During the reporting period, considerable progress was made on this research project. We and others had previously shown that chronic or repeated cocaine administration produces long-term alterations in glutamate neurotransmission in the brain. We therefore previously studied glutamatergic involvement in addiction by studying mGluR5 glutamate receptor antagonism in animal models relating to addiction. We found that blockade of the mGluR5 glutamate brain receptor by the selective, potent, and systemically-active mGluR5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine) inhibits cocaine self-administration and motivation to self-administer cocaine in laboratory rats. We further found that blockade of the mGluR5 glutamate receptor by MPEP significantly inhibits relapse to drug-seeking behavior triggered by cocaine, but not relapse to drug-seeking behavior triggered by either stress or environmental cues previously paired with drug-taking behavior. Using in vivo brain microdialysis methods, we further found that MPEP has no effect on extracellular levels of the neurotransmitter dopamine in the nucleus accumbens of the limbic forebrain in either drug-naive or cocaine-extinguished rats, suggesting a dopamine-independent mechanism underlying MPEP's actions. In contrast, MPEP (administered either systemically or locally into the nucleus accumbens) elevates extracellular glutamate. Furthermore, MPEP dose-dependently inhibited cocaine-induced increases in nucleus accumbens extracellular glutamate in both drug-naive and cocaine-extinguished rats. These data suggested that alterations in nucleus accumbens glutamate underlie MPEP's actions on cocaine-induced reward and cocaine-triggered relapse to drug-seeking behavior, and confirmed that brain glutamate neurotransmission constitutes an attractive target for potential anti-addiction, anti-craving, anti-relapse medications. We also previously studied NAALADase inhibition in animal models relating to addiction. NAALADase (N-acetylated-alpha-linked-acidic dipeptidase;glutamate carboxypeptidase II) is a brain enzyme which hydrolyzes the endogenous brain neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to glutamate and NAA (N-acetyl-aspartate). NAAG is an endogenous mGluR3 glutamate receptor agonist, which inhibits presynaptic glutamate release. Therefore, studies of NAALADase inhibitors in preclinical animal models relating to addiction are of interest in the search for clinically useful pharmacotherapeutic agents for the treatment of addiction, craving, and relapse. Consequently, we studied the effects of 4 NAALADase inhibitors - 2-PMPA, GPI-5693, GPI-16476, and GPI-16477 - in animal models relating to addiction. We found that all 4 NAALADase inhibitors inhibited cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who had been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. This protective effect against cocaine-triggered relapse to drug-seeking behavior was blocked by intracerebral microinjections of LY341495, a selective mGluR2/3 receptor antagonist, directly into the nucleus accumbens in the brain. This implicates the mGluR2/3 glutamate receptor of the brain in this anti-addiction action. We further found that the NAALADase inhibitor 2-PMPA significantly inhibits motivation to self-administer cocaine. We further found that 2-PMPA and NAAG significantly inhibit cocaine-enhanced brain-stimulation reward and intravenous cocaine self-administration in laboratory rats, and that 2-PMPA attenuates coaine-enhanced dopamine in the nucleus accumbens - an effect that was prevented by LY341495, implicating the involvement of mGluR2/3 rceptors in these effects. We also studied the effects of AMN082, a selective mGluR7 agonist, on extracellular dopamine, gamma-aminobutyric acid (GABA), and glutamate in the nucleus accumbens of the brain as measured by in vivo brain microdialysis. We found that systemic or intra-accumbens administration of AMN082 dose-dependently lowered extracellular GABA, increased extracellular glutamate, and had no effect on extracellular nucleus accumbens dopamine levels. We found that these effects were blocked by MSOP, a group III-selective mGluR antagonist. Intra-accumbens perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular and non-vesicular GABA origins for these effects, respectively. We also found that intra-accumbens perfusion of the selective GABA-B receptor antagonist 2-hydroxysaclofen not only abolished the enhanced extracellular glutamate produced by AMN082, but actually decreased extracellular glutamate in a TTX-resistant manner. We further found that systemically-administered AMN082 dose-dependently inhibits cocaine-triggered reinstatement of drug-seeking behavior. Intracerebral micro-injections of AMN082 into the nucleus accumbens or ventral pallidum, but not into the dorsal striatum, also inhibited cocaine-triggered relapse to drug-seeking behavior, an effect that was blocked by local intracerebral co-administration of MMPIP, a selective mGluR7 receptor antagonist. Pre-treatment with AMN082 dose-dependently blocked both cocaine-enhanced nucleus accumbens glutamate and cocaine-triggered relapse to drug-seeking behavior, an effect that was blocked by MMPIP or the selective mGluR2/3 receptor antgaonist LY341497. These findings suggest that mGluR7 activation inhibits cocaine-triggered relapse to drug-seeking behavior by a glutamate-mGluR2/3 mechanism in the nucleus accumbens. Such findings suggest a potential utility for mGluR7 receptor agonists for the treatment of cocaine addiction. During the present reporting period, we once again turned our attention to the mGluR5 receptor system in the brain and to the negative allosteric mGluR5 modulator fenobam (1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4H-imidazol-2-yl)urea). Using multiple animal models of addiction, We found that fenobam and fenobam sulfate show the same anti-cocaine efficacy as we had previously seen with the mGluR5 antagonists MPEP and MTEP (see above), but that the non-competitive AMPA receptor antagonist GYKI-52466 (1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) does not. In addition, during the present reporting period we studied a novel mGluR5 antagonist, MFZ 10-7, and found that it significantly inhibits cocaine-taking and cocaine-seeking behaviors in laboratory rats. In all, these findings suggest that the glutamate neurotransmitter system in the brain continues to be an appropriate target for the development of potential anti-addiction, anti-craving, and anti-relapse medications.

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Keck, Thomas M; Zou, Mu-Fa; Bi, Guo-Hua et al. (2014) A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats. Addict Biol 19:195-209
Li, Xia; Xi, Zheng-Xiong; Markou, Athina (2013) Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence. Neuropharmacology 66:12-23
Keck, Thomas M; Yang, Hong-Ju; Bi, Guo-Hua et al. (2013) Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans. Psychopharmacology (Berl) 229:253-65
Srivastava, Ratika; Xi, Zheng-Xiong; Gardner, Eliot L (2012) Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466: a non-competitive AMPA receptor antagonist. Neurosci Lett 508:106-9
Gardner, Eliot L (2011) Addiction and brain reward and antireward pathways. Adv Psychosom Med 30:22-60
Li, Xia; Li, Jie; Gardner, Eliot L et al. (2010) Activation of mGluR7s inhibits cocaine-induced reinstatement of drug-seeking behavior by a nucleus accumbens glutamate-mGluR2/3 mechanism in rats. J Neurochem 114:1368-80
Xi, Zheng-Xiong; Kiyatkin, Michael; Li, Xia et al. (2010) N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats. Neuropharmacology 58:304-13
Peng, Xiao-Qing; Li, Jie; Gardner, Eliot L et al. (2010) Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats. Eur J Pharmacol 627:156-61
Xi, Zheng-Xiong; Li, Xia; Peng, Xiao-Qing et al. (2010) Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism. J Neurochem 112:564-76
Li, Xia; Li, Jie; Peng, Xiao-Qing et al. (2009) Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism. Neuropsychopharmacology 34:1783-96

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