Differential effects of acute and subchronic administration on phencyclidine‐induced neurodegeneration in the perinatal rat

Abstract

Acute and subchronic administration of N-methyl-D-aspartate antagonists to rats in the early postnatal period has been reported to produce widespread and selectively cortical neurotoxicity, respectively. To resolve this apparent discrepancy, we sought to clarify these data by determining the dose and temporal and regional characteristics of acute and subchronic phencyclidine (PCP)-induced neurotoxicity. Measurement of degenerating neurons with the cupric silver technique following a single dose of PCP on postnatal day (PN) 7 revealed that neurodegeneration increased in all areas measured (frontal, parietal and cingulate cortices, striatum, hippocampus, subiculum, and thalamus) within 9 hr. Silver staining peaked at 9-16 hr and was then not detectable or was greatly reduced after 24 hr depending on the specific region. Dose-response analysis at 9 hr showed that the lowest effective dose was 1, 3, and 10 mg/kg for the frontal cortex, hippocampus, and striatum, respectively. However, repeated PCP administration (10 mg/kg) on PN 7, 9, and 11 elicited an increase in silver staining only in the frontal cortex. To determine whether the loss of effect in the striatum and hippocampus was due to a "tolerance" mechanism or to a developmental phenomenon, we compared the effects of PCP given on PN 7, 9, or 11 with those of two doses given on PN 7 and 9 or three doses administered on PN 7, 9, and 11. Analysis of these experiments shows that both developmental factors and unknown mechanisms of tolerance underlie the apparent selective cortical neurotoxicity observed following subchronic PCP administration in perinatal rat pups.

Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

“…Sub-PCP administration to rodents, followed by a washout period, has been shown to affect hippocampal and fronto-cortical areas, thereby establishing a hypofunction of the prefrontal cortex resembling some aspects of schizophrenia pathology (Cochran et al 2003). Correspondingly, early postnatal treatment of rats with PCP has been proposed as a neurodevelopmental model of schizophrenia (Wang et al 2001) as this treatment paradigm produces widespread neurodegeneration in brain areas relevant to the cognitive deficits observed in schizophrenia patients, such as the hippocampus and frontal cortex (Ikonomidou et al 1999;Wang and Johnson 2005). As performance in the ID/ED task relies heavily on fronto-cortical processing (Birrell and Brown 2000), such a mechanistic theory could be applied to the positive effects of RO4938581 on neo-PCP-induced deficits seen here.…”

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

“…Increased glutamatergic stimulation also may produce excitotoxic neuronal effects (Danbolt, 2001) that could compromise cognitive function. Indeed, elevated glutamine levels or glutamine/glutamate ratios have been observed with other abused drugs such as ketamine (Rowland et al, 2005), phencyclidine (Iltis et al, 2009), and amphetamine (Pereira et al, 2008), which can induce neurotoxicity in animals (Green and Cote, 2009; Wang and Johnson, 2005) and humans (Jeong et al, 2013). …”

Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

“…Nakatani-Pawlak et al (2009) reported that the impairment of social interaction behaviour following neonatal PCP was significantly reversed by administration of clozapine. Neonatal administration of PCP or MK-801 in rodents has been reported to decrease parvalbumin-positive cells and spine density, (Wang and Johnson, 2005;Nakatani-Pawlak et al, 2009), both of which have been reported in schizophrenia (Beneyto and Lewis, 2011). Neonatal NMDAR antagonists have been shown to cause deficits in attentional set shifting (Broberg et al, 2008), novelty discrimination (Terranova et al, 2005;Harich et al, 2007;Pichat et al, 2007;Boulay et al, 2008), reversal and spatial working memory tasks in the Morris water maze, and in the delayed-non-match-to-position task (Kawabe and Miyamoto, 2008).…”