Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review

Abstract

Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

“…Both isolation-rearing (Jones et al, 2011; Watson et al, 2012; McIntosh et al, 2013) and repeated PCP-injection to adult rats (McKibben et al, 2010; Grayson et al, 2015) impair NOR, as does combined PCP-SI (Gaskin et al, 2014; Watson et al, 2016), consistent with findings in this study. Lamotrigine at the low (10mg/kg i.p.)…”

“…The independent impact of exposure to each of these two developmental manipulations has been thoroughly studied before (for reviews see Fone and Porkess [2008] and Grayson et al [2015]) and compared with the combined treatment by us (Gaskin et al, 2014; Watson et al, 2016). The current study was designed to compare the ability of lamotrigine to reverse the resultant behavioral syndrome but not to determine which alterations were produced by either neonatal PCP or isolation alone.…”

“…Illicit use of N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine, and phencyclidine (PCP), produces psychosis in humans (Krystal et al, 1994) and exacerbates symptoms in schizophrenic patients (Lahti et al, 1995). Therefore, repeated NMDA receptor antagonist administration has been widely used to replicate behavioral and neurobiological changes in rodents (Wang et al, 2008; Grayson et al, 2015). In particular, neonatal PCP induces long-term locomotor abnormality, cognitive dysfunction (Depoortere et al, 2005), impaired sensorimotor gating (Wang et al, 2001) and loss of parvalbumin-containing GABAergic neurones accompanied by changes in autophagy (Radonjic et al, 2013; Jevtic et al, 2016), reminiscent of features of schizophrenia.…”

The neurobiology of transition to psychosis

“…Third, dys myelination is consistently noted in neurodevelopmental models that reproduce behavioural features reminiscent of negative symptoms of schizophrenia. This includes perinatal and subchronic administration of phencyclidine, [70][71][72][73][74] ), early social isolation, 80 and excitotoxic developmental lesion models (medial prefrontal 81 ). Cuprizone, a copper chelating agent that actively disrupts myelination, results in diminished social interaction in mice, [81][82][83][84][85][86] but only when dys myelination occurs before adult life.…”

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

“…This activity is focused on the understanding of how genetics and genetic/environment factors combine to trigger and maintain psychopathology (Caspi and Moffitt, 2006;Lesch, 2004), and placing more emphasis on the developmental aspects and plasticity of neuropsychiatric disorders. Further, this activity seeks to integrate genetics and systems biology into the development of animal models (Cope et al, 2016;Grayson et al, 2016;Homberg et al, 2016), as well as improving the identification of specific patient populations most likely to benefit from pharmacotherapy (Schumann et al, 2014;Wong et al, 2011).…”