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Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors
Neuropharmacology 55 (2008) 555–559
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors Hyung Shin Yoon, Ju Kyong Jang, Jeong-Hoon Kim* Department of Physiology, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemungu, Seoul 120-752, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2008 Received in revised form 24 June 2008 Accepted 10 July 2008
It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15 mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5 mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were preexposed to either saline or seven daily injections of cocaine (15 mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0 mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10 mg/kg), but not D2 (eticlopride; 10 or 50 mg/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cocaine LY341495 mGluRs Behavioral sensitization Dopamine
1. Introduction It has been shown that group II metabotropic glutamate receptors (mGluRs) potentially contribute to the expression of behavioral sensitization by psychostimulant drugs such as amphetamine (AMPH) and cocaine. For example, activation of group II mGluRs blocks the expression of locomotor sensitization as well as the enhanced drug taking induced by previous exposure to AMPH (Kim and Vezina, 2002; Kim et al., 2005), and suppresses cocaine seeking behavior motivated by stimuli conditioned to this drug or by drug itself (Baptista et al., 2004; Adewale et al., 2006). On the contrary, it was previously reported that microinjections into the nucleus accumbens (NAcc) of both (RS)-a-methyl-4-carboxyphenylglycine [(RS)-MCPG], a broad-spectrum mGluR antagonist, and LY341495, a selective antagonist with high potency for group II mGluR (Kingston et al., 1998), produced the opposite effect, hyperlocomotion, in rats previously exposed to the drug (Kim and Vezina,
* Corresponding author. Tel.: þ82 2 2228 1704; fax: þ82 2 393 0203. E-mail address: [email protected] (J.-H. Kim). 0028-3908/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2008.07.012
1998; Chi et al., 2006). It was also shown that repeated cocaine produced an enduring reduction in group II mGluR function in the NAcc (Xi et al., 2002). These results indicate that group II mGluRs, particularly those found in the NAcc, may play a modulatory role in the expression of locomotor sensitization by these drugs. Psychostimulant drugs elicit dopamine (DA) as well as glutamate overflows in the NAcc (Reid et al., 1997; Vanderschuren and Kalivas, 2000). Evidence has shown that the interaction of both DA and glutamate in the NAcc is necessary for the expression of psychomotor stimulant-induced behavioral sensitization (Wolf, 1998; Vezina and Kim, 1999; Kim et al., 2001). Group II mGluRs are well known to function as glutamate autoreceptors to negatively regulate presynaptic glutamate release (Manzoni et al., 1997; Cartmell and Schoepp, 2000; Schoepp, 2001; Baker et al., 2002; Xi et al., 2002) and thereby possibly interacting with DA as well, for example, as previously shown that activation of group II mGluRs blocks the sensitized release of NAcc glutamate as well as NAcc DA induced by previous exposure to AMPH (Kim et al., 2005). Although cocaine and AMPH share the ability to increase synaptic DA levels in the mesoaccumbens circuit, the detailed mechanism by which they do is not the same (Hyman, 1996). While
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cocaine simply blocks the DA reuptake transporter (DAT), AMPH has more complex actions like that it promotes reverse transport via DAT to release DA out of cytosol (Pifl et al., 1995; Sulzer et al., 1995; Giros et al., 1996). Numerous literature indicate that cocaine and AMPH don’t always have the same effects on various behavioral and biochemical profiles. For example, continuous long term use of cocaine does not induce axonal degeneration in neostriatum unlike AMPH (Ryan et al., 1988), produces less intense stereotypes and more vivid hallucinatory effects than AMPH (Ellison, 1993). The goal of this study is to examine whether LY341495, a selective group II mGluR antagonist, produces hyper-locomotion in cocaine pre-exposed rats as shown in our previous findings with amphetamine (Chi et al., 2006), and further to reveal the role of DA receptors in these effects. 2. Materials and methods 2.1. Subjects Male Sprague–Dawley rats weighing 230–260 g on arrival were obtained from Samtako (Osan, Korea). They were housed three per cage in a 12-h light/dark cycle room with food and water available at all times. Experiments were all carried out during the light phase of the light cycle. All animal use procedures were conducted according to an approved IACUC protocol. 2.2. Drugs The potent and selective group II mGluR antagonist LY341495 (Tocris, Ellisville, MO) was dissolved in 1.2 equivalent of NaOH solution and stored in small aliquots at 80 C. The selective dopamines D1 and D2 receptor antagonists, R-(þ)-SCH23390 and S-()-eticlopride (Sigma, St. Louis, MO), respectively, were dissolved in sterile 0.9% saline and small aliquots were stored at 80 C. Immediately prior to use, frozen aliquots of the drugs were diluted in sterile saline. Cocaine hydrochloride (Belgopia, Belgium) was dissolved in sterile 0.9% saline. 2.3. Locomotor activity Locomotor activity was measured with a bank of six activity boxes (35 25 40 cm) (IWOO Scientific Corporation, Seoul, Korea) made of translucent Plexiglas. Each box was individually housed in a PVC plastic sound attenuating cubicle. The floor of each box consisted of 21 stainless steel rods (5 mm diameter) spaced 1.2 cm apart center-to-center. Two infrared light photo beams (Med Associates, St. Albans, VT, USA) positioned 4.5 cm above the floor and spaced evenly along the longitudinal axis of the box estimated horizontal locomotion. 2.4. Design and procedure The experiments consisted of a pre-exposure phase and a test for crosssensitization. During the pre-exposure phase, rats in different groups were administered seven injections of either saline (experiment 2) or cocaine (15 mg/kg, IP) (experiments 1–3), one injection every day. Rats were placed in the activity monitoring boxes after their first and last injections, which were preceded 60 min earlier by habituations. Remaining injections were given in the home cage. This procedure is well known to reliably produce robust locomotor sensitization to cocaine (e.g., Pierce et al., 1996; Yoon et al., 2007). On the test for cross-sensitization, either the next day (experiment 1) or 3 weeks (experiments 2–3) after the last pre-exposure injection, rats were placed in the activity boxes and allowed to habituate for 60 min. They were then administered a challenge injection of LY341495 either with (experiment 3) or without (experiments 1 and 2) pre-injection of DA receptor antagonists and immediately returned to the activity boxes where activity counts were measured for a period of 120 min. Experiment 1: The next day after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (0.5, 1.0 or 2.5 mg/kg). Experiment 2: Three weeks after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (1 mg/kg). Experiment 3: Three weeks after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (1 mg/kg) in a counter-balanced way, which were preceded 15 min earlier by IP injections of either saline, SCH23390 (5 or 10 mg/kg), or eticlopride (10 or 50 mg/kg). Systemic doses of LY341495, SCH23390, and eticlopride were all selected to have no statistically significant effects on basal responding (except for LY341495 2.5 mg/ kg) (see Cartmell et al., 2000; O’Neill et al., 2003; Chi et al., 2006, for LY341495; also see O’Neill and Shaw, 1999; Chausmer and Katz, 2001; O’Neill et al., 2003, for SCH23390 and eticlopride). Total 97 rats were used and included all in the statistical analysis in this study.
3. Results Table 1 shows the locomotor activity counts obtained in rats pre-exposed to cocaine or saline. As expected, rats exposed to cocaine showed a significant increase in locomotor activity on day 7 compared to day 1 (P < 0.001–0.01). When challenged on the next day after the last pre-exposure day, a systemic injection of LY341495 produced a dose-dependent increase in locomotor activity in cocaine pre-exposed rats (Fig. 1). The one-way ANOVA conducted on the first hour total locomotor activity counts showed a significant effect between treatments [F(3,12) ¼ 15.40, P < 0.001]. Post hoc Scheffe´ comparisons revealed that two higher doses (1.0 or 2.5 mg/kg) of LY341495 produced a locomotor response that was significantly greater than saline (P < 0.001–0.01) (Fig. 1A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 1B. No significant differences between groups were detected during preinjection. Cocaine-induced cross-sensitization to LY341495 continues to be present after 3 weeks of drug-free period (Fig. 2). The two-way between (pre-exposures)-within (challenge) ANOVA conducted on the first hour total locomotor activity counts showed significant effects of pre-exposure [F(1,41) ¼ 6.93, P < 0.02] and challenge injections [F(1,41) ¼ 7.73, P < 0.009], but of no preexposures challenge interaction [F(1,41) ¼ 2.08, P < 0.16]. Post hoc Scheffe´ comparisons revealed that LY341495 produced a locomotor response that was significantly greater in cocaine compared to saline pre-exposed rats (P < 0.01) (Fig. 2A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 2B. No significant differences between groups were detected during pre-injection. However, when DA D1, but not D2, receptor antagonists were pre-injected, the significant increase of locomotor activity that LY341495 produced in cocaine pre-exposed rats was no longer present (Fig. 3). The two-way between (pre-injections)-within (challenge) repeated measure ANOVA conducted on these data showed a significant effect of challenge injection [F(1,31) ¼ 23.18, P < 0.001]. Post hoc Scheffe´ comparisons revealed LY341495 compared to saline produced significantly greater locomotor responses in either saline or eticlopride pre-injected rats (Ps < 0.01–0.05), while these effects were absent in SCH23390 preinjected rats (Fig. 3A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 3B. No significant change in locomotor activity was observed in saline challenged rats following any of the DA receptor antagonists preinjected.
Table 1 Locomotor activity counts during pre-exposures Pre-exposure group
Day 1
Day 7
Experiment 1 Cocaine (16)
196 47
532 84**
Experiment 2 Saline (24) Cocaine (21)
39 6 323 61yyy
61 11 701 73yyy,***
Experiment 3 Cocaine (36)
225 34
621 62***
All rats were habituated for 1 h and their locomotor activity measured for an additional 1 h following their respective injections. Only at days 1 and 7, locomotor activity was measured during the pre-exposure injections (once daily total seven injections), while remaining injections were given in the home cage. yyyP < 0.001, significant difference in cocaine compared to saline pre-exposed animals. **P < 0.01, ***P < 0.001, significant difference at day 7 compared to day 1 as revealed either by post hoc Scheffe´ comparisons following two-way between-within repeated measure ANOVA (for experiment 2) or by t-test (for experiments 1 and 3). Numbers in parentheses indicate n/group.
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Fig. 1. The group II mGluR antagonist LY341495 produces hyper-locomotor activity when administered systemically on 1 day of drug-free period to rats previously exposed to cocaine. (A) Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 (0.5, 1.0 or 2.5 mg/kg) in rats exposed 1 day earlier to cocaine (7 days of daily injection). Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following one-way ANOVA. **P < 0.01, ***P < 0.001, LY341495 compared with saline challenge. n/ group ¼ 4. (B) Time-course data are shown as group mean (þSEM) locomotor counts obtained during the 2 h following either saline or LY341495 challenge injection, which were administered at time 0. Habituation was preceded for 1 h before injection.
4. Discussion Consistent with our earlier findings that the group II mGluR antagonist LY341495 increased locomotor activity in rats previously exposed to amphetamine (Chi et al., 2006), the present studies revealed that LY341495 also produced enhanced locomotor activity in cocaine pre-exposed rats when tested at both drug-free day 1 and 3 weeks. Further, we extend our previous findings by showing that this effect was absent when LY341495 was pre-injected with the DA D1, but not with DA D2, receptor antagonist. These results support the notion that group II mGluRs are well positioned, possibly by making interactions with DA-mediated neuronal signaling, to modulate the expression of behavioral sensitization by psychomotor stimulants. The doses of LY341495 we used in the present experiments were selected based upon previous findings (O’Neill et al., 2003; Kim et al., 2005; Chi et al., 2006). Although locomotor activity on drugfree day 1 in cocaine pre-exposed rats was increased a little bit higher with 2.5 than 1.0 mg/kg of LY341495 (Fig. 1), they are not
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Fig. 2. The group II mGluR antagonist LY341495 produces hyper-locomotor activity when administered systemically on 3 weeks of drug-free period to rats previously exposed to cocaine. (A) Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 (1 mg/kg) in rats exposed 3 weeks earlier to cocaine or saline. Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following two-way betweenwithin ANOVA. **P < 0.01, cocaine compared with saline pre-exposure in rats LY341495 challenged. yyP < 0.01, LY341495 compared with saline challenge in rats cocaine pre-exposed. Numbers of rats in each group are 10–12. B. Time-course data are shown as group mean (þSEM) locomotor counts obtained during the 2 h following either saline or LY341495 challenge injection, which were administered at time 0. Habituation was preceded for 1 h before injection. Numbers of rats in each group (preexposure-challenge) are following: 12 for saline-saline, 10 for cocaine-saline, 12 for saline-LY341495 and 11 for cocaine-LY341495.
statistically significant. Middle lower dose (1.0 mg/kg) was used for following experiments because a higher one (2.5 mg/kg) has been shown to increase basal locomotor activity in drug naı¨ve mice (O’Neill et al., 2003). The effects of LY341495 on increase of locomotor activity in cocaine pre-exposed rats persist on both short (day 1) and long (3 weeks) term drug-free periods, suggesting that these effects were more likely resulted from neuronal adaptations of group II mGluR-mediated signaling during cocaine preexposures rather than during drug-free periods. There might be a change in the distribution or/and number of these receptors upon repeated exposure to cocaine but it remains to be explored. It is known that mGluRs are peri-synaptically located and this position makes them to selectively well inhibit the enhanced glutamate overflow observed in rats pre-exposed to amphetamine or cocaine (Pierce et al., 1996; Reid et al., 1997; Kim et al., 2005). For example, activation of group II mGluRs can reduce glutamate release (Schoepp, 2001; Xi et al., 2002) by inhibiting calcium conductance (Chivas et al., 1994; Schumacher et al., 2000), or by inhibiting cystine–glutamate exchange (Baker et al., 2002). On the
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Fig. 3. The increase of locomotor activity by group II mGluR antagonist LY341495 in cocaine pre-exposed rats is inhibited by DA D1, but not by D2, receptor antagonist. Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 in a counter-balanced way, which were preceded 15 min earlier by IP injection of either saline, DA D1 receptor antagonist SCH23390 (A), or DA D2 receptor antagonist eticlopride (B). Time-course data are shown in insets for only the control (saline) and higher doses of DA receptor antagonists tested (10 or 50 mg/kg, respectively). They are shown as group mean (þSEM) horizontal locomotion counts obtained during the 1 h preceding (60 through 0 min) and the 2 h following either saline or LY341495 challenge injection (0 to 120 min), which were administered at time 0. Animals were all pre-exposed to cocaine 3 weeks earlier before challenge. Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following two-way between-within repeated measure ANOVA. **P < 0.01, *P < 0.05, LY341495 compared with saline challenge in rats either saline or eticlopride pre-injected, respectively. The saline group (0 mg/kg of DA antagonist) is shown in both panels for illustration purposes only. Numbers of rats in each group are following: eight for saline, five for SCH23390 (5 mg/kg), nine for SCH23390 (10 mg/kg), five for eticlopride (10 mg/kg) and nine for eticlopride (50 mg/kg) pre-injection.
other hand, it would expect for the selective blockade of group II mGluRs to prevent the inhibition of glutamate overflow by these receptors. In the present experiments, considering that no cocaine was administered on the challenge test, glutamate overflow is possibly enhanced by conditioned (Hotsenpiller and Wolf, 2003) or stress (McFarland et al., 2004) cues associated with the testing procedures. By blocking the group II mGluRs, LY341495 may prevent the inhibition of glutamate overflow by these receptors, consequently further enhancing glutamate overflow and, as observed in the present experiments, resulting in hyperlocomotion. Interestingly, it has been shown that group II mGluR function in the NAcc is reduced after repeated exposure to cocaine (Xi et al., 2002), which could conceivably have enhanced glutamate overflow and thereby the effect of LY341495 in cocaine pre-exposed rats. More recently, mGluR2 knockout mice have also shown to significantly increase in locomotor sensitization in association with repeated cocaine administration (Morishima et al., 2005), supporting the notion that the elimination of functional role of group II mGluRs normally afforded to the inhibition of glutamate overflow is enhancing the increase of locomotor activity, consistent with our previous and present findings with LY341495. In the NAcc, psychomotor stimulant drugs elicit DA as well as glutamate overflows (Reid et al., 1997; Vanderschuren and Kalivas, 2000). Evidence has shown that the interaction of both DA and glutamate in the NAcc is necessary for the expression of psychomotor stimulant-induced behavioral sensitization (Wolf, 1998; Vezina and Kim, 1999; Kim et al., 2001). In the present results, we have also shown that cocaine-induced locomotor cross-
sensitization to LY341495 may be produced by interaction with DA neuronal signaling. Interestingly, it was previously shown that the hyperactivity induced in drug naı¨ve mice by a higher dose of a similar group II mGluR antagonist LY366457 (2.5 mg/kg) was significantly attenuated by SCH23390 but only at the dose (25 mg/ kg) that also significantly attenuated spontaneous locomotion (O’Neill et al., 2003). In contrast, our results of the inhibitory effects of SCH23390 on LY341495-induced hyper-locomotion were obtained in cocaine pre-exposed rats with a dose (5–10 mg/kg) that has no spontaneous locomotor attenuating effect, suggesting that group II mGluR-mediated locomotor activity is regulated more sensitively to DA D1 receptor-mediated neuronal signaling in cocaine pre-exposure than in drug naı¨ve state. The signaling mechanisms mediating the action of DA on hyper-locomotion are still not fully understood. Classically, DA D1 receptors have been shown to activate cAMP–PKA (protein kinase A) in the modulation of fast glutamate-mediated neurotransmission (Beaulieu et al., 2007). Interestingly, however, it has been suggested that the new mode of DA D2 receptor signaling, which involves proteins implicated in G-protein coupled receptor desensitization, mediates more slow response of DA dependent behaviors (Beaulieu et al., 2005, 2007). The effect of D1, but not D2, in our present results is more likely to result from its different kinetic action on glutamatemediated behavior (i.e., group II mGluR-mediated locomotor activity in our case). Our previous and present findings, showing that the blockade of peri-synaptically located group II mGluRs produces increased locomotion only in rats previously exposed to psychomotor
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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors Hyung Shin Yoon, Ju Kyong Jang, Jeong-Hoon Kim* Department of Physiology, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchondong, Seodaemungu, Seoul 120-752, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2008 Received in revised form 24 June 2008 Accepted 10 July 2008
It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15 mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5 mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were preexposed to either saline or seven daily injections of cocaine (15 mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0 mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10 mg/kg), but not D2 (eticlopride; 10 or 50 mg/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cocaine LY341495 mGluRs Behavioral sensitization Dopamine
1. Introduction It has been shown that group II metabotropic glutamate receptors (mGluRs) potentially contribute to the expression of behavioral sensitization by psychostimulant drugs such as amphetamine (AMPH) and cocaine. For example, activation of group II mGluRs blocks the expression of locomotor sensitization as well as the enhanced drug taking induced by previous exposure to AMPH (Kim and Vezina, 2002; Kim et al., 2005), and suppresses cocaine seeking behavior motivated by stimuli conditioned to this drug or by drug itself (Baptista et al., 2004; Adewale et al., 2006). On the contrary, it was previously reported that microinjections into the nucleus accumbens (NAcc) of both (RS)-a-methyl-4-carboxyphenylglycine [(RS)-MCPG], a broad-spectrum mGluR antagonist, and LY341495, a selective antagonist with high potency for group II mGluR (Kingston et al., 1998), produced the opposite effect, hyperlocomotion, in rats previously exposed to the drug (Kim and Vezina,
* Corresponding author. Tel.: þ82 2 2228 1704; fax: þ82 2 393 0203. E-mail address: [email protected] (J.-H. Kim). 0028-3908/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2008.07.012
1998; Chi et al., 2006). It was also shown that repeated cocaine produced an enduring reduction in group II mGluR function in the NAcc (Xi et al., 2002). These results indicate that group II mGluRs, particularly those found in the NAcc, may play a modulatory role in the expression of locomotor sensitization by these drugs. Psychostimulant drugs elicit dopamine (DA) as well as glutamate overflows in the NAcc (Reid et al., 1997; Vanderschuren and Kalivas, 2000). Evidence has shown that the interaction of both DA and glutamate in the NAcc is necessary for the expression of psychomotor stimulant-induced behavioral sensitization (Wolf, 1998; Vezina and Kim, 1999; Kim et al., 2001). Group II mGluRs are well known to function as glutamate autoreceptors to negatively regulate presynaptic glutamate release (Manzoni et al., 1997; Cartmell and Schoepp, 2000; Schoepp, 2001; Baker et al., 2002; Xi et al., 2002) and thereby possibly interacting with DA as well, for example, as previously shown that activation of group II mGluRs blocks the sensitized release of NAcc glutamate as well as NAcc DA induced by previous exposure to AMPH (Kim et al., 2005). Although cocaine and AMPH share the ability to increase synaptic DA levels in the mesoaccumbens circuit, the detailed mechanism by which they do is not the same (Hyman, 1996). While
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cocaine simply blocks the DA reuptake transporter (DAT), AMPH has more complex actions like that it promotes reverse transport via DAT to release DA out of cytosol (Pifl et al., 1995; Sulzer et al., 1995; Giros et al., 1996). Numerous literature indicate that cocaine and AMPH don’t always have the same effects on various behavioral and biochemical profiles. For example, continuous long term use of cocaine does not induce axonal degeneration in neostriatum unlike AMPH (Ryan et al., 1988), produces less intense stereotypes and more vivid hallucinatory effects than AMPH (Ellison, 1993). The goal of this study is to examine whether LY341495, a selective group II mGluR antagonist, produces hyper-locomotion in cocaine pre-exposed rats as shown in our previous findings with amphetamine (Chi et al., 2006), and further to reveal the role of DA receptors in these effects. 2. Materials and methods 2.1. Subjects Male Sprague–Dawley rats weighing 230–260 g on arrival were obtained from Samtako (Osan, Korea). They were housed three per cage in a 12-h light/dark cycle room with food and water available at all times. Experiments were all carried out during the light phase of the light cycle. All animal use procedures were conducted according to an approved IACUC protocol. 2.2. Drugs The potent and selective group II mGluR antagonist LY341495 (Tocris, Ellisville, MO) was dissolved in 1.2 equivalent of NaOH solution and stored in small aliquots at 80 C. The selective dopamines D1 and D2 receptor antagonists, R-(þ)-SCH23390 and S-()-eticlopride (Sigma, St. Louis, MO), respectively, were dissolved in sterile 0.9% saline and small aliquots were stored at 80 C. Immediately prior to use, frozen aliquots of the drugs were diluted in sterile saline. Cocaine hydrochloride (Belgopia, Belgium) was dissolved in sterile 0.9% saline. 2.3. Locomotor activity Locomotor activity was measured with a bank of six activity boxes (35 25 40 cm) (IWOO Scientific Corporation, Seoul, Korea) made of translucent Plexiglas. Each box was individually housed in a PVC plastic sound attenuating cubicle. The floor of each box consisted of 21 stainless steel rods (5 mm diameter) spaced 1.2 cm apart center-to-center. Two infrared light photo beams (Med Associates, St. Albans, VT, USA) positioned 4.5 cm above the floor and spaced evenly along the longitudinal axis of the box estimated horizontal locomotion. 2.4. Design and procedure The experiments consisted of a pre-exposure phase and a test for crosssensitization. During the pre-exposure phase, rats in different groups were administered seven injections of either saline (experiment 2) or cocaine (15 mg/kg, IP) (experiments 1–3), one injection every day. Rats were placed in the activity monitoring boxes after their first and last injections, which were preceded 60 min earlier by habituations. Remaining injections were given in the home cage. This procedure is well known to reliably produce robust locomotor sensitization to cocaine (e.g., Pierce et al., 1996; Yoon et al., 2007). On the test for cross-sensitization, either the next day (experiment 1) or 3 weeks (experiments 2–3) after the last pre-exposure injection, rats were placed in the activity boxes and allowed to habituate for 60 min. They were then administered a challenge injection of LY341495 either with (experiment 3) or without (experiments 1 and 2) pre-injection of DA receptor antagonists and immediately returned to the activity boxes where activity counts were measured for a period of 120 min. Experiment 1: The next day after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (0.5, 1.0 or 2.5 mg/kg). Experiment 2: Three weeks after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (1 mg/kg). Experiment 3: Three weeks after the last pre-exposure injection, rats were administered IP challenge injections of either saline or LY341495 (1 mg/kg) in a counter-balanced way, which were preceded 15 min earlier by IP injections of either saline, SCH23390 (5 or 10 mg/kg), or eticlopride (10 or 50 mg/kg). Systemic doses of LY341495, SCH23390, and eticlopride were all selected to have no statistically significant effects on basal responding (except for LY341495 2.5 mg/ kg) (see Cartmell et al., 2000; O’Neill et al., 2003; Chi et al., 2006, for LY341495; also see O’Neill and Shaw, 1999; Chausmer and Katz, 2001; O’Neill et al., 2003, for SCH23390 and eticlopride). Total 97 rats were used and included all in the statistical analysis in this study.
3. Results Table 1 shows the locomotor activity counts obtained in rats pre-exposed to cocaine or saline. As expected, rats exposed to cocaine showed a significant increase in locomotor activity on day 7 compared to day 1 (P < 0.001–0.01). When challenged on the next day after the last pre-exposure day, a systemic injection of LY341495 produced a dose-dependent increase in locomotor activity in cocaine pre-exposed rats (Fig. 1). The one-way ANOVA conducted on the first hour total locomotor activity counts showed a significant effect between treatments [F(3,12) ¼ 15.40, P < 0.001]. Post hoc Scheffe´ comparisons revealed that two higher doses (1.0 or 2.5 mg/kg) of LY341495 produced a locomotor response that was significantly greater than saline (P < 0.001–0.01) (Fig. 1A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 1B. No significant differences between groups were detected during preinjection. Cocaine-induced cross-sensitization to LY341495 continues to be present after 3 weeks of drug-free period (Fig. 2). The two-way between (pre-exposures)-within (challenge) ANOVA conducted on the first hour total locomotor activity counts showed significant effects of pre-exposure [F(1,41) ¼ 6.93, P < 0.02] and challenge injections [F(1,41) ¼ 7.73, P < 0.009], but of no preexposures challenge interaction [F(1,41) ¼ 2.08, P < 0.16]. Post hoc Scheffe´ comparisons revealed that LY341495 produced a locomotor response that was significantly greater in cocaine compared to saline pre-exposed rats (P < 0.01) (Fig. 2A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 2B. No significant differences between groups were detected during pre-injection. However, when DA D1, but not D2, receptor antagonists were pre-injected, the significant increase of locomotor activity that LY341495 produced in cocaine pre-exposed rats was no longer present (Fig. 3). The two-way between (pre-injections)-within (challenge) repeated measure ANOVA conducted on these data showed a significant effect of challenge injection [F(1,31) ¼ 23.18, P < 0.001]. Post hoc Scheffe´ comparisons revealed LY341495 compared to saline produced significantly greater locomotor responses in either saline or eticlopride pre-injected rats (Ps < 0.01–0.05), while these effects were absent in SCH23390 preinjected rats (Fig. 3A). Pre- and post-injection time-course for locomotor activity in the different groups is shown in Fig. 3B. No significant change in locomotor activity was observed in saline challenged rats following any of the DA receptor antagonists preinjected.
Table 1 Locomotor activity counts during pre-exposures Pre-exposure group
Day 1
Day 7
Experiment 1 Cocaine (16)
196 47
532 84**
Experiment 2 Saline (24) Cocaine (21)
39 6 323 61yyy
61 11 701 73yyy,***
Experiment 3 Cocaine (36)
225 34
621 62***
All rats were habituated for 1 h and their locomotor activity measured for an additional 1 h following their respective injections. Only at days 1 and 7, locomotor activity was measured during the pre-exposure injections (once daily total seven injections), while remaining injections were given in the home cage. yyyP < 0.001, significant difference in cocaine compared to saline pre-exposed animals. **P < 0.01, ***P < 0.001, significant difference at day 7 compared to day 1 as revealed either by post hoc Scheffe´ comparisons following two-way between-within repeated measure ANOVA (for experiment 2) or by t-test (for experiments 1 and 3). Numbers in parentheses indicate n/group.
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Fig. 1. The group II mGluR antagonist LY341495 produces hyper-locomotor activity when administered systemically on 1 day of drug-free period to rats previously exposed to cocaine. (A) Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 (0.5, 1.0 or 2.5 mg/kg) in rats exposed 1 day earlier to cocaine (7 days of daily injection). Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following one-way ANOVA. **P < 0.01, ***P < 0.001, LY341495 compared with saline challenge. n/ group ¼ 4. (B) Time-course data are shown as group mean (þSEM) locomotor counts obtained during the 2 h following either saline or LY341495 challenge injection, which were administered at time 0. Habituation was preceded for 1 h before injection.
4. Discussion Consistent with our earlier findings that the group II mGluR antagonist LY341495 increased locomotor activity in rats previously exposed to amphetamine (Chi et al., 2006), the present studies revealed that LY341495 also produced enhanced locomotor activity in cocaine pre-exposed rats when tested at both drug-free day 1 and 3 weeks. Further, we extend our previous findings by showing that this effect was absent when LY341495 was pre-injected with the DA D1, but not with DA D2, receptor antagonist. These results support the notion that group II mGluRs are well positioned, possibly by making interactions with DA-mediated neuronal signaling, to modulate the expression of behavioral sensitization by psychomotor stimulants. The doses of LY341495 we used in the present experiments were selected based upon previous findings (O’Neill et al., 2003; Kim et al., 2005; Chi et al., 2006). Although locomotor activity on drugfree day 1 in cocaine pre-exposed rats was increased a little bit higher with 2.5 than 1.0 mg/kg of LY341495 (Fig. 1), they are not
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Fig. 2. The group II mGluR antagonist LY341495 produces hyper-locomotor activity when administered systemically on 3 weeks of drug-free period to rats previously exposed to cocaine. (A) Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 (1 mg/kg) in rats exposed 3 weeks earlier to cocaine or saline. Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following two-way betweenwithin ANOVA. **P < 0.01, cocaine compared with saline pre-exposure in rats LY341495 challenged. yyP < 0.01, LY341495 compared with saline challenge in rats cocaine pre-exposed. Numbers of rats in each group are 10–12. B. Time-course data are shown as group mean (þSEM) locomotor counts obtained during the 2 h following either saline or LY341495 challenge injection, which were administered at time 0. Habituation was preceded for 1 h before injection. Numbers of rats in each group (preexposure-challenge) are following: 12 for saline-saline, 10 for cocaine-saline, 12 for saline-LY341495 and 11 for cocaine-LY341495.
statistically significant. Middle lower dose (1.0 mg/kg) was used for following experiments because a higher one (2.5 mg/kg) has been shown to increase basal locomotor activity in drug naı¨ve mice (O’Neill et al., 2003). The effects of LY341495 on increase of locomotor activity in cocaine pre-exposed rats persist on both short (day 1) and long (3 weeks) term drug-free periods, suggesting that these effects were more likely resulted from neuronal adaptations of group II mGluR-mediated signaling during cocaine preexposures rather than during drug-free periods. There might be a change in the distribution or/and number of these receptors upon repeated exposure to cocaine but it remains to be explored. It is known that mGluRs are peri-synaptically located and this position makes them to selectively well inhibit the enhanced glutamate overflow observed in rats pre-exposed to amphetamine or cocaine (Pierce et al., 1996; Reid et al., 1997; Kim et al., 2005). For example, activation of group II mGluRs can reduce glutamate release (Schoepp, 2001; Xi et al., 2002) by inhibiting calcium conductance (Chivas et al., 1994; Schumacher et al., 2000), or by inhibiting cystine–glutamate exchange (Baker et al., 2002). On the
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Fig. 3. The increase of locomotor activity by group II mGluR antagonist LY341495 in cocaine pre-exposed rats is inhibited by DA D1, but not by D2, receptor antagonist. Data are shown as group mean (þSEM) locomotor counts obtained for 1 h following a challenge injection of either saline or LY341495 in a counter-balanced way, which were preceded 15 min earlier by IP injection of either saline, DA D1 receptor antagonist SCH23390 (A), or DA D2 receptor antagonist eticlopride (B). Time-course data are shown in insets for only the control (saline) and higher doses of DA receptor antagonists tested (10 or 50 mg/kg, respectively). They are shown as group mean (þSEM) horizontal locomotion counts obtained during the 1 h preceding (60 through 0 min) and the 2 h following either saline or LY341495 challenge injection (0 to 120 min), which were administered at time 0. Animals were all pre-exposed to cocaine 3 weeks earlier before challenge. Symbols indicate significant differences as revealed by post hoc Scheffe´ comparisons following two-way between-within repeated measure ANOVA. **P < 0.01, *P < 0.05, LY341495 compared with saline challenge in rats either saline or eticlopride pre-injected, respectively. The saline group (0 mg/kg of DA antagonist) is shown in both panels for illustration purposes only. Numbers of rats in each group are following: eight for saline, five for SCH23390 (5 mg/kg), nine for SCH23390 (10 mg/kg), five for eticlopride (10 mg/kg) and nine for eticlopride (50 mg/kg) pre-injection.
other hand, it would expect for the selective blockade of group II mGluRs to prevent the inhibition of glutamate overflow by these receptors. In the present experiments, considering that no cocaine was administered on the challenge test, glutamate overflow is possibly enhanced by conditioned (Hotsenpiller and Wolf, 2003) or stress (McFarland et al., 2004) cues associated with the testing procedures. By blocking the group II mGluRs, LY341495 may prevent the inhibition of glutamate overflow by these receptors, consequently further enhancing glutamate overflow and, as observed in the present experiments, resulting in hyperlocomotion. Interestingly, it has been shown that group II mGluR function in the NAcc is reduced after repeated exposure to cocaine (Xi et al., 2002), which could conceivably have enhanced glutamate overflow and thereby the effect of LY341495 in cocaine pre-exposed rats. More recently, mGluR2 knockout mice have also shown to significantly increase in locomotor sensitization in association with repeated cocaine administration (Morishima et al., 2005), supporting the notion that the elimination of functional role of group II mGluRs normally afforded to the inhibition of glutamate overflow is enhancing the increase of locomotor activity, consistent with our previous and present findings with LY341495. In the NAcc, psychomotor stimulant drugs elicit DA as well as glutamate overflows (Reid et al., 1997; Vanderschuren and Kalivas, 2000). Evidence has shown that the interaction of both DA and glutamate in the NAcc is necessary for the expression of psychomotor stimulant-induced behavioral sensitization (Wolf, 1998; Vezina and Kim, 1999; Kim et al., 2001). In the present results, we have also shown that cocaine-induced locomotor cross-
sensitization to LY341495 may be produced by interaction with DA neuronal signaling. Interestingly, it was previously shown that the hyperactivity induced in drug naı¨ve mice by a higher dose of a similar group II mGluR antagonist LY366457 (2.5 mg/kg) was significantly attenuated by SCH23390 but only at the dose (25 mg/ kg) that also significantly attenuated spontaneous locomotion (O’Neill et al., 2003). In contrast, our results of the inhibitory effects of SCH23390 on LY341495-induced hyper-locomotion were obtained in cocaine pre-exposed rats with a dose (5–10 mg/kg) that has no spontaneous locomotor attenuating effect, suggesting that group II mGluR-mediated locomotor activity is regulated more sensitively to DA D1 receptor-mediated neuronal signaling in cocaine pre-exposure than in drug naı¨ve state. The signaling mechanisms mediating the action of DA on hyper-locomotion are still not fully understood. Classically, DA D1 receptors have been shown to activate cAMP–PKA (protein kinase A) in the modulation of fast glutamate-mediated neurotransmission (Beaulieu et al., 2007). Interestingly, however, it has been suggested that the new mode of DA D2 receptor signaling, which involves proteins implicated in G-protein coupled receptor desensitization, mediates more slow response of DA dependent behaviors (Beaulieu et al., 2005, 2007). The effect of D1, but not D2, in our present results is more likely to result from its different kinetic action on glutamatemediated behavior (i.e., group II mGluR-mediated locomotor activity in our case). Our previous and present findings, showing that the blockade of peri-synaptically located group II mGluRs produces increased locomotion only in rats previously exposed to psychomotor
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