Postweaning social isolation exacerbates neurotoxic effects of the NMDA receptor antagonist MK-801 in rats

Abstract

The glutamate hypothesis of schizophrenia postulates NMDA receptor hypofunction as important pathophysiological mechanism. In rodents, NMDA receptor antagonists induce together with psychosis-like effects cortical injury. Stress during adolescence can trigger schizophrenia by unknown mechanisms. Here we show in rats that juvenile chronic isolation significantly increases MK-801-triggered expression of heat shock protein 70, a marker of neuronal injury, in the retrosplenial cortex. These data suggest an additive effect of juvenile stress and NMDA receptor blockade, with possible relevance for schizophrenia.

The use of antioxidant compounds in the treatment of first psychotic episode: Highlights from preclinical studies

“…With respect to psychosis, animal models of this mental disorder have become increasingly important, attempting to develop specific pharmacological options for this psychiatric condition. Although several reliable animal models of psychosis are actually available and largely used in neuropsychiatric research, mainly based on pharmacologic, genetic, environmental, and neurochemical manipulations, no rodent models which specifically mimic the peculiarities of first psychotic episode in humans have been developed yet. Indeed, so far, progress in the understanding of the molecular pathways underlying this specific phase of the psychotic disorder has been based on the use of animal models only partially reproducing the neuropathological events occurring during the prenatal, perinatal, and juvenile stages of CNS development .…”

Investigating the Robustness of a Rodent “Double Hit” (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review

“…Through different study selection processes, 17 articles met the inclusion criteria for this systematic review [ 33 , 34 , 35 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Eight studies used Sprague Dawley rats [ 34 , 39 , 40 , 41 , 42 , 43 , 44 , 48 ], three studies used Lister-hooded rats [ 46 , 47 , 49 ], three studies used Wistar rats [ 38 , 45 , 50 ], and another three studies used mice [ 33 , 35 , 51 ]. All studies used male animals except one that used both male and female animals [ 45 ].…”

“…All studies used male animals except one that used both male and female animals [ 45 ]. Most studies originated from Europe; the United Kingdom [ 46 , 47 , 49 ], and Spain [ 33 , 35 , 51 ] each had three studies, Hungary [ 38 , 45 ] had two, while France [ 50 ] and Germany [ 44 ] had one each. North America (Canada) produced five papers [ 39 , 40 , 41 , 42 , 43 ], and Asia (China) two papers [ 34 , 48 ].…”

“…Ten studies found that the “double hit” model is more effective when compared to the intervention using social isolation on its own or an NMDA receptor antagonist [ 33 , 35 , 40 , 44 , 45 , 46 , 47 , 49 , 50 , 51 ]. Three of these studies were able to produce positive symptoms of schizophrenia, which is the impairment on the locomotor activity [ 40 , 47 , 50 ].…”

“…Other studies showed that the “double hit” model produced impairments on the novel object discrimination test [ 46 , 47 ]; furthermore, another study showed impairment on the social recognition test [ 50 ], and these are related to cognitive symptoms of schizophrenia. Another study reported the presence of heat shock protein 70 in brain regions of animals treated with the “double hit” model of schizophrenia [ 44 ]. The “double hit” model induces reductions in prepulse inhibition and reduced cingulate 1 cortex volume [ 35 ].…”