Effect of MS-153, a glutamate transporter activator, on the conditioned rewarding effects of morphine, methamphetamine and cocaine in mice

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1 Behavioural Brain Research 156 (2005) Research report Effect of MS-153, a glutamate transporter activator, on the conditioned rewarding effects of morphine, methamphetamine and cocaine in mice Takayuki Nakagawa, Mayumi Fujio, Tohru Ozawa, Masabumi Minami, Masamichi Satoh Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto , Japan Received 18 December 2003; received in revised form 21 May 2004; accepted 25 May 2004 Available online 19 July 2004 Abstract There is a body of evidence implying the involvement of the glutamatergic system in the conditioned rewarding effects of drugs of abuse. It is recognized that the release of extracellular glutamate from nerve terminals is counterbalanced by the functions of neuronal and glial glutamate transporters. In the present study, we investigated the effects of (R)-( )-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a glutamate transporter activator, on the induction of the conditioned place preference to morphine, methamphetamine and cocaine in mice. In the conditioned place preference paradigm, mice were conditioned with repeated subcutaneous injections of morphine (5 mg/kg), methamphetamine (2 mg/kg) or cocaine (8 mg/kg) in combination with or without MS-153 (3 and 10 mg/kg). Co-administration of MS-153 at a dose of 10 mg/kg, but not 3 mg/kg, significantly attenuated the induction of conditioned place preference to morphine, methamphetamine and cocaine. However, MS-153 itself produced neither conditioned place preference nor aversion. On the other hand, co-administration of MS-153 (10 mg/kg) did not alter the acute locomotor activation elicited by a single injection of morphine, methamphetamine and cocaine. These results suggest that MS-153, a glutamate transporter activator, has an inhibitory effect on the conditioned rewarding effects of morphine, methamphetamine and cocaine without affecting their acute locomotor responses Elsevier B.V. All rights reserved. Keywords: Morphine; Methamphetamine; Cocaine; Conditioned place preference; MS-153; Glutamate transporter 1. Introduction Opiates, such as morphine, and psychostimulants, such as methamphetamine and cocaine, share the ability to cause addiction in humans, and to induce addiction-related behaviors including behavioral sensitization, drug self-administration and conditioned place preference (CPP) in rodents [24,43]. Although these drugs of abuse primarily act through different mechanisms, it is considered that they activate common neural pathways and neurotransmitters that produce their rewarding effects. One of them is the mesolimbic dopaminergic neuron, which projects from the ventral tegmental area to the nucleus accumbens and other regions of the forebrain [50]. On the other hand, electrophysiological [15,40,55] and in vivo microdialysis [18,25,31] studies have shown that the Corresponding author. Tel.: ; fax: address: msatoh@pharm.kyoto-u.ac.jp (M. Satoh). mesolimbic dopaminergic system could be regulated by the glutamatergic system [17]. In the CPP paradigm, many studies have reported that the induction of CPP to morphine and psychostimulants is dependent on the glutamatergic system [7], although there are conflicting results. It has been shown that various types of glutamate receptor antagonists prevented the induction of CPP to morphine [11,35,36,44,46,47], amphetamines [22] and cocaine [8,16,23]. Controversially, it was reported that a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, did not affect the induction of CPP to amphetamine [14]. On the other hand, the expression of CPP to morphine [26,36,47], amphetamines [30] and cocaine [8,16] was also reported to involve the glutamatergic system. Furthermore, Tzschentke and Schmidt [48] demonstrated that riluzole, which is a functional inhibitor for glutamatergic transmission [13], attenuated the induction of CPP to both morphine and amphetamine. Taken together, these findings suggest that glutamate receptors play /$ see front matter 2004 Elsevier B.V. All rights reserved. doi: /j.bbr

2 234 T. Nakagawa et al. / Behavioural Brain Research 156 (2005) important roles in the conditioned rewarding effects of morphine and psychostimulants. It is recognized that the release of extracellular glutamate from nerve terminals is counterbalanced by the functions of glutamate transporters in neurons and glial cells, thereby terminating the glutamatergic signal transmission and protecting neurons from the excitotoxic action of glutamate [19,38]. We previously reported that the mrna expression of a glial glutamate transporter GLT-1 changed in some brain regions of morphine-dependent and naloxone-precipitated withdrawal rats [34]. Furthermore, we have shown that intracerebroventricular administration of d,l-threo- -benzyloxyaspartate, a glutamate transporter inhibitor, facilitated the expression of somatic and negative affective components of morphine withdrawal, and induction of CPP to morphine [39], and that gene transfer of GLT-1 into the locus coeruleus attenuated physical dependence on morphine in rats [33]. These results support the possibility that glutamate transporters such as GLT-1 could be involved in drug dependence. (R)-( )-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a novel cerebroprotective agent, has been shown to reduce the area of cerebral infarction and to minimize neurological deficits induced by occlusion of the middle cerebral artery in rats [21,49]. It has been reported that MS-153 reduced the increase in the extracellular glutamate level in the ischemic penumbra zone during occlusion of the middle cerebral artery [49]. Shimada et al. [41] found that MS-153 accelerated glutamate uptake through a glutamate transporter GLT-1 expressed in COS-7 cells, and inhibited the depolarizationand ischemia-induced efflux of glutamate, but not other amino acids, in rat hippocampal slices. These findings suggest that MS-153 could be used as an activator of glutamate transporters. Recently, we reported that co-administration of MS-153 with morphine reduced the development of morphine tolerance and physical dependence in mice [32]. In the present study, to examine the roles of glutamate transporters in the conditioned rewarding effects of morphine, methamphetamine and cocaine, we investigated the effects of MS-153 on the induction of CPP to these drugs of abuse in the CPP paradigm using mice. Further, to determine whether MS-153 could affect the acute effects of morphine, methamphetamine and cocaine, the effects of MS-153 on the acute locomotor responses elicited by a single injection of these drugs of abuse were also investigated. 2. Materials and methods 2.1. Animals Male ddy mice weighing g at the beginning of the experiment were used. They were kept at a constant ambient temperature of 24 ± 1 C under a 12-h light/12-h dark cycle with free access to food and water for at least 3 days before experiments started. The experiments were conducted in accordance with the ethical guidelines of Kyoto University Animal Experimentation Committee, and the guidelines of the Japanese Pharmacological Society Materials MS-153 was a gift from the Life Science Laboratory of Mitsui Chemical (Chiba, Japan). Morphine hydrochloride and cocaine hydrochloride were purchased from Takeda Chemical Industries (Osaka, Japan). d,l-methamphetamine hydrochloride was purchased from Dainippon Pharmaceutical Co. (Osaka, Japan). All drugs were freshly dissolved in saline each day, and subcutaneously (s.c.) injected in a volume of 1 ml/kg Locomotor activity We measured locomotor activity using an activity chamber consisting of a circular corridor (13.2 cm in height, 8 cm in width and 16 cm in external diameter) crossed by 144 infrared beams (Melquest Co., Ltd, Toyama, Japan). The activity chamber was enclosed by a sound- and light-attenuated box. The locomotor activity was detected and recorded automatically in a blind fashion when animals interrupted the beams. For measurements of locomotor activity, mice were placed in the activity chamber and acclimatized for at least 60 min. Next day, after a further 60-min acclimatization, mice were s.c. injected with saline or drugs of abuse in combination with or without MS-153, and then their locomotor activity was measured every 15 min for 120 min CPP paradigm Apparatus A place-conditioning apparatus, consisting of a shuttle box (15 cm 30 cm 15 cm: width length height) divided into two equal-sized compartments, was used. The inner surface of one compartment was black with a smooth floor; the other was white with a textured floor to create equally preferred compartment. The infrared beam sensors were positioned on each cover, and the time spent in each compartment during a period of 900 s was measured in a blind fashion automatically using a computer system (KN-80; Natsume Seisakusyo, Tokyo, Japan). The shuttle box was enclosed by a sound- and light-attenuated box under conditions of dim illumination (about 40 lx) and white noise masking Procedures The experimental process consisted of three distinct sessions: a preconditioning session, conditioning session, and test session. On days 1 and 2 (preconditioning session), the partition separating the two compartments was raised 7 cm above the floor, and a neutral platform (3 cm 1cm 7 cm) was inserted along the seam separating the compartments. Mice were individually placed on the platform and stepped down to the horizontal floor. The mice were allowed to freely

3 T. Nakagawa et al. / Behavioural Brain Research 156 (2005) explore the two compartments for 900 s and acclimatized to the apparatus. There was no significant difference between time spent in the black compartment with a smooth floor (441 ± 8.5 s, n = 115) and the white compartment with a textured floor (458 ± 8.5 s, n = 115). Biased mice that spent more than 600 s in one side were excluded from further analysis. The conditioning session was conducted once daily for six consecutive days (days 3 8). Assignment of the drug-paired compartment was performed randomly and counterbalanced across the subjects, and in the preconditioning session, there were no significant differences in the time spent in drugpaired compartment across each treatment (data not shown). The mice were s.c. injected with either drugs or saline and confined to one compartment for 1 h. The next day, the mice that had been given drugs were s.c. injected with saline, while those that had received saline were injected with drugs, respectively, and confined to the other compartment for 1 h. MS-153 (3 and 10 mg/kg) was co-administered in combination with each drug of abuse. From days 3 to 8, the conditioning was repeated three times. Control groups received saline instead of drugs. On day 9 (test session), the time spent in each compartment for 900 s was measured in the drug-free state as described above. The CPP score represents the time spent in the drug-paired compartment minus the time spent in the saline-paired compartment in the test session, and is expressed as the mean ± S.E.M Statistical analysis Results on locomotor activity were analyzed using the two-way analysis of variance (ANOVA). In the case of CPP experiments, statistical significance was analyzed using the one-way ANOVA followed by the Student Newman Keuls post hoc test. Differences with P < 0.05 were considered significant. 3. Results 3.1. Effect of MS-153 on acute locomotor responses to morphine, methamphetamine and cocaine The effects of co-administration of MS-153 on the acute locomotor activation elicited by a single s.c. injection of morphine, methamphetamine and cocaine are shown in Fig. 1. Although a single s.c. injection of saline or MS-153 (10 mg/kg) alone slightly increased locomotor activity in the first 15- min period, there was no significant difference among groups (F 1,80 = 0.25, P = 0.97). A single s.c. injection of morphine (5 mg/kg), methamphetamine (2 mg/kg) or cocaine (8 mg/kg) increased the locomotor activity. Co-administration of MS- 153 (10 mg/kg) did not alter the acute locomotor activation elicited by morphine (F 1,96 = 0.50, P = 0.48), Fig. 1. Effects of MS-153 on the acute locomotor responses to morphine, methamphetamine and cocaine in mice. Animals were s.c. injected with saline (A), 5 mg/kg morphine (B), 2 mg/kg methamphetamine (C) or 8 mg/kg cocaine (D) in combination with (closed circle) or without (open circle) 10 mg/kg MS-153 at time zero, and then the locomotor activity was measured every 15 min for 120 min. Data are expressed as means ± S.E.M. of locomotor activity counts (n = 6 9).

4 236 T. Nakagawa et al. / Behavioural Brain Research 156 (2005) Fig. 2. Effects of MS-153 on the induction of CPP to morphine, methamphetamine and cocaine in mice. Animals were conditioned with saline (A), 5 mg/kg morphine (B), 2 mg/kg methamphetamine (C) or 8 mg/kg cocaine (D) in combination with or without MS-153 (3 and 10 mg/kg) in an unbiased version of the CPP paradigm as described in Section 2. Each column represents the CPP scores expressed as means ± S.E.M (n = 8 12); P < 0.05 compared with the mice paired with each drug of abuse alone, # P < 0.05 compared with the mice paired with 8 mg/kg cocaine and 3 mg/kg MS-153 using the Student Newman Keuls post hoc test. methamphetamine (F 1,104 = 0.00, P = 0.99) and cocaine (F 1,104 = 0.36, P = 0.55) Effect of MS-153 on the induction of CPP to morphine, methamphetamine and cocaine The effects of co-administration of MS-153 on the induction of CPP to morphine, methamphetamine and cocaine are shown in Fig. 2. In saline-paired control mice, the CPP score was 23.5 ± 38.8 s. In the control mice, MS-153 (3 and 10 mg/kg) had no effect on the CPP score ( 10.9 ± 47.6 s and 0.88 ± 43.8 s, respectively). There was no significant difference among groups (F 2,24 = 0.071, P = 0.93). Furthermore, MS-153 (3 and 10 mg/kg) had no significant effect on the numbers across the line between the white/textured and black/smooth compartments for 15 min (data not shown). Morphine (5 mg/kg)-paired mice showed significant CPP (129.5 ± 21.6 s), compared with saline-paired control mice (P < 0.01; Student s t-test). Co-administration of MS-153 (3 and 10 mg/kg) with morphine attenuated the morphineinduced CPP (79.1 ± 37.2 s and 10.7 ± 32.3 s, respectively). The one-way ANOVA demonstrated a significant difference among groups (F 2,30 = 3.42, P < 0.05). Post hoc comparison using the Student Newman Keuls test revealed that MS-153 at a dose of 10 mg/kg, but not 3 mg/kg, produced a significant attenuation of the morphine-induced CPP, compared with the mice paired with morphine alone (P < 0.05). Methamphetamine (2 mg/kg)-paired mice showed significant CPP (205.2 ± 28.6 s), compared with saline-paired control mice (P < 0.001). Co-administration of MS-153 (3 and 10 mg/kg) with methamphetamine attenuated the methamphetamine-induced CPP (116.0 ± 33.5 s and 83.0 ± 30.9 s, respectively). The one-way ANOVA demonstrated a significant difference among groups (F 2,26 = 3.98, P < 0.05), and post hoc comparison revealed that MS-153 at a dose of 10 mg/kg, but not 3 mg/kg, produced a significant attenuation, compared with methamphetamine alone (P < 0.05).

5 T. Nakagawa et al. / Behavioural Brain Research 156 (2005) Cocaine (8 mg/kg)-paired mice showed significant CPP (236.2 ± 28.9 s), compared with saline-paired control mice (P < 0.001). Co-administration of MS-153 (3 and 10 mg/kg) with cocaine attenuated the cocaine-induced CPP (222.7 ± 71.6 s and 64.1 ± 47.2 s, respectively). The one-way ANOVA demonstrated a significant difference among groups (F 2,23 = 4.18, P < 0.05), and post hoc comparison revealed that MS- 153 at a dose of 10 mg/kg produced a significant attenuation, compared with cocaine alone (P < 0.05) and cocaine in combination with MS-153 at a dose of 3 mg/kg (P < 0.05). 4. Discussion MS-153, a novel cerebroprotective agent, has been reported to accelerate the uptake of l-[ 3 H]glutamate in COS-7 cells expressing GLT-1, a glutamate transporter, but not the uptake of [ 3 H]gamma-aminobutyric acid (GABA) in COS- 7 cells expressing GAT-3, a GABA transporter [41], although its effects on other glutamate transporters are yet to be determined. Moreover, MS-153 has no effect on NMDA or -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors [4] and Ca 2+ channels [41]. These findings suggest that MS-153 could inhibit the function of the glutamatergic system by accelerating glutamate uptake, although there is a possibility that MS-153 could also decrease the glutamate release. In the present study, we showed that co-administration of MS-153 at a dose of 10 mg/kg, but not 3 mg/kg, significantly attenuated the induction of CPP to morphine, methamphetamine and cocaine in mice. Since MS-153 alone failed to produce either CPP or conditioned place aversion, the inhibitory effect was unlikely to be due to the effect of MS-153 itself on the place preference. On the other hand, the same dose of MS-153 (10 mg/kg) did not affect the acute locomotor activation elicited by a single injection of morphine, methamphetamine or cocaine. These results suggest that MS-153 attenuated the conditioned rewarding effects, but not acute locomotor responses, to morphine, methamphetamine and cocaine. The acute locomotor responses to morphine, methamphetamine and cocaine are mainly dependent on the mesolimbic and nigrostriatal dopaminergic systems, which are known to be regulated by the glutamatergic system [18]. It was reported that their acute locomotor responses were inhibited by several glutamate receptor antagonists, following systemic administration at high doses or local administration into the nucleus accumbens or striatum [6,20,37]. However, it was demonstrated that systemic administration of NMDAor AMPA-receptor antagonists at low doses did not affect the acute locomotor responses to morphine, amphetamine and cocaine, while even at low doses the antagonists prevented the induction of behavioral sensitization [6,27,52,53]. These findings suggest that glutamate receptors play a role in acute locomotor responses to morphine and psychostimulants, but are most important in mediating neuronal adaptations induced by repeated administration of morphine and psychostimulants (for review, see [51]). In the present study, 10 mg/kg of MS-153, a dose which attenuated the induction of CPP, may not have been sufficient to affect the acute locomotor responses to morphine and psychostimulants. Furthermore, we have reported that MS-153 at 10 mg/kg did not alter the acute antinociceptive effect of morphine [32]. On the other hand, Abekawa et al. [1,2] have reported that intraperitoneal pretreatment with MS-153 (10 and 100 mg/kg) enhanced acute locomotion, ataxia and stereotypy induced by a single injection of phencyclidine. Unlike morphine and psychostimulants, since phencyclidine primarily blocks NMDA receptors, it is postulated that phencyclidine blocks the receptors on GABAergic interneurons to disinhibit glutamatergic pyramidal neurons from GABAergic tonic inhibition in the prefrontal cortex, to induce an increase of glutamate release in the prefrontal cortex. As a result, activation of the glutamatergic neurons projecting from the prefrontal cortex to the nucleus accumbens and ventral tegmental area probably via non-nmda receptors may contribute to the enhancement of the acute responses [3,45]. Abekawa et al. [1,2] discussed that the facilitative effects of MS-153 on phencyclidine-induced acute responses are due to a deterioration of glutamatergic function caused by MS-153, which synergically enhances the phencyclidine-induced direct reduction of glutamatergic neural transmission via the blocking of NMDA receptors. Thus, a difference in the mechanism behind the acute locomotor responses between phencyclidine and morphine, methamphetamine or cocaine may contribute to the difference in the effects of MS-153. Several lines of evidence suggest that the mesolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and other regions of the forebrain, play an important role in the rewarding effect of drugs of abuse [24]. Since glutamate receptor antagonists have been shown to prevent the induction of CPP to various drugs of abuse, it is hypothesized that the neuronal adaptation of the mesolimbic dopaminergic system mediated via glutamate receptors contributes to conditioned rewarding effects. However, it should be noted that the involvements of subtypes of glutamate receptors in the induction of CPP to morphine, amphetamines and cocaine is not consistent. For example, the induction of CPP to morphine and cocaine were prevented by non-competitive NMDA receptor antagonists such as MK-801 [8,11,23,46,47], while MK-801 failed to affect the induction of CPP to amphetamine ([14], but see [22]). MPEP, a selective antagonist for the type 5 metabotropic glutamate receptor, prevented the induction of CPP to cocaine, but not morphine and amphetamine ([29], but see [36]). On the other hand, since MS-153 lowers the extracellular glutamate level by accelerating glutamate uptake, it is suggested that the functional suppression of all glutamate receptor subtypes by MS-153 could attenuate the induction of CPP to morphine, methamphetamine and cocaine. It is interesting to know whether MS-153 could affect the expression of CPP to these drugs of abuse, because some of glutamate receptor antagonists have distinct effects on the induction and expression of CPP to them [8,14,47]. On the other hand,

6 238 T. Nakagawa et al. / Behavioural Brain Research 156 (2005) consistent with our data, it has been reported that riluzole, which is also considered a functional inhibitor that prevents glutamatergic transmission by inhibiting glutamate release, blocking postsynaptic glutamate receptors and accelerating glutamate uptake [5,13], attenuated the induction of CPP to both morphine and amphetamine [48], although riluzole is known to have diverse effects such as the blocking of sodium channels, prevention of Ca 2+ mobilization and inhibition of GABA uptake [13]. However, since studies have shown that glutamate receptor antagonists impair various forms of learning and conditioning [9], it is difficult to determine whether the inhibitory effect of MS-153 is due to a reduction of the primary rewarding effects or due to impairment of associative learning during conditioning. Although we and another group demonstrated that MS-153 had attenuating effects on the development of morphine tolerance and physical dependence [32] and behavioral sensitization to methamphetamine [1,2] with minimal influence on memory and learning processes, additional experiments, such as assessment of the effect on the CPP to food, are needed to elucidate whether MS-153 affected the learning and memory. To date, five subtypes of Na + -dependent high-affinity glutamate transporters have been cloned and characterized, namely, GLT-1, GLAST, EAAC1, EAAT4 and EAAT5. GLT-1 and GLAST are mainly expressed in astrocytes, whereas EAAC1 and EAAT4 are mainly found in neurons and EAAT5 exists predominantly in the retina [38].We have reported that the mrna expression of a glial glutamate transporter, GLT-1, was decreased in the striatum and thalamus of morphine-dependent rats [34], suggesting the enhancement of glutamatergic transmission following a decrease in glutamate transporter expression levels might contribute to the induction of morphine dependence. Other groups have also suggested the involvement of changes in the expression and function of glutamate transporters in dependence on morphine as well as other drugs of abuse [12,28,42,54]. On the other hand, it was shown that a glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid increased extracellular glutamate as well as dopamine levels in the striatum [10], indicating that glutamate transporters could regulate dopamine release from the striatal dopaminergic nerve terminals. More recently, we have shown that intracerebroventricular administration of d,l-threo- -benzyloxyaspartate, a glutamate transporter inhibitor, facilitated the induction of CPP to morphine [39]. Taken together, it is conceivable that an inhibition of the glutamatergic system following, at least in part, the activation of glutamate transporters by MS-153 reduces activation of the dopaminergic system during repeated treatment with morphine or psychostimulants, to block the neuronal adaptations related to their conditioned rewarding effects. Additional investigations are needed to determine whether MS-153 affects the increase in the extracellular dopamine level after single and repeated injections of morphine and psychostimulants with in vivo microdialysis studies. In conclusion, we found that co-administration of MS- 153, a glutamate transporter activator, attenuated the induction of CPP to morphine, methamphetamine and cocaine without affecting acute locomotor responses. 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