production in various cell types (Lee et al. 2003). Recently, we demonstrated that sauchinone attenuated methamphetamine-induced NO production in dorsal striatum of mouse (Jang et al. 2012). Inhibitory effect of sauchinone on NO production resulted in protection dopaminergic nerve terminal from methamphetamine-induced neurotoxicity. Dopamine is key mediator to be responsible for reward and reinforcing effects of psychostimulant such as methamphetamine. It also contributes to continued drug abuse (Bardo 1998; Koob et al. 1994). Specifically, activation of the dopamine system within the shell region of the nucleus accumbens appears to play a key role in brain reward mechanisms (McBride et al. 1999).

Methamphetamine is one of the substituted amphetamines that affect the central nervous system (CNS). Acute methamphetamine produces euphoria, alertness, decreased appetite, increased locomotor activity and wakefulness. Those psychostimulant effects of methamphetamine have been known to stimulate neurotransmitter release such as dopamine and NO in reward circuit (Nestler et al. 2001). Among neurotransmitters, NO is a gaseous neurotransmitter that may play a role in synaptic plasticity and in behavioral effect of psychostimulant drugs. Treatment of NOS inhibitor reduced cocaine-induced drug seeking behaviors (Orsini et al. 2002) and methypheniclate-induced hyperlocomotion in experimental animals (Itzhak and Martin 2002). Besides, a recent study demonstrated that the increase in NO release was detectable in acute cocaine treated rat striatum (Lee et al. 2010).

Based on previous reports, we hypothesized that sauchinone might have an effect on psychostimulant induced behavioral changes.

Materials and methods

Subjects and chemicals

Male ICR mice, initially weighing 28-32 g, were obtained from Hyochang Science (Hyuchang, Pusan, South Korea). The animals were housed in groups of six in clear plastic cages with free access to water and food in a room kept at a controlled temperature, humidity, and a 12 h light/dark cycle. New groups of animals were used in each experiment. Experiments were run between 09:00 and 16:00 under standard conditions with controlled temperature, dim lighting, and low noise. Every effort was made to minimize animal suffering and the number of animals used. All experiments were conducted according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023. revised 1996). The experimental procedures were approved by Daegu Haany University Committee on Animal Care and Use. Methamphetamine (purity > 98%. obtained from Korean Food and Drug Administration) was dissolved in saline. Sauchinone was provided by Dr. Kim (Daegu Haany University. South Korea) and dissolved in vehicle (40% polyethylene glycol in saline). The structure and formula of sauchinone is presented in Fig. 1. Methamphetamine was administered intraperitoneally (i.p.) in a volume of 0.1 ml/30g, and a dose of 1.5 mg/kg. All the other chemicals used were from commercial sources and of the highest available purity.

Locomotor activity test

Mice were allowed to habituate to the environment for more than 1 week. All animals orally received sauchinone (2.5, 5 or 10 mg/kg in vehicle) or vehicle (40% polyethylenglycol (PEG) 400 in saline) 1 h prior to methamphetamine or saline administration. Locomotor activity was measured in a rectangular container (20cm x 20 cm x 25 cm) equipped with a video camera above the center of the floor. The locomotor activity was monitored by a video-trackingsystem using the Ethovision program (Noldus Information Technology BV, Wageningen, Netherlands). Animals were adapted for 2 h in the box. Distance traveled was recorded for 1 h after methamphetamine (1.5 mg/kg, i.p.) or saline challenge. Molsidomine (50 mg/kg, i.p.) was dissolved in saline and administrated just before sauchinone injection.

Conditioned place preference apparatus

The conditional place preference (CPP) apparatus was purchased from San Diego Ins and consisted of three rectangular-based chambers (20cm x 15 cm x 15 cm) separated by a guillotine door. A battery of place-preference device suitable for the application of an "unbiased" place conditioning design was employed. Two chambers featured with distinct visual cue. One of the chambers was colored with alternating black and white vertical stripes (width 1 cm), and the other was colored with black clots (diameter 2.5 cm) on a white background. Entrance into and movements within the middle chambers were automatically recorded by computer, which recorded the time spent in each chamber during the session.

Acquisition of methamphetamine-induced CPP

The experiment included three phases: preconditioning, conditioning and a final test. During preconditioning session, animals were habituated to the apparatus by being placed in a particular chamber designated as the start chamber and allowed to freely explore both chambers for 900 s each day for 2 days. On the third day, the pre-CPP test was carried out, which meant that the time each mouse spent in the two chambers was recorded automatically for a 900 s period. The chamber occupied for less time was designated as the less preferred side. During conditioning session, mice were received either methamphetamine (1.5 mg/kg) or saline 1 h after sauchinone (10 mg/kg) or vehicle injection on even days (days 4, 6 and 8). And then the animals were confined for 1 h in the drug-paired chamber (less preferred side). On odd days (days 5, 7 and 9), mice were given saline 1 h after vehicle injection and confined for 1 h in the opposite compartment (saline-paired chamber). In the final test, mice were placed in the apparatus and given free access to the two chambers for 900 s and the amount of time spent in each chamber was recorded. The time spent in each chamber was automatically recorded for 900 s. The time difference between post- and pre-CPP test is a measure of the degree of reward induced by methamphetamine.

Expression of methamphetamine-induced CPP

The day after the pre-CPP test was completed, mice were received either methamphetamine (1.5 mg/kg) or saline on even day (days 4, 6, and 8) and then confined for 1 h in the drug-paired chamber. On days 5, 7 and 9, animals were injected with saline and confined in the opposite chamber for 1 h. On the following day, mice conditioned with methamphetamine were given sauchinone (10 mg/kg) or vehicle 1 h before being placed in the apparatus (post-CPP test), with free access to both chambers. Also, mice conditioned with saline were vehicle 1 h before post-CPP test. The time spent in each chamber was automatically recorded for 900 s. The time difference between post- and pre-CPP test is a measure of the degree of reward induced by methamphetamine.

Statistical analysis

Statistical analysis of data was carried out using the SPSS 11.0 software programs. Data of locomotor activity and CPP (Fig. 2a) were statistically analyzed with one-way ANOVA followed by posthoc Tukey tests. Student-t test was used for analysis of Fig. 2b and c. p < 0.05 and p < 0.01 was considered significant in this study.

Results

Effect of suchinone on methamphatmine-induced locomotor activity

First, we examined the effect of sauchinone on methamphetamine-induced hyperlocomotion in mouse. Fig. 2 presents the effect of sauchinone on locomotor activity. ANOVA on data from sauchinone treatment revealed a significant effect [F(5, 42) = 23.8, p < 0.01]. Post hoc comparisons revealed that both 10 mg/kg and 5 mg/kg sauchinone significantly decreased locomotor activity induced by methamphetamine (p < 0.01, p < 0.05, respectively). Sauchinone at dose 2.5 mg/kg did not show significant inhibition of methamphetamine-induced hyperlocomotion (p = 0.383). In addition, the only sauchinone treated group did not show any change on locomotor activity compared with vehicle control group (p= 1.000). Therefore, sauchinone might exert the suppressive effect specifically on methamphetamine-induced hyperlocomotion (Fig. 2a). Next, we examined that the effect of sauchinone appeared in a certain time point or during whole test time by dissecting locomotor activity every 10 min. As shown in Fig. 2b, the locomotor activity induced by methamphetamine treatment was gradually increased and peaked at 40min after methamphetamine injection, and declined gradually. This increased locomotor activity was significantly decreased in 10 mg/kg sauchinone treated group at each time point (p < 0.01) except at 10 min point (p < 0.05). And 5 mg/kg sauchinone inhibited the increase of locomotor activity at 30 min, 40 min (p < 0.01) and 50 min point (p < 0.05). Thus, sauchinone at dose 10 mg/kg blocked the hyperlocomotion induced by methamphetamine treatment during whole test time. Notice that the highest doses of sauchinone (10 mg/kg) tested on locomotor activity was applied in the CPP tests. In order to evaluate the role of NO on the mechanism of sauchinone, mouse was treated with molsidomine (50 mg/kg, i.p.) just before sauchinone or vehicle injection. As shown in Fig. 2C, molsidomine treatment reversed the inhibitory effect of sauchinone on hyperlocomotion induced by methamphetamine [F(2, 20)= 13.7, p < 0.01].

Effect of sauchinone on methamphetamine-induced place preference

Next, we examined the effect of sauchinone on methamphetamine-induced CPP in mouse. Fig. 3 shows the effect of sauchinone on CPP induced by methamphetamine. Since 10 mg/kg sauchinone showed the substantial suppressive effect on methamphetamine-induced locomotor activity, we used same close of sauchinone to examine its effect on methamphetamine-induced place preference. First, we test whether sauchinone could induce place preference or place aversion. As shown in Fig. 3a, mouse did not show sauchinone-conditioned place preference or place aversion as compared with saline control group (p = 1.000). However, 1.5 mg/kg of methamphetamine produced a significant place preference (F(3, 20)= 10.65, p < 0.01) in mice. Fig. 3b shows the effect of sauchinone on the acquisit ion of methamphetamine-induced CPP. Sauchinone administration blocked the acquisition of methamphetamine-induced place preference. The student-t test revealed a significant reduction in the shift of time spent in the methamphetamine-paired chamber in the group pretreated with sauchinone before methamphetamine administration (t(11.3) = 22, p < 0.01). Fig. 3c presents the effect of sauchinone on the expression of methamphetamine-induced CPP. Sauchinone treatment 1 h before post-CPP also decreased methamphetamine-induced CPP (t(3.8)= 18, p < 0.05).

Discussion

Saururus chinensis has been used in traditional herbal medicine for the treatment of hepatitis, edema, jaundice, and gonorrhea (Chung and Shin 1990). S. chinensis has various active compounds such as sauchinone, asuchinoe A and 10-epi-sauchinone. Among these active compounds, sauchinone has been released to have a variety of biological effects, such as hepatoprotective, anti-inflammatory and antioxidant activity in several cell types (Sung et al. 2006; Lee et al. 2003). However, to date there are no data to document the effects of sauchinone on behavioral changes in drug addiction models. Present study is the first to show the inhibitory effect of sauchinone on psychostimulant-induced behavioral changes in mice. Several reports have shown that phytochemicals isolated from herbal medicine may have efficacy to reduce the symptoms of drug addiction. For example, isoliquiritigenin (obtained from licorice) decreased psychositimulant-induced dopamine release and behavior activities in rats (Jang et al. 2008; Jeon et al. 2008). And ibogaine (alkaloid from Tabernanthe iboga) has been shown to suppress intake and reinstatement of ethanol in ethanol-preferring animals (He et al. 2005). Here, we examined whether sauchinone extracted from S. chinensis has effects on methamphetamine-induced hyperlocomotion and CPP in mouse.

The administration of 1.5 mg/kg methamphetamine to mice produced hyperlocomotion and CPP. Treatment of sauchinone significantly suppressed the hyperlocomotion and CPP induced by methamphetamine in mice. Sauchinone is well known as an inhibitor of NO production. It suppressed not only endotoxin-, stimulus- or stress-induced in various cell types (Lee et al. 2003) but also methamphetamine-induced NO production in mouse brain (Jang et al. 2012).

Although NO has been known as a vasodilator and inflammatory mediator, it also plays a role in reinforcing effect of psychostimulants in brain. Psychostimulants produce reinforcing or rewarding effects by activation of dopamine system (Wise and Bozaith 1987), which consists of dopaminergic neurons in the ventral tegment area (VTA) and their target neurons in the nucleus accumbens (NAc). Recently Hartung et al. reported that NO donor enhanced extracellular dopamine (DA) release in nucleus accumbens (NAc) (Hartung et al. 2011). The enhanced dopaminergic neurotransmission leads to the release of Glutamate (Glu). The Glu can activate NMDA receptor, in response to which calcium influx leads to NO release. The NO has been proposed to act as a retrograde neural messenger in long-term potentiation (O'Dell et al. 1991) and to be involved in behavioral changes to psychostimulants. For example, pretreatment of NO synthase inhibitors prior to daily methamphetamine injections suppresses the development of sensitization to the locomotor-activating effect of methamphetamine in mice (Ohno and Watnabe 1995). In addition, 7-nitroindazole, a potent inhibitor of neuronal NOS (nNOS), attenuated the methamphetamine-induced CPP in rats (Li et al. 2002). It attenuated not only the acquisition of methamphetamine-induced CPP, but also the expression of CPP produced by methamphetamine. Therefore, NO might be closely involved in mechanisms underlying the development of reinforcing effect of abuse drugs.

Based on these data, the action of sauchinone on methamphetamine-induced hyperlocomotion might be due to block NO production involving the reinforcing effects of methamphetamine. Sauchinone used in present study showed consistent result with 7-nitroindazole, a potent inhibitor of nNOS (Li et al. 2002). Molsidomine reversed the sauchinone's action on behavioral change induced by methamphetamine. Molsidomine has been known as a NO donor and it restored the effect of 7-nitroindazole on nicotine-induced DA activation (Di Matteo et al. 2010). This result indicates that the mechanism of sauchinone action is profoundly related to NO.

On the other hand, there is a possibility that sauchinone could cause an aversion to the conditioned place. However, the present results show that sauchinone does not exhibit significant motivational properties in the CPP, i.e. there were no variations in the time spent by the mice in the sauchinone-paired chamber after conditioning. Therefore, this possibility can be excluded. Taken together, the decrease of methamphetamine-induced hyperlocomotion and CPP might be due to sauchinone blocking the reinforcing effects induced by methamphetamine.

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2010-0007690).

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Dahn Hyo Kim (b), Chae Ha Yang (a), (b), **, Meeyul Hwang (a), *

(a) The Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University, Daegu 706-060, South Korea

(b) Department of Oriental Medicine, College of Oriental Medicine. Daegu Haany University, Daegu 706-060, South Korea

* Corresponding author at: The Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University, 162-4, Sang-Dong, Suseong-Gu, Daegu 706-060, South Korea. Tel.: +82 53 770 2296; fax: +82 53 770 2335.

** Co-corresponding author at: Department of Oriental Medicine, College of Oriental Medicine, Daegu Haany University, Daegu 706-060, South Korea. Tel.: +82 53 770 2254; fax: +82 53 770 2254.

E-mail addresses: chyang@haany.ac.kr (C.H. Yang), meeyulh@gmail.com, meeyulh@nate.com (M. Hwang).
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Title Annotation:Short communication
Author:Kim, Dahn Hyo; Yang, Chae Ha; Hwang, Meeyul
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9SOUT
Date:Sep 15, 2013
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