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. Author manuscript; available in PMC: 2011 Sep 1.
Published in final edited form as: J Neurochem. 2010 Jun 8;114(5):1368–1380. doi: 10.1111/j.1471-4159.2010.06851.x

Activation of mGluR7s Inhibits Cocaine-Induced Reinstatement of Drug-Seeking Behavior by a Nucleus Accumbens Glutamate-mGluR2/3 Mechanism in Rats

Xia Li 1, Jie Li 1, Eliot L Gardner 1, Zheng-Xiong Xi 1,*
PMCID: PMC2923231  NIHMSID: NIHMS217010  PMID: 20534005

Abstract

The metabotropic glutamate receptor 7 (mGluR7) has been reported to be involved in cocaine and alcohol self-administration. However, the role of mGluR7 in relapse to drug seeking is unknown. Using a rat relapse model, we found that systemic administration of AMN082, a selective mGluR7 allosteric agonist, dose-dependently inhibits cocaine-induced reinstatement of drug-seeking behavior. Intracranial microinjections of AMN082 into the nucleus accumbens (NAc) or ventral pallidum (VP), but not the dorsal striatum (DS), also inhibited cocaine-primed reinstatement, an effect that was blocked by local co-administration of MMPIP, a selective mGluR7 antagonist. In vivo microdialysis demonstrated that cocaine priming significantly increased extracellular dopamine (DA) in the NAc, VP and DS, while increasing extracellular glutamate in the NAc only. AMN082 alone failed to alter extracellular DA, but produced a slow-onset long-lasting increase in extracellular glutamate in the NAc only. Pretreatment with AMN082 dose-dependently blocked both cocaine-enhanced NAc glutamate and cocaine-induced reinstatement, an effect that was blocked by MMPIP or LY341497 (a selective mGluR2/3 antagonist). These data suggest that mGluR7 activation inhibits cocaine-induced reinstatement of drug-seeking behavior by a glutamate-mGluR2/3 mechanism in the NAc. The present findings support the potential use of mGluR7 agonists for the treatment of cocaine addiction.

Keywords: mGluR7, AMN082, cocaine, reinstatement, dopamine, glutamate, relapse

Introduction

Drug addiction is a chronic disorder characterized by craving and relapse to drug use after abstinence. Medication development to attenuate relapse remains a major challenge in this field. Recent studies suggest that nucleus accumbens (NAc) dopamine (DA) and glutamate may be critically involved in cocaine-induced reinstatement of drug-seeking behavior (Anderson and Pierce, 2005; Xi and Gardner, 2008; Knackstedt and Kalivas, 2009). This is based on findings that cocaine priming significantly increases extracellular NAc DA and glutamate (Baker et al., 2003; McFarland et al., 2003; Xi et al., 2006, 2010). Microinjections of DA, D1-like, D2-like or AMPA receptor agonists into the NAc reinstate cocaine-seeking behavior (Cornish et al., 1999; Cornish and Kalivas, 2000; Schmidt et al., 2006; Schmidt and Pierce, 2006), while microinjections of D1-like, D2-like, or AMPA receptor antagonists attenuate cocaine- or cocaine-associated cue-induced reinstatement of drug-seeking behavior (Cornish et al., 1999; Cornish and Kalivas, 2000; Vorel et al., 2001; Suto et al., 2004; Bari and Pierce, 2005). In addition, several metabotropic glutamate receptors (mGluRs) have been shown to be involved in cocaine reward and addiction (Kenny and Markou, 2004; Olive, 2009). Genetic deletion or pharmacological blockade of mGluR5s significantly inhibits intravenous cocaine self-administration (Chiamulera et al., 2001; Tessari et al., 2004; Kenny et al., 2005; Paterson and Markou, 2005), and cocaine- or cocaine-associated cue-induced reinstatement of drug-seeking behavior (Lee et al., 2005; Bäckström and Hyytiä, 2007; Kumaresan et al., 2009). In addition, systemic administration of mGluR2/3 agonists also significantly inhibits intravenous cocaine self-administration, cocaine-induced reinstatement, as well as cocaine priming-induced increases in extracellular glutamate and DA (Baptista et al., 2004; Adewale et al., 2006; Peters and Kalivas, 2006; Xi et al., 2010). These data suggest that mGluR5 and mGluR2/3 subtypes could be important targets in medication development for the treatment of cocaine addiction. We note, however, that not all evidence supports this suggestion. For example, it is reported that the mGluR5 antagonist MPEP alters neither cocaine-enhanced brain-stimulation reward (Harrison et al., 2002; Kenny et al., 2003) and cocaine-induced conditioned place preference (Herzig and Schmidt, 2004), nor expression of cocaine-induced behavioral sensitization (Dravolina et al., 2006). The mGluR2/3 agonist LY379268, at doses that inhibit cocaine reward or reinstatement, also inhibits food-taking or food-seeking behavior (Peters and Kalivas, 2006; Liechti et al., 2007). These data suggest that blockade of mGluR5 may only alter some, but not all, pharmacological actions of cocaine, while activation of mGluR2/3 receptors may produce unwanted side-effects such as suppression of natural reward.

In contrast to mGluR5 and mGluR2/3, the role of other mGluRs such as group III mGluRs(4, 6, 7, 8) in cocaine reward and addiction is largely unknown, due to lack of systemically active, subtype-selective agents. With the recent development of N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), a selective mGluR7 allosteric agonist (Mitsukawa et al., 2005), we have been able to recently report that activation of mGluR7s by AMN082 significantly inhibits NAc GABA release, which produces an increase in NAc glutamate release by a GABAergic disinhibition mechanism (Li et al., 2008). In addition, AMN082 also significantly inhibits intravenous cocaine or oral alcohol self-administration and cocaine-enhanced electrical brain-stimulation reward (Salling et al., 2008; Li et al., 2009). It remains unclear, however, whether mGluR7s are also involved in cocaine-induced reinstatement of drug-seeking behavior.

Given the importance of NAc glutamate in relapse to drug seeking (Knackstedt and Kalivas, 2009) and previous findings that renormalization (elevation) of extracellular NAc glutamate inhibits cocaine-induced reinstatement of drug seeking (Baker et al., 2003; Xi et al., 2006), it seems plausible that AMN082-induced increases in NAc glutamate (Li et al., 2008, 2009) may alter cocaine-induced reinstatement of drug-seeking behavior. In the present study, we tested this hypothesis and explored possible underlying mechanisms. We first observed the effects of systemic administration of AMN082 on cocaine- or sucrose-triggered reinstatement of reward-seeking behavior, and then investigated the loci of action, by using intracranial microinjection techniques, in such brain regions as the NAc, ventral pallidum (VP) and dorsal striatum (DS) where high densities of mGluR7s are located (Bradley et al., 1998; Corti et al., 1998; Kinoshita et al., 1998). Further, we used in vivo brain microdialysis to measure cocaine-, sucrose-, or AMN082-induced changes in extracellular DA and glutamate in the NAc, VP and DS during reinstatement testing. Both the mGluR2/3 antagonist LY341495 and the selective mGluR7 antagonist MMPIP (Suzuki et al., 2007) were used to explore receptor mechanisms underlying AMN082’s action.

MATERIALS AND METHODS

Animals

Total 156 male Long-Evans rats (Charles River Laboratories, Raleigh, NC, USA) weighing 250 to 300 g were used for all experiments. They were housed individually in a climate-controlled animal room with free access to food and water. The animals were maintained in a facility fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care. All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the U.S. National Research Council, and were approved by the Animal Care and Use Committee of the National Institute on Drug Abuse.

Experiment 1: Cocaine-triggered reinstatement of drug-seeking behavior

Surgery

All animals were prepared for experimentation by surgical catheterization of the right external jugular vein. The jugular catheters were constructed of microrenathane (Braintree Scientific Inc., Braintree, MA, USA), and catheterization was performed under sodium pentobarbital anaesthesia (65 mg/kg, i.p.) with standard aseptic surgical techniques. After exiting the jugular, the catheter passed subcutaneously to the top of the skull, where it exited into a connector (a modified 24 gauge cannula; Plastics One, Roanoke, VA, USA). To determine the loci of action in rat brain, additional groups of rats were also surgically implanted with intracranial guide cannulae (20 gauge, 14 mm; Plastics One, Roanoke, VA, USA) into the NAc (AP +1.7 mm, ML ±2.0 mm, DV −5.0 mm, 6° angle from vertical), VP (AP −0.24 mm, ML ±3.2 mm, DV −6.5 mm, 6° angle from vertical) or DS (AP 2.04 mm, ML ±2.5 mm, DV −3.0 mm, 6° angle from vertical), according to the atlas of Paxinos and Watson (1986). Both the self-administration cannulae and intracranial guide cannulae were fixed to the skull with 4 stainless steel jeweler’s screws (Small Parts Inc., Miami Lakes, FL, USA) and dental acrylic. During experimental sessions, the self-administration catheter was connected to the injection pump via tubing encased in a protective metal spring from the head-mounted connector to the top of the experimental chamber. To help prevent clogging, the catheters were flushed daily with a gentamicin-heparin-saline solution (0.1 mg/ml gentamicin, 30 IU/ml heparin; ICN Biochemicals, Cleveland, OH, USA).

Apparatus

Intravenous (i.v.) self-administration experiments were conducted in operant response test chambers (32 × 25 × 33 cm) from MED Associates Inc. (Georgia, VT, USA). Each test chamber had 2 levers: 1 active and 1 inactive, located 6.5 cm above the floor. Depression of the active lever activated the infusion pump; depression of the inactive lever was counted but had no consequence. A cue light and a speaker were located 12 cm above the active lever. The house light was turned on at the start of each 3 hr test session. Scheduling of experimental events and data collection was accomplished using MED Associates software.

Cocaine self-administration

After recovery from surgery, each rat was placed into a test chamber and allowed to lever-press for i.v. cocaine (1 mg/kg/infusion) delivered in 0.08 ml over 4.6 sec, on a fixed ratio 1 (FR1) reinforcement schedule. Each cocaine infusion was associated with presentation of a stimulus light and tone. During the 4.6 sec infusion time, additional responses on the active lever were recorded but did not lead to additional infusions. Each session lasted 3 hr. FR1 reinforcement was used for 3–5 days until stable cocaine self-administration was established. Then subjects were allowed to continue cocaine (0.5 mg/kg/infusion) self-administration under FR2 reinforcement. The dose of cocaine was chosen based on previous studies showing that 0.5 mg/kg/infusion of cocaine lies within the middle range of the descending limb of the cocaine dose-response self-administration curve, where reliable dose-dependent effects can be observed (Mantsch et al., 2009; Xi et al., 2010). In addition, we chose 0.5 mg/kg, rather than 1 mg/kg, of cocaine in order to increase the work demand (i.e., lever presses) of the animals for the same amount of drug intake. In our experience, this approach increases the sensitivity of measuring changes in drug-seeking behavior. To avoid cocaine overdose during the self-administration period, each animal was limited to a maximum of 50 cocaine injections per 3 hr session.

Extinction

After stable cocaine-maintained responding was achieved (i.e., less than 10% variability in mean inter-response interval and less than 10% variability in mean active lever presses for at least 3 consecutive days), animals were exposed to extinction conditions, during which cocaine was replaced by saline, and the cocaine-associated cue-light and tone were turned off. Active lever pressing led only to saline infusion. Daily 3 h extinction sessions for each rat continued until that rat lever-pressed less than 10 times per 3 h session for at least 3 consecutive days. The rats then were divided into several groups for reinstatement testing.

Reinstatement test

On the reinstatement test day, rats without intracranial guide cannulae randomly received either vehicle (0.5% Tween-80, i.p.), 1 dose of AMN082 (1, 3, 10, 20 mg/kg, i.p.) or LY341495 (1 mg/kg, i.p.). Rats with intracranial guide cannulae randomly received vehicle (1 μl 25% 2-hydroxypropyl-β-cyclodextrin), 1 dose of AMN082 (3, 5 μg/μl) or MMPIP (5 μg/μl) bilaterally into the NAc, VP or DS. The intracranial microinjection was made with a syringe pump (Beehive MD-1020, Bioanalytical System Inc., W. Lafayette, IN, USA) at a constant flow rate of 1.0 μl/min for 1 min. One additional min was allowed to elapse before removing the internal injector from within the guide cannula. Thirty minutes after microinjection, all rats were given a priming injection of cocaine (10 mg/kg, i.p.) immediately before the initiation of reinstatement testing. During the reinstatement test, the conditions were identical to those in extinction sessions. Cocaine-induced active-lever presses (reinstatement) were recorded, although these did not lead to either cocaine infusions or presentation of the conditioned cue-light and tone. Reinstatement test sessions lasted 3 hr.

Experiment 2. Sucrose-triggered reinstatement of sucrose-seeking behavior

The procedures for sucrose self-administration and extinction were identical to the procedures for cocaine self-administration and extinction except for the following: 1) no surgery was performed on the animals in the sucrose experiment; and 2) active lever presses led to delivery of 0.16 ml of 5 % sucrose solution into a liquid food tray on the operant chamber wall. After sucrose-seeking behavior was extinguished, animals were divided into three dose groups (vehicle, 10, 20 mg/kg AMN082, i.p., 30 min prior to reinstatement test) to determine the effects of AMN082 on sucrose seeking triggered by 5 non-contingent sucrose deliveries. Subsequent lever presses were recorded, but did not lead to either sucrose delivery or presentation of the conditioned cue-light and tone.

Experiment 3: In vivo brain Microdialysis

In vivo microdialysis sampling was performed in rats after cocaine or sucrose self-administration and extinction training, i.e., the period after the cocaine-seeking behavior has been extinguished. The procedures for i.v. surgery, cocaine self-administration, extinction and reinstatement were identical to the procedures described above, except that the guide cannulae for microdialysis sampling were surgically implanted into the NAc (core and shell) (AP +1.6, ML ± 2.0, DV −4.0 mm, 6° from vertical), VP (AP −0.3, ML ±3.2, DV −5.5 mm, 6° angle from vertical) or DS (AP 2.04, ML ±2.5, DV −2.0 mm, 6° angle from vertical), according to the rat brain atlas of Paxinos and Watson (1998). The night before the experiment, concentric microdialysis probes (with 2 mm of active membrane) were inserted 2 mm beyond the tips of the guide cannulae into the NAc, VP or DS. At 12 hrs after probe implantation, dialysis buffer (5 mM KCl, 140 mM NaCl, 1.4 mM CaCl2 1.2 mM MgCl2, 5.0 mM glucose, plus 0.2 mM phosphate-buffered saline to give a pH of 7.4) was perfused through the probe at a rate of 2 μL/min via syringe pump (Bioanalytical Systems, W. Lafayette, IN, USA). At 2 hrs after start of perfusion, microdialysis samples were collected every 20 min into 10 μl 0.1 M perchloric acid to prevent DA degradation. After collection, samples were frozen at −80°C. Dialysate DA and glutamate were measured using high pressure liquid chromatography (HPLC) with electrochemical and flourometric detection, respectively, as we have reported previously (Li et al., 2008, 2009).

Quantification of DA

Dialysate DA was measured with the ESA electrochemical detection system (ESA Inc., Chelmsford, MA, USA). The DA mobile phase contained 4.76 mM citric acid, 150 mM Na2HPO4, 3 mM sodium dodecyl sulfate, 50 mM EDTA, 10% methanol, and 15% acetylnitrile, pH5.6. DA was separated using an ESA MD-150 × 3.2 mm reverse phase column and oxidized/reduced using an ESA Coulochem III detector. Three electrodes were used: a pre-injection port guard cell (+0.25 V) to oxidize the mobile phase, a reduction analytical electrode (E1, −0.1V), and an oxidation analytical electrode (E2, 0.2 V). The area under curve (AUC) of the DA peak was measured using an “EZChrom Elite” ESA chromatography data system. DA values were quantified with an external standard curve (generated by three standard concentrations: 10, 100, 1000 pM). The limit of detection for DA was ~1 pM.

Quantification of Glutamate

Concentrations of glutamate in the dialysis samples were determined using HPLC with flourometric detection. The mobile phase consisted of 18% acetylnitrile (v/v), 100 mM Na2HPO4, 0.1 mM EDTA, pH 6.04. A reverse-phase column (RP-18, 10 cm × 3 μm ODS, Bioanalytical systems Inc., West Lafayette, IN, USA) was used to separate the amino acids, and precolumn derivatization of amino acids with o-phthalaldehyde was performed using an ESA Model 542 autosampler (ESA Inc. Chelmsford, MA, USA). Glutamate was detected by a fluorescence detector (L-2480, Hitachi, Japan). One set of excitation wavelengths (Exλ, 314 nm) and emission wavelengths (Emλ, 394 nm) was used to measure glutamate levels from the same samples. The AUCs of the glutamate peaks were measured using an “EZChrom Elite” ESA chromatography data system. Glutamate values were quantified with external standard curves (generated by three standard concentrations: 0.1, 1.0, 5μM). The limit of detection for glutamate was 10 nM.

Drugs

Cocaine HCl was purchased from Sigma Chemical Co. (Saint Louis, MO, USA). N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP) and LY341495 were purchased from Tocris Bioscience (Ellisville, MO, USA). For intraperitoneal (i.p.) injection, AMN082 was dissolved in 0.5% Tween-80 (Sigma-RBI, St. Louis, MO, USA). For intracranial microinjection, AMN082 or MMPIP was dissolved in 25% 2-hydroxypropyl-β-cyclodextrin (Sigma-RBI, St. Louis, MO, USA). LY341495 was dissolved in 25% 2-hydroxypropyl-β-cyclodextrin. Drug injection times were determined based upon pilot studies and literature reports.

Histology

After the completion of microinjections or microdialysis experiments, rats were euthanized by pentobarbital overdose (>100 mg/kg i.p.) and perfused transcardially with 0.9% saline followed by 10% formalin. Brains were removed and placed in 10% formalin for 1 week. The tissue was blocked around the NAc, VP or DS, and coronal sections (100 μm thick) cut by vibratome. The sections were stained with cresyl violet and examined by light microscopy.

Data analyses

All data are presented as means (± S.E.M.). One-way analysis of variance (ANOVA) and/or two-way ANOVA for repeated measures were used to analyze the effects of AMN082 or MMPIP and cocaine on behavioral and neurochemical changes. Individual group comparisons were carried out using the Tukey-Kramer method.

RESULTS

AMN082 inhibits cocaine- or sucrose-induced reinstatement of cocaine- or sucrose-seeking behavior

Figure 1A illustrates the numbers of active lever presses observed during the last session of cocaine self-administration, the last session of extinction, and the reinstatement test in the different AMN082 dose groups. There were no significant differences in the numbers of active lever presses in the last session of cocaine self-administration or extinction among the different groups. A single-dose, non-contingent cocaine priming (10 mg/kg, i.p.) produced robust reinstatement responding in rats extinguished from cocaine self-administration (vehicle treated animals vs. last extinction: t=5.37, p<0.001). Pretreatment with AMN082 (1, 3, 10, or 20 mg/kg, i.p.) dose-dependently attenuated cocaine-induced reinstatement of drug-seeking behavior (F4,51=15.30, p<0.001). Individual group comparisons revealed a statistically significant reduction in cocaine-induced reinstatement after 10 mg/kg (q=8.98, p<0.001) or 20 mg/kg AMN082 (q=9.13, p<0.001), but not after 1 mg/kg (q=2.31, p=NS) or 3 mg/kg AMN082 (q=3.90, p=NS), when compared with the vehicle treatment group. Figure 1B illustrates the inactive lever responses during the last session of cocaine self-administration, the last session of extinction, and the reinstatement test session. AMN082 did not produce any alteration in inactive lever responses during reinstatement testing (F4,51=1.94, p=NS).

Figure 1.

Figure 1

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Effects of systemic administration of AMN082 on cocaine- or sucrose-induced reinstatement of reward-seeking behavior. A, B: active or inactive lever responses during the last session of cocaine self-administration (Last Self-Adm.), last session of extinction (Last Extinction) and reinstatement test in the different AMN082 dose treatment groups. C, D: active or inactive lever responses during the last session of oral sucrose self-administration, last session of extinction, and reinstatement test in the different AMN082 dose treatment groups. *p<0.05, ***p<0.001, compared to each group during the last extinction; ###p<0.001, compared to vehicle treatment group during the reinstatement testing.

Figure 1C illustrates that five deliveries of non-contingent sucrose priming (0.16 ml/2–3 min × 5) evoked significant sucrose-seeking behavior (vehicle treated animals vs. last extinction: t=3.86, p<0.01). Pretreatment with AMN082 (10, 20 mg/kg, i.p.) dose-dependently attenuated sucrose-induced reinstatement (F2,21=4.47, p<0.05). Individual group comparisons revealed a statistically significant reduction in sucrose-induced reinstatement after 20 mg/kg AMN082 (q=4.23 p<0.05), but not after 10 mg/kg (q=2.10, p=NS), when compared to the vehicle treatment group. Figure 1D illustrates inactive lever responses. There were no differences in inactive lever responses during reinstatement testing (F2,21=0.28, p=NS) between the vehicle group and any AMN082 treatment group.

Intra-NAc or intra-VP, but not intra-DS, microinjections of AMN082 inhibit cocaine-induced reinstatement of cocaine-seeking behavior

Figure 2A illustrates that intra-NAc microinjections of AMN082 (3, 5 μg) dose-dependently inhibited cocaine-triggered reinstatement (Active lever: F2,16=6.32, p<0.01; Inactive lever: F2,16=0.96, p=NS). Individual group comparisons revealed a statistically significant reduction in active lever presses after 5 μg (q=5.02, p<0.01), but not 3 μg (q=2.05, p=NS) AMN082, when compared to the vehicle group. Figure 2B illustrates that intra-NAc co-administration of MMPIP (5 μg/μl/side) significantly attenuated the antagonism by AMN082 (5 μg/μl/side) of cocaine-induced reinstatement (F3,21=4.69, p<0.05). Individual group comparisons revealed a statistically significant difference in active lever presses between Veh + Veh and Veh + AMN (q=5.16, p<0.01), and between Veh + AMN and MMPIP + AMN (q=3.67, p<0.05). MMPIP alone had no effect on cocaine-triggered reinstatement (q=1.73, p=NS). Figure 2C illustrates that intra-VP microinjections of AMN082 dose-dependently inhibited cocaine-triggered reinstatement (Active lever: F2,16=3.92, p<0.05; Inactive lever: F2,24=0.26, p=NS). Figure 2D illustrates that intra-DS microinjections of AMN082 had no effect on cocaine-induced reinstatement of drug-seeking behavior (Active lever: F2,22=0.2, p=NS; Inactive lever: F2,22=1.71, p=NS).

Figure 2.

Figure 2

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Effects of intracranial microinjections of AMN082 and/or MMPIP into the NAc (A, B), VP (C) or DS (D) on cocaine-induced reinstatement of drug-seeking behavior. NAc – nucleus accumbens; VP – ventral pallidum; DS – DS; AMN – AMN082; Veh – vehicle;. * p<0.05, ** p<0.01, compared to vehicle treatment group; # p<0.05, compared to (Veh + AMN) group.

AMN082 inhibits cocaine-induced increases in extracellular NAc glutamate, but not DA in the NAc, VP or DS

Table 1 shows basal levels of extracellular DA and glutamate in the NAc, VP and DS observed prior to reinstatement testing. Figure 3A illustrates that acute cocaine (10 mg/kg, i.p.) produced a significant increase (~350%) in extracellular NAc DA (Time main effect: F11,330=54.06, p<0.001). Pretreatment with AMN082 (10, 20 mg/kg) failed to alter cocaine-enhanced NAc DA (Treatment main effect: F2,30=0.66, p=NS). Figure 3B illustrates that cocaine priming also produced a significant increase (~150%) in extracellular NAc glutamate (time main effect: F2,60=3.89, p<0.05). Pretreatment with AMN082 (10, 20 mg/kg) almost completely blocked cocaine-enhanced extracellular glutamate (treatment main effect: F2,30=10.46, p<0.001). Individual group comparisons revealed a significant reduction in extracellular glutamate after 10 mg/kg (q=5.84, p<0.001) or 20 mg/kg (q=5.60, p<0.01) AMN082.

Table 1.

Basal levels of extracellular DA and glutamate in the NAc, VP, and DS prior to reinstatement testing

Brain region DA (nM) Glutamate (μM)
NAc 0.21 ± 0.07 (n=15) 0.43 ± 0.10 (n=16)
VP 0.11 ± 0.03 (n=15) 0.41 ± 0.06 (n=14)
DS 0.23 ± 0.04 (n=13) 0.54 ± 0.26 (n=12)
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Figure 3.

Figure 3

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Effects of systemic administration of AMN082 on cocaine-enhanced extracellular DA (A, C, E) and glutamate (B, D, F) in the NAc (A, B), VP (C, D) and DS (E, F). * p<0.05, ** p<0.01, *** p<0.001, compared to baseline before cocaine administration; # p<0.05, ##p<0.01, ###p<0.001, compared to vehicle group.

Figure 3C illustrates that acute cocaine (10 mg/kg, i.p.) also produced a significant increase (~300%) in extracellular DA in the VP. Pretreatment with AMN082 (10, 20 mg/kg, i.p.) failed to alter cocaine-enhanced VP DA (F2,27=0.07, p=NS). Figure 3D shows that cocaine priming failed to alter extracellular VP glutamate (F2,29=0.03, p=NS) in any group of rats.

Figure 3E illustrates that acute cocaine (10 mg/kg, i.p.) significantly increased extracellular DA (~300%) in DS (time main effect: F11,121=39.31, p<0.001). Pretreatment with AMN082 (20 mg/kg, i.p.) failed to alter cocaine-enhanced DA in DS (F1,11=0.04, p=NS). Figure 3F shows that cocaine priming failed to significantly alter extracellular glutamate in DS (F1,12=1.04, p=NS).

Intra-NAc MMPIP blocks AMN082’s action on NAc glutamate

Figure 4A illustrates that local perfusion of AMN082 or MMPIP (1, 10, 100 μM) failed to alter basal levels of extracellular NAc DA (Fig. 4A: F2,20=0.34, p=NS). Figure 4B illustrates that AMN082 significantly increased, while MMPIP alone decreased extracellular NAc glutamate (F2,20=10.27, p<0.01). Local intra-NAc perfusion of AMN082 and/or MMPIP (100 μM) failed to alter cocaine-enhanced extracellular NAc DA (Figure 4C: F3,37=0.97, p=NS). However, intra-NAc administration of MMPIP blocked 10 mg/kg AMN082-induced reduction in cocaine-enhanced NAc glutamate (Figure 4D: F2,26=4.59, p<0.05).

Figure 4.

Figure 4

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Effects of intra-NAc local perfusion of AMN082 or MMPIP on basal extracellular DA (A) and glutamate (B), and on cocaine-enhanced extracellular DA (C) and glutamate (D) in the NAc. *p<0.05, **p<0.01, ***p<0.001, compared to baseline before cocaine administration; ##p<0.01, ###p<0.001, compared to (Veh + Veh) group.

AMN082 alone increases extracellular glutamate in the NAc only

Figure 5A illustrates that AMN082 alone (10, 20 mg/kg i.p.) failed to alter basal levels of extracellular NAc DA (F2,17=0.03, p=NS). Figure 5B illustrates that AMN082 significantly and dose-dependently increased extracellular NAc glutamate (F2,17=7.49, p<0.01). Figures 5C and 5D illustrate that AMN082 altered neither extracellular VP DA (F2,19=0.13, p=NS), nor extracellular VP glutamate (F2,22=0.46, p=NS).

Figure 5.

Figure 5

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Effects of systemic administration of AMN082 alone on extracellular DA (A, C) and glutamate (B, D) in the NAc (A, B) or VP (C, D). *p<0.05, **p<0.01, ***p<0.001, compared to baseline before AMN082 administration.

LY341495 blocks the inhibitory effects of AMN082 on cocaine-enhanced NAc glutamate and on cocaine-induced reinstatement

Figure 6A illustrates that neither AMN082 alone (10 mg/kg i.p.) nor LY341495 (1 mg/kg i.p.) plus AMN082 (10 mg/kg i.p.) altered cocaine-enhanced extracellular DA (F2,26=1.25, p=NS). Figure 6B illustrates that LY341495 (1 mg/kg i.p.) pretreatment blocked AMN082–induced reduction in cocaine-enhanced extracellular glutamate. Two-way ANOVA for repeated measurements over time revealed a significant treatment main effect (F2,28=16.06, p<0.001), a time main effect (F11,308=7.74, p<0.001) and a treatment × time interaction (F22,308=7.27, p<0.001). Individual group comparisons revealed a significant reduction in cocaine-enhanced glutamate after 10 mg/kg AMN082 (q=5.02, p<0.01), but not after co-administration of LY341495 and AMN082, when compared to the vehicle pretreatment group.

Figure 6.

Figure 6

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Effects of LY341495 and/or AMN082 on cocaine-induced increases in extracellular NAc DA and glutamate (A, B), or on basal DA and glutamate (C), and on cocaine-induced reinstatement of drug-seeking behavior (D). AMN – AMN082 (10 mg/kg i.p.); LY - LY341495 (1 mg/kg i.p.). *p<0.05, **p<0.01, ***p<0.001, compared to baseline (A, B, C) or each group during the last extinction (D); ##p<0.01, ###p<0.001, compared to vehicle group (B) or AMN082 group during the reinstatement testing (D).

Figure 6C illustrates that LY341495 (1 mg/kg i.p.) alone failed to alter basal extracellular DA, but significantly increased extracellular NAc glutamate (F1,20=9.59, p<0.01). LY341495-enhanced extracellular glutamate displayed a slow-onset long-acting (at least 3 h) profile. Figure 6D illustrates that LY341495 pretreatment (1 mg/kg i.p., 20 min prior to AMN082) failed to significantly alter cocaine-induced reinstatement, but significantly attenuated AMN082-induced inhibition of cocaine-seeking behavior (F2,32=12.12, p<0.001) in the same group of rats subjected to in vivo microdialysis sampling of NAc DA and glutamate (Fig. 6D).

Sucrose priming failed to evoke detectable changes in extracellular NAc DA or glutamate

Figures 7A and 7B illustrate that oral sucrose priming did not alter either extracellular NAc DA (F1,15=2.52, p=NS) or extracellular NAc glutamate (F1,15=0.17, p=NS) in rats during sucrose-triggered reinstatement.

Figure 7.

Figure 7

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Effects of sucrose priming on extracellular DA (A) or glutamate (B) in the NAc measured during reinstatement testing.

Verification of microinjection guide cannula and microdialysis probes in the brain

Figure 8A shows the microinjection locations in the NAc, VP and DS. Figure 8B shows the locations of in vivo microdialysis probes in the NAc, VP and DS.

Figure 8.

Figure 8

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Schematic reconstructions of positions of intracranial microinjections or microdialysis probes in rat brain, indicating that the tips of microinjection guide cannula were located in the NAc (A, upper), VP (A, middle) or DS (A, bottom), and that active microdialysis membranes were located in the NAc (B, upper), VP (B, middle) or DS (B, bottom).

DISCUSSION

The major findings of the present study were that systemic or local administration of AMN082 into the NAc, VP, but not DS, significantly inhibited cocaine-induced reinstatement of drug-seeking behavior. In vivo microdialysis demonstrated that cocaine priming significantly increased extracellular DA in NAc, VP and DS, but increased extracellular glutamate only in the NAc. Pretreatment with AMN082 significantly attenuated cocaine-induced increases in extracellular NAc glutamate, but not cocaine-induced increases in extracellular DA in NAc, VP or DS. AMN082 alone produced a slow-onset long-lasting increase in extracellular NAc glutamate without any change in extracellular DA in any brain region tested. Blockade of mGluR7 or mGluR2/3 prevented the antagonism by AMN082 of both cocaine-enhanced NAc glutamate and cocaine-induced reinstatement. Although AMN082, at high doses, also inhibited sucrose-induced reinstatement, sucrose priming did not induce any detectable changes in extracellular NAc DA or glutamate. These findings suggest that activation of mGluR7s inhibits cocaine-induced reinstatement of drug-seeking behavior. The underlying mechanism could involve AMN082-enhanced extracellular glutamate, which subsequently activates presynaptic mGluR2/3s and inhibits cocaine-induced increases in NAc glutamate release.

The present finding that AMN082 inhibits cocaine-induced reinstatement is consistent with our previous finding that AMN082 inhibits cocaine’s rewarding effects, as assessed by electrical brain-stimulation reward and intravenous cocaine self-administration (Li et al., 2009). The neural circuitry underling cocaine-induced reinstatement of drug-seeking behavior has been well studied (Kalivas and McFarland, 2003; Schmidt et al., 2005; Knackstedt and Kalivas, 2009). Briefly, the mesolimbic dopaminergic, prefrontal-accumbens (core) glutamatergic, and NAc-VP GABAergic projections appear to be crucial for the ability of cocaine to elicit drug-seeking behavior. Given that mGluR7s are highly expressed in the striatum (including NAc) and VP (Bradley et al., 1998; Corti et al., 1998; Kinoshita et al., 1998), AMN082 was locally administered into these brain regions. We found that microinjections of AMN082 into NAc or VP, but not DS, significantly and dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior, suggesting that both the NAc and VP are important brain regions where AMN082 acts to modulate drug-seeking behavior. Intra-NAc co-administration of MMPIP, a selective mGluR7 antagonist (Suzuki et al., 2007), blocked AMN082’s action on reinstatement, suggesting an effect mediated by activation of mGluR7s.

AMN082-induced reduction in reinstatement responding to cocaine priming is unlikely due to operant behavior incapacity because systemic or local administration of AMN082 selectively inhibited cocaine-induced reinstatement responding only on the active lever, but not on the inactive lever (Figs. 1B, 1D; Figs. 2A, 2C); Second, we have previously shown that AMN082, at the same doses, alters neither basal or cocaine-enhanced locomotion, nor oral sucrose self-administration in rats (Li et al., 2009); and third, intra-NAc or intra-VP perfusion of AMN082 inhibited intravenous cocaine self-administration, but failed to alter rotarod locomotor performance (Li et al., 2009).

Cocaine priming significantly increased extracellular DA in the NAc, VP and DS, but elevated extracellular glutamate only in the NAc. Systemic administration of AMN082 failed to alter either basal or cocaine-enhanced extracellular DA in any brain region tested, suggesting that a non-DA mechanism underlies the antagonism by AMN082 of cocaine-induced reinstatement. This is consistent with our previous finding that AMN082 has no effect on extracellular DA in either the NAc or VP in naïve rats or in cocaine self-administration rats (Li et al., 2008, 2009). It is also consistent with the fact that mGluR7s are located predominantly on striatal glutamatergic and GABAergic terminals, but not on DA terminals (Shigemoto et al., 1997; Kinoshita et al., 1998; Kosinski et al., 1999; Ferraguti and Shigemoto, 2006).

Another important finding of the present study is that cocaine priming or AMN082 alone elevated extracellular glutamate levels only in the NAc, but not in the VP or DS, suggesting that a glutamatergic mechanism may mediate the pharmacological interaction between cocaine and AMN082. This brain regional specificity of cocaine-induced increases in extracellular glutamate is consistent with previous reports that chronic cocaine lowers basal levels of extracellular glutamate only in the NAc, but not in the DS or prefrontal cortex (Pierce et al., 1996; Baker et al., 2003). We and others have previously reported that cocaine-enhanced NAc glutamate is derived from tetrodotoxin-sensitive neuronal sources (McFarland et al. 2003; Xi et al. 2006), and that presynaptic mGluR2/3s functionally inhibit NAc glutamate release (Xi et al. 2002). These data suggest that AMN082-enhanced NAc glutamate, produced by a reduction in NAc GABA release (Li et al., 2008), may activate presynaptic mGluR2/3s, and therefore, inhibit cocaine priming-induced enhancement of glutamate release and reinstatement of drug-seeking behavior. To test this hypothesis, we used LY341495, a selective mGluR2/3 antagonist (Kingston et al., 1998), and found that LY341495 pretreatment significantly blocked the antagonism by AMN082 of cocaine-enhanced extracellular glutamate and cocaine-induced reinstatement of drug-seeking behavior (Fig. 6). This is consistent with our previous finding that elevation of extracellular glutamate produced by blocking presynaptic cannabinoid CB1 receptors inhibits cocaine-enhanced NAc glutamate and cocaine-induced reinstatement of drug-seeking behavior, an effect that is also blocked by LY341495 (Xi et al., 2006). Together, these data support an important role for glutamate-mGluR2/3 mechanisms in mediating AMN082’s action.

We note that systemic administration of AMN082 also significantly increased extracellular NAc glutamate (Fig. 5B), but failed to reinstate drug-seeking behavior by itself (data not shown). This could be related to the findings that AMN082 failed to alter extracellular DA, but produced a slow-onset (~60 min) long-term (at least 3 h) increase in extracellular NAc glutamate (Figs. 5–6), which contrasts to cocaine’s fast-onset (<20 min) short-term (~1 h) enhancement of both extracellular NAc DA and glutamate. These data suggest that a slow-onset long-acting increase in extracellular glutamate is insufficient to reinstate drug-seeking behavior in rats. In addition, LY341495 (a mGluR2/3 antagonist) itself also produced a slow-onset long-term increase in extracellular glutamate, but neither inhibited cocaine-enhanced NAc glutamate (Xi et al., 2006) nor cocaine-induced reinstatement of drug-seeking behavior (present study; Peng et al., 2010; Xi et al., 2006, 2010). We submit that this is because LY341495-enhanced NAc glutamate is mediated by blockade of mGluR2/3s, which subsequently disinhibits (potentiates) the glutamate response to cocaine priming. This is in contrast to the action of AMN082. AMN082 initially inhibits NAc GABA release, leading to an increase (via disinhibition) in NAc glutamate release (Li et al., 2008). This increase in glutamate then activates NAc mGluR2/3s and inhibits cocaine-enhanced NAc glutamate as discussed above.

We also note that intra-VP microinjections of AMN082 inhibited cocaine-induced reinstatement, while cocaine priming or AMN082 failed to alter extracellular glutamate in VP, suggesting that a non-DA (discussed above), non-glutamate mechanism may underlie this behavioral effect. We have previously reported that AMN082 inhibits intravenous cocaine self-administration by a VP GABAergic mechanism, i.e., AMN082 attenuates cocaine-induced reduction in VP GABA release in cocaine self-administration rats (Li et al., 2009), suggesting that a VP GABAergic mechanism may underlie the antagonism by intra-VP AMN082 of cocaine-triggered reinstatement. However, our present data do not appear to support this hypothesis because AMN082 or cocaine priming did not alter VP GABA release in rats during reinstatement (data not shown). This suggests that neuroadaptations may occur in VP GABAergic transmission in rats after prolonged (2–3 weeks) extinction from cocaine self-administration. Further, differential neural mechanisms appear to underlie the antagonism by AMN082 of intravenous cocaine self-administration (by a VP GABAergic mechanism) and of cocaine-induced reinstatement of drug-seeking behavior (by a NAc glutamate mechanism). Thus, more studies are required to more fully explicate the manner in which intra-VP AMN082 inhibits cocaine-induced reinstatement of drug-seeking behavior.

Previous studies have shown that systemic administration of AMN082 significantly increases plasma corticosterone and ACTH levels (Mitsukawa et al., 2005), which raises the possibility that AMN082’s observed actions in the present study may have been mediated by elevation of blood stress hormones. We think this unlikely because activation of the hypothalamic-pituitary-adrenal axis or elevation of blood corticosterone levels fails to alter cocaine self-administration or cocaine-induced reinstatement of drug-seeking behavior under short-access conditions in either rats or non-human primates (Lee et al., 2003; Mantsch and Katz, 2007). Further, hypothalamic-pituitary-adrenal activation or elevation of blood corticosterone facilitates (not attenuates as observed in the present study) cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior under long-access self-administration conditions (Mantsch et al., 2009).

Finally, AMN082, at high dose (20 mg/kg), also significantly inhibits sucrose-induced reinstatement of reward-seeking behavior, suggesting that mGluR7s may be involved in both drug and non-drug-triggered reinstatement. Unexpectedly, in vivo microdialysis did not detect significant changes in extracellular NAc DA or glutamate in rats during sucrose reinstatement. One possibility is that sucrose priming does not induce such robust increases in extracellular DA or glutamate as seen after cocaine priming. Alternatively, the present in vivo microdialysis techniques may not be sufficiently sensitive to detect sucrose-induced small changes in extracellular DA and glutamate. A third possibility is that a non-DA, non-glutamate mechanism may underlie sucrose-induced reinstatement of sucrose-seeking behavior.

In conclusion, the present study demonstrates that systemic administration of the mGluR7 agonist AMN082 significantly inhibits cocaine-induced reinstatement of drug-seeking behavior. We posit that the underlying mechanism involves AMN082-enhanced extracellular NAc glutamate, with subsequent activation of presynaptic mGluR2/3s and inhibition of cocaine-induced increases in NAc glutamate. Thus, the present data, combined with our previous reports that AMN082 inhibits cocaine self-administration (Li et al., 2009), suggest that AMN082 or other selective mGluR7 agonists may have potential in medication development for the treatment of cocaine addiction. As a caution, however, AMN082 also inhibits sucrose-triggered reinstatement of reward-seeking behavior, suggesting possible unwanted effects on natural reward.

Acknowledgments

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health.

References

  1. Anderson SM, Pierce RC. Cocaine-induced alterations in dopamine receptor signaling: implications for reinforcement and reinstatement. Pharmacol Ther. 2005;106:389–403. doi: 10.1016/j.pharmthera.2004.12.004. [DOI] [PubMed] [Google Scholar]
  2. Anderson SM, Schmidt HD, Pierce RC. Administration of the D2 dopamine receptor antagonist sulpiride into the shell, but not the core, of the nucleus accumbens attenuates cocaine priming-induced reinstatement of drug seeking. Neuropsychopharmacology. 2006;31:1452–61. doi: 10.1038/sj.npp.1300922. [DOI] [PubMed] [Google Scholar]
  3. Bäckström P, Hyytiä P. Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2007;192:571–80. doi: 10.1007/s00213-007-0753-8. [DOI] [PubMed] [Google Scholar]
  4. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci. 2003;6:743–749. doi: 10.1038/nn1069. [DOI] [PubMed] [Google Scholar]
  5. Bari AA, Pierce RC. D1-like and D2 dopamine receptor antagonists administered into the shell subregion of the rat nucleus accumbens decrease cocaine, but not food, reinforcement. Neuroscience. 2005;135:959–68. doi: 10.1016/j.neuroscience.2005.06.048. [DOI] [PubMed] [Google Scholar]
  6. Bradley SR, Rees HD, Yi H, Levey AI, Conn PJ. Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain. J Neurochem. 1998;71:636–645. doi: 10.1046/j.1471-4159.1998.71020636.x. [DOI] [PubMed] [Google Scholar]
  7. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci. 2001;4:873–874. doi: 10.1038/nn0901-873. [DOI] [PubMed] [Google Scholar]
  8. Cornish JL, Duffy P, Kalivas PW. A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience. 1999;93:1359–1367. doi: 10.1016/s0306-4522(99)00214-6. [DOI] [PubMed] [Google Scholar]
  9. Cornish JL, Kalivas PW. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci. 2000;20:RC89. doi: 10.1523/JNEUROSCI.20-15-j0006.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Corti C, Restituito S, Rimland JM, Brabet I, Corsi M, Pin JP, Ferraguti F. Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8. Eur J Neurosci. 1998;10:3629–3641. doi: 10.1046/j.1460-9568.1998.00371.x. [DOI] [PubMed] [Google Scholar]
  11. Dravolina OA, Danysz W, Bespalov AY. Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats. Psychopharmacology. 2006;187:397–404. doi: 10.1007/s00213-006-0440-1. [DOI] [PubMed] [Google Scholar]
  12. Ferraguti F, Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res. 2006;326:483–504. doi: 10.1007/s00441-006-0266-5. [DOI] [PubMed] [Google Scholar]
  13. Harrison AA, Gasparini F, Markou A. Nicotine potentiation of brain stimulation reward reversed by DHβE and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology. 2002;160:56–66. doi: 10.1007/s00213-001-0953-6. [DOI] [PubMed] [Google Scholar]
  14. Herzig V, Schmidt WJ. Effects of MPEP on locomotion, sensitization and conditioned reward induced by cocaine or morphine. Neuropharmacology. 2004;47:973–984. doi: 10.1016/j.neuropharm.2004.07.037. [DOI] [PubMed] [Google Scholar]
  15. Kalivas PW, McFarland K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology. 2003;168:44–56. doi: 10.1007/s00213-003-1393-2. [DOI] [PubMed] [Google Scholar]
  16. Kalivas PW. Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res. 2008;14:185–9. doi: 10.1007/BF03033809. [DOI] [PubMed] [Google Scholar]
  17. Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A. Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology. 2005;179:247–254. doi: 10.1007/s00213-004-2069-2. [DOI] [PubMed] [Google Scholar]
  18. Kenny PJ, Markou A. The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci. 2004;25:265–272. doi: 10.1016/j.tips.2004.03.009. [DOI] [PubMed] [Google Scholar]
  19. Kenny PJ, Paterson NE, Boutrel B, Semenova S, Harrison AA, Gasparini F, Koob GF, Skoubis PD, Markou A. Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats. Ann N Y Acad Sci. 2003;1003:415–418. doi: 10.1196/annals.1300.040. [DOI] [PubMed] [Google Scholar]
  20. Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology. 1998;37:1–12. doi: 10.1016/s0028-3908(97)00191-3. [DOI] [PubMed] [Google Scholar]
  21. Kinoshita A, Shigemoto R, Ohishi H, van der Putten H, Mizuno N. Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: a light and electron microscopic study. J Comp Neurol. 1998;393:332–352. [PubMed] [Google Scholar]
  22. Knackstedt LA, Kalivas PW. Glutamate and reinstatement. Curr Opin Pharmacol. 2009;9:59–64. doi: 10.1016/j.coph.2008.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;242:715–723. doi: 10.1126/science.2903550. [DOI] [PubMed] [Google Scholar]
  24. Kosinski CM, Bradley SR, Conn PJ, Levey AI, Landwehrmeyer GB, Penney JB, Jr, Young AB, Standaert DG. Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia. J Comp Neurol. 1999;415:266–284. [PubMed] [Google Scholar]
  25. Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC. Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res. 2009;202:238–44. doi: 10.1016/j.bbr.2009.03.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lee B, Platt DM, Rowlett JK, Adewale AS, Spealman RD. Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. J Pharmacol Exp Ther. 2005;312:1232–1240. doi: 10.1124/jpet.104.078733. [DOI] [PubMed] [Google Scholar]
  27. Lee B, Tiefenbacher S, Platt DM, Spealman RD. Role of the hypothalamic-pituitary-adrenal axis in reinstatement of cocaine-seeking behavior in squirrel monkeys. Psychopharmacology. 2003;168:177–183. doi: 10.1007/s00213-003-1391-4. [DOI] [PubMed] [Google Scholar]
  28. Liechti ME, Lhuillier L, Kaupmann K, Markou A. Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J Neurosci. 2007;27:9077–85. doi: 10.1523/JNEUROSCI.1766-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Li X, Gardner EL, Xi ZX. The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats. Neuropharmacology. 2008;54:542–551. doi: 10.1016/j.neuropharm.2007.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Li X, Li J, Peng XQ, Spiller K, Gardner EL, Xi ZX. Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism. Neuropsychopharmacology. 2009;34:1783–1796. doi: 10.1038/npp.2008.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP. Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology. 2009;195:591–603. doi: 10.1007/s00213-007-0950-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mantsch JR, Katz ES. Elevation of glucocorticoids is necessary but not sufficient for the escalation of cocaine self-administration by chronic electric footshock stress in rats. Neuropsychopharmacology. 2007;32:367–376. doi: 10.1038/sj.npp.1301077. [DOI] [PubMed] [Google Scholar]
  33. Mitsukawa K, Yamamoto R, Ofner S, Nozulak J, Pescott O, Lukic S, Stoehr N, Mombereau C, Kuhn R, McAllister KH, van der Putten H, Cryan JF, Flor PJ. A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc Natl Acad Sci U S A. 2005;102:18712–18717. doi: 10.1073/pnas.0508063102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Olive MF. Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev. 2009;2:83–98. doi: 10.2174/1874473710902010083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Paterson NE, Markou A. The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology. 2005;179:255–261. doi: 10.1007/s00213-004-2070-9. [DOI] [PubMed] [Google Scholar]
  36. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4. Academic Press; San Diego, CA: 1998. [Google Scholar]
  37. Peng XQ, Li J, Gardner EL, Ashby CR, Jr, Thomas A, Wozniak K, Slusher BS, Xi ZX. Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats. Eur J Pharmacol. 2010;627:156–161. doi: 10.1016/j.ejphar.2009.10.062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Peters J, Kalivas PW. The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats. Psychopharmacology. 2006;186:143–149. doi: 10.1007/s00213-006-0372-9. [DOI] [PubMed] [Google Scholar]
  39. Pierce RC, Bell K, Duffy P, Kalivas PW. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci. 1996;16:1550–1560. doi: 10.1523/JNEUROSCI.16-04-01550.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Salling MC, Faccidomo S, Hodge CW. Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082. Pharmacol Biochem Behav. 2008;91:14–20. doi: 10.1016/j.pbb.2008.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schmidt HD, Anderson SM, Pierce RC. Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behavior in the rat. Eur J Neurosci. 2006;23:219–28. doi: 10.1111/j.1460-9568.2005.04524.x. [DOI] [PubMed] [Google Scholar]
  42. Schmidt HD, Pierce RC. Cooperative activation of D1-like and D2-like dopamine receptors in the nucleus accumbens shell is required for the reinstatement of cocaine-seeking behavior in the rat. Neuroscience. 2006;142:451–461. doi: 10.1016/j.neuroscience.2006.06.004. [DOI] [PubMed] [Google Scholar]
  43. Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci. 1997;17:7503–7522. doi: 10.1523/JNEUROSCI.17-19-07503.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Suto N, Tanabe LM, Austin JD, Creekmore E, Pham CT, Vezina P. Previous exposure to psychostimulants enhances the reinstatement of cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacology. 2004;29:2149–59. doi: 10.1038/sj.npp.1300533. [DOI] [PubMed] [Google Scholar]
  45. Suzuki G, Tsukamoto N, Fushiki H, Kawagishi A, Nakamura M, Kurihara H, Mitsuya M, Ohkubo M, Ohta H. In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J Pharmacol Exp Ther. 2007;323:147–156. doi: 10.1124/jpet.107.124701. [DOI] [PubMed] [Google Scholar]
  46. Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol. 2004;499:121–133. doi: 10.1016/j.ejphar.2004.07.056. [DOI] [PubMed] [Google Scholar]
  47. Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW. Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther. 2002;300:162–171. doi: 10.1124/jpet.300.1.162. [DOI] [PubMed] [Google Scholar]
  48. Xi Z-X, Gardner EL. Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev. 2008;1:303–327. doi: 10.2174/1874473710801030303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Xi ZX, Gilbert JG, Peng XQ, Pak AC, Li X, Gardner EL. Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci. 2006;26:8531–8536. doi: 10.1523/JNEUROSCI.0726-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Xi ZX, Li X, Peng XQ, Li J, Gardner EL, Thomas AG, Slusher BS, Ashby CR. Inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism. J Neurochem. 2010;112:564–576. doi: 10.1111/j.1471-4159.2009.06478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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