Activation of Medial Prefrontal Cortex by Phencyclidine is Mediated via a Hippocampo-prefrontal Pathway

Abstract

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy persons, and administration of PCP to animals is used as a pharmacological model of schizophrenia. We recently demonstrated that systemic administration of PCP to rats produces long-lasting activation of medial prefrontal cortex (mPFC) neurons with augmentation of locomotor activity, whereas direct application of PCP to mPFC neurons has little effect on their firing activity. These findings suggest that PCP-induced activation of mPFC neurons is elicited mainly via excitatory inputs from regions outside the mPFC. In the present study, we examined effects of local application of PCP to the ventral hippocampus (vHIP) on firing activity of PFC neurons in freely moving rats. PCP locally perfused into the vHIP increased spontaneous discharges of PFC neurons during perfusion with augmentation of locomotor activity. Local application of a more selective NMDA receptor antagonist, MK801, to vHIP neurons under anesthesia increased the spontaneous firing rates of most neurons directly projecting to the mPFC, whereas local application of MK801 to mPFC neurons did not induce excitatory responses in any of those neurons. The present results indicate that tonic excitatory inputs from the vHIP to the PFC may trigger development of behavioral abnormalities.

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…The fact that local perfusion of PCP, ketamine, and MK-801 in the mPFC failed to elicit the increase in glutamate and/or 5-HT (Lorrain et al, 2003;Amargós-Bosch et al, 2006, this study) indicates that the NMDA receptors responsible for these effects are located outside the mPFC. Our results are consistent with other data showing that the increased locomotion and firing or EPSCs of putative pyramidal neurons of the mPFC following systemic administration of NMDA receptor antagonists (Suzuki et al, 2002;Jodo et al, 2003;Jackson et al, 2004) were not mimicked by intra-mPFC application of these compounds (Aghajanian and Marek, 2000;Suzuki et al, 2002;Jodo et al, 2005). What is the actual localization of these NMDA receptors and the source of the cortical hyperglutamatergic transmission induced by their blockade?…”

“…In accordance with these findings, it has been shown that the local application of PCP into the hippocampus increases locomotion and the firing of pyramidal neurons of the mPFC in freely moving rats (Jodo et al, 2005). Furthermore, Sharp and coworkers have described that the blockade of NMDA receptors in the anterior thalamus by MK-801 resulted in injury of cortical pyramidal neurons measured by an increased synthesis of heat-shock protein 70 (HSP-70) in limbic cortex (Tomitaka et al, 2000;Sharp et al, 2001).…”

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

“…Several studies have shown that PCP, ketamine, and other NMDAR antagonists can induce aberrant glutamatergic neurotransmission by altering the firing of cortical neurons in rats (Jodo et al, 2005;Jackson et al, 2004;Tamminga et al, 2003;Shi and Zhang, 2003). Thus the efficacy of lamotrigine in these models and in the present study supports the hypothesis that the psychotomimetic effects of NMDAR antagonists arise through dysregulation of cortical neural activity and possibly an increase in excitatory transmission.…”

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

“…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). …”

“…Importantly, those neurons mediating the psychotomimetic actions of non-competitive NMDAR antagonists are still unknown. 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).…”