It has been shown by Bita Moghaddam (Moghaddam and Adams 1998, Cartmell et al., 1999, 2000) that stimulation of group II metabotropic glutamate receptors (using mGluR2/3 agonist, LY354740) attenuated the disruptive effects of phencyclidine (PCP) on working memory, stereotypy, locomotion and cortical glutamate release in rats. Phencyclidine (blocker of NMDA receptor) elicits positive and negative schizophrenia-like symptoms in animals (Zukin and Javitt 1989).

Schizophrenia is one of the most common debilitating neurological disorders, since about 1% of the world population exhibits symptoms of schizophrenia. About 60% of schizophrenia sufferers live in poverty and about 5% end up homeless (Javitt and Coyle 2004). Cognitive deficiencies, emotional withdrawal, lack of social skills, agitation, paranoia, and hallucinations are common symptoms of schizophrenia. Due to the complexity of this disease, understanding of the development and the progression of schizophrenia still remains unknown.

For many years hyperactivity of dopamine receptors was perceived as a primary cause of schizophrenia (dopamine theory). Dopamine receptor antagonists (D2 antagonists) are the only known effective treatments for schizophrenic psychosis. However, the discovery that phencyclidine and ketamine cause symptoms which resemble schizophrenia (Javitt 1991; Zukin and Javitt 1989) and that studies on postmortem brains (Konradi and Heckers 2003) indicate that hypofunction (Tsai and Coyle, 2002) of glutamatergic neurotransmission is involved in the development and manifestation of schizophrenia (glutamate theory). Interestingly, even a single dose of phencyclidine elicits schizophrenic symptoms in animals (Zukin and Javitt 1989), whereas other treatments that produce schizophrenia-like symptoms require chronic application.

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are localized on the presynaptic terminal and regulate the release of glutamate from the synapse (Ohishi et al., 1993). NMDA antagonists, like phencyclidine and ketamine (Adams and Moghaddam 1998), increase release of glutamate in the prefrontal cortex, while the agonists of mGluR2/3 reverse the effects of PCP through the decrease in presynaptic release of glutamate. Group II metabotropic glutamate receptor agonists (e.g. LY341495) stimulate both pre- and postsynaptic receptors. Although the role of postsynaptic mGluR2/3 receptors is not clear yet, recent data shows that stimulation of postsynaptic mGluR2/3 enhances NMDA receptor currents in pyramidal neurons of rat prefrontal cortex (Tyszkiewicz et al., 2004).

In our studies, instead of using exogenous agonists of group II metabotropic glutamate receptors, we used peptidase inhibitors (ZJ43) presuming that inhibition of peptidases (ZJ43 - Ki of 0.8 nM and 23 nM for GCPII and GCPIII, respectively) increases levels of NAAG (an endogenous, selective agonist of mGluR3 receptor, (Wroblewska et al., 1997) and increased NAAG activates mGluR3 receptors. Following the application of PCP rats displayed series of stereotypic behaviors like, including stereotypic mouth movements, falling while walking, walking in circles, head bobbing, head sideways movement, and tremors (Olszewski et al., 2004). Some of these behaviors were significantly decreased in the presence of peptidase inhibitor (stereotypic mouth movements, falling while walking, walking in circles, head bobbing), while others were not affected. When animals were co-injected with metabotropic glutamate receptor antagonist (LY341495) some of these beneficial effects were abolished (Olszewski et al., 2004). Application of LY341495 alone exacerbated some of the PCP-induced motor activity. This may suggest that in the PCP-induced motor activity blocking the interaction between endogenous NAAG and mGluR3 receptor increases effects of PCP.

It has been shown that NAAG activates presynaptic mGluR3 receptors and participates in the regulation of the release of neurotransmitters (Berent-Spillson et al., 2004; Garrido Sanabria et al., 2004; Slusher et al., 1999; Zhao et al., 2001). Since NAAG is colocalized with several neurotransmitters (Renno et al., 1997) the effects on the presynaptic release maybe very important in both physiological and pathological conditions.

However, there is also mGluR3 receptor present on the glial cells, astrocytes (Wroblewska et al., 1998), giant axon myelinizing cells (Urazaev et al., 2001) Schwann cells (Berger et al., 1995) and microglia (Taylor et al., 2002, Taylor et al., 2005). Very little is known about the role of this receptor in the physiology of NAAG.

Our understanding of the consequences of the increase in NAAG levels in the central nervous system and the interactions of NAAG with its receptors increased considerably in the recent years. Nevertheless, we still don't know enough about the synthesis of NAAG, and we have no information about transport of NAAG in the brain. More research is this field is needed, especially with regard to recent discoveries on the possible importance of endogenous NAAG in the physiology and pathology of the brain.

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