Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs

Abstract

Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.amphetamine ͉ NMDA ͉ dopamine ͉ prefrontal cortex ͉ schizophrenia T wo longstanding views about the pathophysiology of schizophrenia state that it is associated with a hyperactive dopamine system (1, 2) and a state of ''hypofrontality,'' the latter referring to reduced activation of the dorsal prefrontal cortex (PFC) during performance of cognitive tasks with a working memory component (3, 4). The dopaminergic hyperactivity is linked to the so-called positive symptoms, which include hallucinations and delusions, whereas hypofrontality is thought to subserve the cognitive deficits associated with schizophrenia. Several recent findings, however, have questioned these prevailing notions. Specifically, the principal finding that supports a role for dopamine hyperactivity in schizophrenia has been that all antipsychotic drugs, which are effective in treating these symptoms, inhibit the dopamine D2 receptors. A recent report that an agonist of the metabotropic glutamate 2/3 (mGlu2/3) receptor has comparable efficacy to the antipsychotic drug olanzapine in treating positive and negative symptoms of schizophrenia (5) suggests that blocking dopamine receptors is not necessary for antipsychotic efficacy. The notion of a cortical hypoactivity that is limited to dor...

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

“…Reversal of PCP-induced motor hyperactivity was demonstrated for one of the first selective mGlu2/3 receptor agonists, LY354740 (Moghaddam and Adams, 1998), and was repeatedly confirmed for this and other mGlu2/3 receptor agonists in several laboratories (Cartmell et al, 1999). Various motor stereotypes induced by PCP-like drugs and 5-HT 2A agonists [(Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] are also readily inhibited by mGlu2/3 receptor stimulation (Gewirtz and Marek, 2000;Homayoun and Moghaddam, 2008).…”

“…e Harsing et al, 2003Depoortere et al, 2005;Boulay et al, 2008;Singer et al, 2009. f Chan et al, 2008Homayoun and Moghaddam, 2008;Liu et al, 2008. NMDA receptor antagonists would preferentially block active NMDA channels in interneurons rather than pyramidal cells, resulting in a disinhibition of circuits.…”

Striatum processes reward differently in adolescents versus adults

“…Recordings were made as described previously (28) while rats performed a behavioral task. Single units were isolated using Offline Sorter (Plexon) through a combination of manual and semiautomatic sorting techniques (44).…”

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

“…Hence, mGluR5 is of current interest as a novel therapeutic target for the treatment of schizophrenia. Studies of mGluR5 positive allosteric modulators (PAMs) have repeatedly reported antipsychotic-like effects in rodent models of schizophrenia (see Vinson and Conn, 2012), which have been shown, in part, to be mediated through the frontal cortex (Homayoun and Moghaddam, 2008). Most interestingly, PAMs of mGluR5 reverse drug-induced negative and cognitive impairments in rodents, which are aspects of schizophrenia symptomatology mostly untreated by current therapeutics in a large percentage of patients.…”