domoic-acid and Schizophrenia

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 h 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.

Topics: Age Factors; Animals; Animals, Newborn; Attention; Conditioning, Psychological; Disease Models, Animal; Female; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Isolation

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.

Topics: Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Female; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Schizophrenia

Schizophrenia is a debilitating neurological disorder characterized by positive, negative, cognitive and/or emotional symptoms. Decreased social interaction is a common negative symptom. Social interaction can be readily observed in rats and is therefore an ideal target behaviour when evaluating an animal model of schizophrenia. The purpose of this study was to determine whether early alterations in glutamate signaling resulted in social withdrawal; a finding which would be consistent with existing animal models of schizophrenia and is observed within the clinical population. In the present study, male and female SD rat pups received daily injections (s.c.) of very low doses of the glutamate agonist domoic acid (DOM; 20 microg/kg) or saline during a critical period of CNS development (i.e., PND 8-14). As adults, rats were assessed for degree of social interaction. During testing, each test rat was placed in a social interaction arena and scored for social contact with and avoidance of, a same-sex untreated conspecific. No differences were found in overall activity, nor were differences present for time spent engaged in neutral behavior (i.e., not engaged in behaviour, either directed toward or in avoidance of, the stimulus rat). However, domoate-treated male rats demonstrated evidence of social withdrawal, as evidenced by a significantly greater amount of time spent in avoidance behaviour and a significantly less amount of time spent engaged in social contact. These findings are discussed in context of the significance of early alteration to glutamate signaling in the development of human neuropathological disorders.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Critical Period, Psychological; Disease Models, Animal; Excitatory Amino Acid Agonists; Female; Glutamic Acid; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Behavior

Altered functioning of the glutamate system during critical periods of development is believed to play a role in various neurodevelopmental disorders, such as schizophrenia. Prepulse inhibition (PPI) of the acoustic startle response is deficient in people with schizophrenia. This study investigated the theory that neonatal treatment with domoic acid (DOM), a glutamate agonist, leads to deficient PPI. Results indicate that neonatal treatment with DOM leads to lowered PPI in adult males and an increased startle response in adult females.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Female; Glutamic Acid; Humans; Kainic Acid; Male; Neuromuscular Depolarizing Agents; Rats; Reflex, Acoustic; Reflex, Startle; Schizophrenia; Sex Factors; Time Factors