7 November 2008. Like any new kid on the block, the latest schizophrenia drug candidate has raised some eyebrows. Clinical trial results suggest that Eli Lilly’s metabotropic glutamate receptor activator, LY404039, treats positive and negative symptoms of schizophrenia with efficacy comparable to their current antipsychotic drug olanzapine (see SRF related meeting news and SRF related news story). The finding is both welcome and surprising. Welcome, because clinicians are currently limited to antipsychotic drugs that aim for just one molecular target, the dopamine D2 receptor. And surprising because it is not clear how a metabotropic glutamate agonist could have the same antipsychotic effects as dopamine antagonists.
The answer, at least for the orbitofrontal cortex, appears to be that though the drugs have different molecular targets, the end result is the same—they both restore activity of the same neurons. “This was very interesting because there is a lot of data, which is not discussed that much, implicating orbitofrontal cortex function in psychosis, cognitive dysfunction, and negative symptoms of schizophrenia,” said the study’s principal author, Bita Moghaddam, University of Pittsburgh, Pennsylvania. Disruptions to those three domains are characteristic of the disease.
Moghaddam and first author Houman Homayoun came to their conclusions by studying rodent models of schizophrenia. In one, NMDA (N-methyl-D-aspartate)-type glutamate neurotransmitter receptors are chemically blocked. This model has some validity since off-label, recreational use of such NMDA antagonists has been linked to schizophrenia-like episodes in humans, not to mention the fact that the original work that justified the Lilly trial was conducted by Moghaddam in the rat NMDA model. NMDA blockade disrupts neurotransmission in the prefrontal cortex (PFC), which encompasses the OFC, and many researchers believe that abnormalities in the PFC, specifically the dorsolateral PFC, are the key to better understanding and better treating the disease. In a second model the researchers treated rats with amphetamine, which activates dopaminergic circuits and has also been studied as a pharmacologic model for schizophrenia because it can cause psychosis (see SRF related news story).
By measuring the activity of individual neurons in vivo, the researchers found that the NMDA blockade activated regular-firing (RF) pyramidal neurons in the OFC, while inhibiting fast-firing (FF) interneurons. The researchers had previously reported that amphetamine has the same activation effect on RF neurons in the OFC, but not in the medial PFC (see Homayoun and Moghaddam, 2007). “What we saw was that in contrast to other cortical areas, two very different psychotomimetic drugs, NMDA antagonists and amphetamine, have very similar effects on the orbitofrontal cortex,” said Moghaddam. Amphetamine did not activate RF neurons in the medial PFC, which is the rodent equivalent of the human dorsolateral PFC. “That is key, that in another area that has been implicated in schizophrenia, and may be responsible for cognitive deficits, we are not seeing this shared effect, which seems to be selective to OFC,” she said.
If disruption of OFC neurotransmission is to blame for schizophrenia, as these models suggest, then one might expect antipsychotic drugs should restore normal OFC function. In fact, this is what the researchers found. When they pretreated rats with the approved antipsychotics haloperidol and clozapine, it reversed the effect of the NMDA receptor blocker, MK-801, and also reversed the effect of amphetamine. Interestingly, metabotropic NMDA receptor activators, of which Lilly’s LY404039 is one, had exactly the same effect. Homayoun and Moghaddam found that LY354740, an agonist for the mGlu2/3 type receptor, and the mGlu5 activator CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), restored normal firing in RF neurons. These candidate schizophrenia drugs also reversed behavioral stereotypy, or repetitive movements, in the NMDA antagonist model. “For animal models of schizophrenia, stereotypy is a good measure because it reflects disruption to cortex-limbic interactions,” said Moghaddam.
While the dorsolateral PFC has been a major focus for schizophrenia researchers, the authors note that there are studies linking the disease to the OFC via studies of dopamine receptors (Meador-Woodruff et al., 1997) and DISC1 protein (Sawamura et al., 2005). DISC1, or disrupted in schizophrenia 1, is a major schizophrenia susceptibility gene candidate (see SRF related news story). Of course there are many potential gene candidates for the disease and one interesting facet of this work is that it ties in several types of neurons—dopaminergic, glutamatergic, and GABAergic—that have been implicated in various ways in schizophrenia. Looking at the disease as more of a neural network problem may help explain how a different group of genes can end up causing the same disease if they end up disrupting the same group of cells or the same network of cells, suggested Moghaddam. “I’m really optimistic, in that by starting to look at schizophrenia as more of a network disease, people may start thinking more creatively and be far more open to looking at different treatment options and novel targets,” she said.—Tom Fagan.
Homayoun H, Moghaddam B. Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. PNAS 2008 November 3 online.