A toast to success, or new wine in an old skin?
Patil et al. present a landmark study. It is the kind of study that represents the best of how science should work. It pulls together the numerous strands of schizophrenia research from the last 50 years, from the development of PCP psychosis as a model for schizophrenia in the late 1950s, through the links to glutamate, the discovery of metabotropic receptors, and the seminal discovery in 1998 by Moghaddam and Adams that metabotropic glutamate 2/3 receptor (mGluR2/3) agonists reverse the neurochemical and behavioral effects of PCP in rodents (Moghaddam and Adams, 1998. The story would not be possible without the elegant medicinal chemistry of Eli Lilly, which provided the compounds needed to test the theories; the research support of NIMH and NIDA, who have been consistent supporters of the “PCP theory”; or the hard work of academic investigators, who provided the theories and the platforms for testing. The study is large and the effects robust. Assuming they replicate...  Read more

View all comments by Dan Javitt

In the field of the psychopharmacology of schizophrenia, a lot of research work has been done on dopaminergic systems. Thus, this research news is excellent news because it explores an alternative neurotransmission system in schizophrenia, the glutamatergic system. Since the work of Dr. Bita Moghaddam in 1998, published in Science, a lot of research studies have turned to the important role of glutamate in schizophrenia. More studies are needed to focus on the exact role of this neurotransmitter.

View all comments by Patricia Estani

The pioneering research over the past decade on group II metabotropic glutamate receptor (mGluR) agonists from the Lilly Labs and Bita Moghaddam's research group has provided a strong foundation for the view that activation of these receptors reduces schizophrenia-like behaviors in the PCP and amphetamine models. These phase 2 clinical trials bring mGluR agonists one step closer to clinical use as therapy or co-therapy.

These same data provide the foundation for current and future research aimed at increasing the concentration of the peptide transmitter, N-acetylaspartylglutamate (NAAG) in the synaptic cleft by systemic administration of NAAG peptidase inhibitors. NAAG is the third most prevalent transmitter in the mammalian nervous system and a selective group II mGluR agonist with preference for mGluR3 (Neale et al., 2005). Our research group demonstrated that a NAAG peptidase inhibitor substantially reduces positive and negative behaviors induced in PCP models of schizophrenia (Olszewski et al., 2007;   Read more

View all comments by Joseph Neale

First, Zhang and colleagues examine multiple polymorphisms in the D2 receptor gene and find that none of the "standard" ones that have been linked to clinical characteristics actually affected D2 receptor density in prefrontal cortex or striatum. However, they find that two other, previously unstudied polymorphisms altered the relative expression of short versus long isoforms of the D2 receptor, likely reflecting presynaptic and postsynaptic D2 receptors, respectively. These findings could provide a basis for understanding several perplexing effects in the literature, such as opposing effects of D2 receptor drugs on cognition in individuals with low and high working memory ability, who are shown here to have differential pre- versus postsynaptic D2 receptor function.

Further, the presynaptic receptor is thought to regulate phasic dopamine signaling via its autoreceptor functions (in addition to controlling glutamate release in corticostriatal terminals via the heteroreceptors alluded to in the article). Thus, based on current evidence, it is expected that these...  Read more

View all comments by Michael J. Frank

Altered receptor dimerization: a new paradigm in the pathology of schizophrenia
Understanding the pathology of complex diseases such as schizophrenia requires the use of the full arsenal at the disposal of medical research. Such an approach has been used to make an exciting new discovery that suggests that abnormal dimerization between the serotonin 2A receptor (2AR) and the metabotropic glutamate 2 receptor(mGluR2) may underlie some of the symptoms of schizophrenia (González-Maeso et al., 2008).

This discovery is based on an initial finding that 2AR is coexpressed with mGluR2 in layer 5 of the mouse somatosensory cortex (SCx) and that levels of mGluR2 were decreased in the cortex of 2AR-/- mice, suggesting a relationship between the expression of the two genes. This hypothesis was further supported by data showing that expression of mGluR2 was selectively restored in mice where 2AR expression had been re-established in layer 5 of the SCx. From these data, and data from other studies suggesting G protein-coupled...  Read more

View all comments by Brian Dean

Another bicycle trip?
Ever since dopamine was first implicated in the therapeutic effects of antipsychotic drugs by Arvid Carlsson and colleagues over 50 years ago, and then dopamine D2 receptors were implicated in the Parkinsonian side effects and late-evolving movement disorders, an intense search has been underway for antipsychotic drugs that might act through other mechanisms. In parallel with this search, drugs with psychotomimetic effects in healthy volunteers or exacerbating psychosis have also been used to discover new antipsychotic drugs. With an evolving understanding of the neuropharmacology underlying ketamine or PCP, amphetamines, and serotonergic hallucinogens (LSD, mescaline, and psilocybin), glutamatergic, dopaminergic, and serotonergic theories of psychotic pathophysiology have been advanced. Converging evidence points to activation of 5-HT2A receptors as a necessary action in the psychotomimetic effects of the serotonergic “hallucinogens.” The recent description of a proof-of-concept clinical study where a prodrug for a metabotropic glutamate2/3...  Read more

View all comments by Gerard J. Marek

The article by Homayoun and Moghaddam is another in an excellent series of articles investigating effects of metabotropic agents on brain function relevant to schizophrenia. As opposed to previous studies by this group that targeted rodent medial prefrontal cortex, which is used as a model of dorsolateral prefrontal cortex in humans, this study targets orbitofrontal cortex. The main finding of this study, like prior studies by this group, is that effects of the NMDA antagonist MK-801 can be reversed by the LY354740, a selective metabotropic group 2/3 agonist. LY354740 has previously been shown to reverse ketamine effects in humans (Krystal et al., 2005) and to be effective in treatment of generalized anxiety disorder in humans (Dunayevich et al., 2008). It is pharmacologically related to LY2130023 (Rorick-Kehn et al., 2007), a compound that has shown efficacy in treatment of schizophrenia (Patil...  Read more

View all comments by Dan Javitt

Homayoun and Moghaddam (PNAS) present important new data concerning the glutamatergic system and psychosis. They suggest the orbital frontal cortex (OFC) is particularly important in the pathophysiology of schizophrenia. They show that treatment with an NMDA receptor (NMDAR) antagonist induces OFC pyramidal neuron hyperactivity (secondary to GABA interneuron hypoactivity). This was reversed with haloperidol, clozapine, and a selective mGlu2/3 agonist, LY354740. This brief essay emphasizes how their findings support hypotheses of a common pathway in the biology of psychotic disorders. This group’s work (Adams et al., 2001; Moghaddam and Adams, 1998) contributes to an extensive body of research on the biology of psychosis. Human research shows that extensive frontal cortical systems and diverse molecular interactions may converge to form a common pathway to produce psychosis.

In their formulations of schizophrenia, Olney (Olney and Farber,...  Read more

View all comments by Henry Holcomb