Studies have shown that chronic or repeated cocaine administration produces long-term alterations in glutamate neurotransmission in the brain. We had previously studied glutamatergic involvement in addiction by studying mGluR5 glutamate receptor antagonism and NAALADase inhibition 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 under fixed-ratio reinforcement conditions and inhibits cocaine self-administration under progressive-ratio reinforcement conditions in laboratory rats (i.e., significantly reduces the amount of work that laboratory rats are willing to expend to receive intravenous cocaine infusions). 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. By 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 suggest that alterations in nucleus accumbens glutamate may underlie MPEP's actions on cocaine-induced reward and cocaine-triggered relapse to drug-seeking behavior. We also 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 3 NAALADase inhibitors - 2-PMPA, GPI-16476, and GPI-16477 - in animal models relating to addiction. We found that all 3 NAALADase inhibitors had no effect on intravenous cocaine self-administration under fixed-ratio reinforcement conditions, but significantly inhibited cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who has been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that the NAALADase inhibitor 2-PMPA significantly inhibits cocaine self-administration under progressive-ratio reinforcement conditions (i.e., significantly reduces the amount of work that laboratory rats are willing to expend to receive intravenous cocaine infusions). In the present reporting period, we 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. Further, during the present reporting period we found that: 1) the metabotropic glutamate receptor 7 (mGluR7) modulates cocaine's rewarding effect in laboratory rats via a ventral pallidal GABAergic mechanism, 2) N-acetyl-aspartatylglutamate (NAAG) attenuates cocaine-enhanced brain-stimulation reward in rats, 3) N-acetyl-aspartatylglutamate (NAAG) attenuates intravenous cocaine self-administration in rats, 4) inhibition of NAALADase by 2-PMPA attenuates cocaine-triggered relapse to drug-seeking behavior via a NAAG-mGluR2/3-mediated mechanism in the brain, 5) the NAALADase inhibitor GPI-5693 attenuates cocaine-triggered relapse to drug-seeking behavior in rats, 6) activation of mGluR7s in the brain inhibits cocaine-triggered relapse to drug-seeking behavior via a nucleus accumbens gltamate-mGluR2/3 brain mechanism. In all, these findings suggest that the glutamate neurotransmitter system in the brain may be an appropriate target-of-action for the development of potential anti-addiction, anti-craving, and anti-relapse medications.
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