Glutamatergic compounds for treating drug addiction

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During the period 01 Oct 04 to 30 Sept 05, significant progress was made on this research project. Recent studies have shown that chronic or repeated cocaine administration produces long-term alterations in glutamate neurotransmission in the brain. 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). We further 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. We further found that, using in vivo brain microdialysis methods, 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. 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.