Glutamate carboxypeptidase II (N-acetylated a-linked-acidic dipeptidase; EC or NAAL-ADase is a neuropeptidase that catalyzes the cleavage of glutamate from N-acetyl-aspartyl-glutamate (NAAG), the most prevalent and widely distributed neuropeptide in the mammalian nervous system (187). Thus, inhibition of NAALADase would decrease glutamate levels and increase levels of NAAG. Theoretically then, NAALADase inhibition would have the potential to negatively modulate gluta-matergic neurotransmission by two separate mechanisms. First, NAALADase inhibition would produce decreases in glutamate levels. Second, as NAAG is known to act at mGlu3 receptors (188), NAALADase inhibition could have the additional effect characteristic of mGluR3 agonists of dampening glutamate-mediated neurotransmission.

Until recently, pharmacological tools for selectively inhibiting NAALADase were not available. However, this situation changed with the design and synthesis of 2-(phosphonomethyl) pentanedioic acid (2-PMPA) (189), which is a high-affinity (K = 280 pM) and selective NAALADase inhibitor (190). In addition to its potential role in the therapy of conditions associated with excessive glutamate, recent reports suggest a role for NAALADase inhibition in modulating the behavioral and toxic effects of drugs of abuse. Thus, 2-PMPA blocks the development of behavioral sensitization resulting from repeated exposure to cocaine in rats without affecting acute stimulant effects of cocaine (191). 2-PMPA also attenuates both the expression and development of cocaine-kindled seizures in mice without producing the motor side effects seen with NMDA receptor antagonists (192).

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