Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine

Abstract

NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3-4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-fos expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-fos expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade.neuronal oscillations ͉ NMDA receptor antagonists ͉ schizophrenia ͉ delta frequency ͉ thalamus S chizophrenia is associated with alterations in several brain areas, including the thalamus, the hippocampus, the amygdala, and the prefrontal cortex (PFC), which are thought to underlie the deficits in working memory and executive functions exhibited by schizophrenic patients (1-3). Autopsy and neuroimaging studies have revealed the existence of a reduced PFC volume, reduced layer thickness, tight packing of pyramidal neurons and reduced neuropil in the brains of schizophrenic patients (1, 2, 4, 5). Moreover, alterations in key neurotransmitters such as glutamate, GABA, and dopamine have been reported in PFC (3,5,6).Noncompetitive N-methyl-D-aspartate (NMDA) receptor (NMDA-R) antagonists such as the dissociative anesthetics ketamine and phencyclidine (PCP), have been extensively used as pharmacological models of schizophrenia because of their ability to evoke positive and negative symptoms of schizophrenia as well as the characteristic cognitive deficits of the illness in humans (3, 7). Neuroimaging studies suggest that these effects are associated with an increased PFC activity (8). On the other hand, NMDA-R antagonists evoke a behavioral syndrome in experimental animals characterized by hyperlocomotion, stereoty...

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

“…More specifically, PCP-induced c-Fos-IR was observed all PFC subregions examined (PrL, IL, Cg1 and VLO) as well as motor cortex, S1, RS, CA1, NAc core and MD. Overall, this observation agrees with previous studies showing that acute PCP administration at the same dose as used here induced elevations in c-Fos mRNA in the PFC, RS, S1, motor cortex and MD (Kargieman et al 2007;Santana et al 2011), but not CA1 (Santana et al 2011). Studies using other doses of PCP or other non-competitive NMDAR antagonists also report c-Fos mRNA or protein elevations in these areas (Habara et al 2001 (Jackson et al 2004;Jodo et al 2005;Kargieman et al 2007;Homayoun and Moghaddam, 2007;Santana et al 2011).…”

“…The rats were injected with PCP (10 mg/kg; 2 ml/kg, s.c.) or vehicle (0.9% saline; 2 ml/kg, s.c.) and returned to their home cage for 60 min before transcardial perfusion. This particular dose of PCP was chosen since it has been shown to induce c-Fos in cortical and subcortical regions, alter discharge activity in neurons and also induce changes in c-Fos expression in GABAergic interneurons (Kargieman et al 2007;Santana et al 2011;Sato et al 1997;Jodo et al 2010).…”

“…Several studies have shown that the PFC and MD are the predominant sites mediating the actions of non-competitive NMDAR antagonists, including changes in neurotransmission and behaviour (Amargós-Bosch et al 2006;López-Gil et al 2007;Kargieman et al 2007;Zhang et al 2009Zhang et al , 2012Santana et al 2011;Kiss et al 2011;López Hill and Scorza 2012). Furthermore, it has been proposed that PCP acts on the cortico-thalamo-cortical circuit involving the PFC, RS 15 and thalamus (Celada et al 2013).…”

“…Another important aspect to take into account is that also subcortical areas are relevant for PCP-or MK-801-mediated changes in activity and neurotransmission (Suzuki et al 2002;Jodo et al 2005;Amargós-Bosch et al 2006;López-Gil et al 2007). Several studies point to the mediodorsal and centromedial thalamic nuclei, that are reciprocally connected to the PFC (Berendse and Groenewegen, 1991;Fuster, 2008), to be of major importance in mediating the effects of non-competitive NMDAR antagonists (Kargieman et al 2007;Santana et al 2011;Kiss et al 2011;Celada et al 2013). …”

“…It is wellestablished that acute systemic administration of PCP increases levels of the immediate early gene (IEG) c-Fos in several areas including PFC, hippocampus, nucleus accumbens (NAc) and thalamic nuclei in rodents (Näkki et al 1996;Sato et al 1997;Griffiths et al 1999;Habara et al 2001;Gotoh et al 2002;Kargieman et al 2007;Kargieman et al 2008;Kalinichev et al 2008;Santana et al 2011;Castañe et al 2015). It has been reported that PCP-induced c-Fos mRNA occurs in GAD67-neurons in the hippocampus, amygdala, as well as somatosensory and retrosplenial cortex (Santana et al 2011).…”