Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

Abstract

Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

“…Therefore, reductions in freezing following reEuropean Neuropsychopharmacology 20 exposure to the context or cue probably result from a deficit in cognition rather than alteration in pain perception or emotional motivated associative learning. Attenuation of freezing in isolates in response to the context and cue are consistent with previous findings (Gaskin et al, 2014; Jones et al, 2011a; McIntosh et al, 2013) and may result from altered hippocampal and amygdala function (Goosens and Maren, 2001;Richmond et al, 1999). At no point did acute drug treatment with either cariprazine or aripiprazole significantly reverse the CFR deficit in the PCP/Iso/Veh group.…”

“…We recently showed that combining neonatal PCP administration with subsequent isolation rearing, as a novel 'dual-hit' neurodevelopmental model (Lim et al, 2012), causes all the behavioral changes seen with isolation alone (Gaskin et al, 2014), but importantly also attenuated social interaction (McIntosh et al, 2012) which may be a useful predictive index of negative symptoms such as social withdrawal (Sams-Dodd, 1999; Wilson and Koenig, 2014). The current study therefore recorded a battery of behavioral tests in neonatal PCP treated and isolation-reared rats and controls to examine reversal of surrogate markers for positive, negative and cognitive deficits by the novel potential antipsychotic compound, cariprazine.…”

“…The majority of studies were performed on rats which received both neonatal PCP and were subsequently reared in social isolation following weaning from the dam. The separate impact of exposure to each of these two manipulations has been thoroughly studied before (for reviews see (Bubenikova-Valesova et al, 2008; Fone and Porkess, 2008; Jones et al, 2011b)) and compared with the combined treatment by us (Gaskin et al, 2014).…”

“…In the time-delayed NOR studies adolescent rats (Charles River UK weighing between 175-200g) were housed in groups of four and allowed to habituate for a week before testing. For the combined neonatal PCP and social isolation experiment (Gaskin et al, 2014) litters of five male Lister hooded pups arrived with their dam on post-natal day (PND) 3-4 (Charles River UK). Pups from each litter were injected with either sterile saline or PCP HCl (10mg/kg s.c.) on PND 7, 9 and 11.…”

“…The majority of studies were performed on rats which received both neonatal PCP and were subsequently reared in social isolation following weaning from the dam. The separate impact of exposure to each of these two manipulations has been thoroughly studied before (for reviews see (Bubenikova-Valesova et al, 2008; Fone and Porkess, 2008; Jones et al, 2011b)) and compared with the combined treatment by us (Gaskin et al, 2014).Isolation alone in Lister hooded rats does not attenuate social interaction (a useful index of negative symptoms) while neonatal PCP combined with isolation does, making this dual manipulation the method of choice for use herein. This study was designed to compare the ability of cariprazine and aripiprazole to reverse the resultant behavioral syndrome and not to determine which changes were produced by either neonatal PCP or isolation, so these separate groups were not included.…”