Neonatal domoic acid treatment produces alterations to prepulse inhibition and latent inhibition in adult rats

Schizophrenia is a complex and severe mental disorder characterized by positive, negative and cognitive symptoms. Characteristic behavioral alterations reflecting these categories of symptoms have been observed in many animal models of this disorder, and are consistent with those manifested in the clinical population. The purpose of this study was to determine whether early alterations in glutamate signaling would result in alterations to prepulse inhibition (PPI) and latent inhibition (LI); two assessments used for evaluating putative novel animal models with relevance to schizophrenia. In the present experiment, daily subcutaneous (s.c.) injections of 20μg/kg of domoic acid (DOM) were administered to rat pups from postnatal days (PND) 8-14. When tested as adults, DOM treated rats displayed deficits in PPI that were dependant on both sex and time of day. No differences in startle amplitude, habituation, or movement were found during any test, indicating that the PPI deficits seen could not be attributed to baseline startle differences. Deficits in LI were also apparent when adult rats were tested using a conditioned taste aversion task, with DOM-treated animals displaying a significantly suppressed LI. These results suggest that early treatment with DOM may serve as a useful tool to model schizophrenia which in turn may lead to a better understanding of the contribution of glutamate, and in particular, kainate receptors, to the development and/or manifestation of schizophrenia or schizophrenia-like symptoms in the clinical population

Temporal memory dysfunction and alterations in Tyrosine hydroxylase immunoreactivity in adult rats following neonatal exposure to Domoic acid

The purpose of the present study was to determine whether early alterations in glutamate signaling, via daily injections of the glutamate agonist, domoic acid (DOM; 20 μg/kg), during a critical period of CNS development (PND 8 - 14), would result in temporal memory deficits and/or alterations in tyrosine hydroxylase (TH) immunoreactivity. As adults, subjects were assessed for temporal memory ability using a recency discrimination paradigm. Both number and duration of exploratory contacts directed at familiar objects, differing by one hour in recall delay, were measured. Analyses revealed that DOM-treated females demonstrated temporal memory dysfunction, as evidenced in a significantly lower proportion of total exploratory behaviour directed toward the remote object. Integrity of the dopamine system was assessed using immunohistochemistry to examine TH immunoreactivity in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Sections obtained from DOM-treated males had significantly less TH immunoreactivity in the right mPFC, while DOM-treated females had significantly greater TH immunoreactivity in the left core and right shell of the NAcc. These findings are discussed in context of early alterations to glutamate signaling in the development of human neuropsychiatric disorders

Neonatal domoic acid abolishes latent inhibition in male but not female rats and has differential interactions with social isolation

Deficits in attention have long been identified as a core feature in schizophrenia and related neuropsychiatric disorders. We have investigated the combined effects of neonatal treatment with domoic acid (DOM) and social isolation rearing (both putative animal models of schizophrenia) on latent inhibition (LI), a measure of attentional processing. Daily subcutaneous injections of 20 μg/kg DOM or saline were administered to rat pups from postnatal days (PND) 8-14. After weaning, rats were housed either alone or in groups of 4 until LI was assessed at PND 110 using a lick-suppression conditional emotional response paradigm. Neonatal treatment with DOM abolished LI behaviour in adult male rats regardless of housing condition when tested 48 hours after conditioning, but this effect was not observed in female rats. Social isolation rearing also reduced LI in male rats, but not to the same extent as DOM. When tested again one week later, single-housed males treated with DOM displayed significant LI whereas saline treated or group-housed DOM males did not. No significant differences were found with females 1 week later. We conclude that neonatal DOM and social isolation both impair attentional processing in young adult male, but not female, rats although the mechanisms by which this occurs appear to be different