Cocaine‐ and Amphetamine‐Regulated Transcript Peptide (CART) Alleviates the Cognitive Deficits Following MK‐801 Induced Schizophrenia

N ‐methyl‐D‐aspartate receptor (NMDAR) hypofunction and disturbed Ca 2+ signaling play a central role in the pathophysiology of positive symptoms and cognition deficits in schizophrenia. Cocaine‐ and amphetamine‐regulated transcript peptide (CART) is known to regulate both NMDAR and Ca 2+ signaling and improves memory formation. With a view to test the role of CART in schizophrenic dementia and hyperactivity, we injected MK‐801, which induces psychotic‐like symptoms that are similar to acute episodes of schizophrenia. Adult Wistar rats were allowed to interact with a juvenile rat (session‐1) and 30‐min or 24‐h thereafter with same (familiar) or different (novel) juvenile (session‐2). Investigation time for juvenile rat was noted for 5 min, wherein social recognition is indicated by a decrease in investigation of a familiar juvenile rat in session‐2. While saline/aCSF control rats showed intact social recognition at 30‐min inter‐trial interval (ITI), cognitive impairment was noticed at 24‐h. MK‐801 (0.025 or 0.05 mg/kg, intraperitoneally) produced cognition deficits at 30‐min ITI which was reversed by pretreatment with CART [250 or 500 ng/rat, intracerebroventricularly (icv)]. ERK‐inhibitor (U0126, 4 μg/rat, icv) blocked the effect of CART in MK‐801 injected cognitive deficit rats. MK‐801 treated rats also showed increase in the locomotion in open field test. Pretreatment with CART blocked this hyperactivity, indicating role of CART in controlling positive symptoms of schizophrenia. A significant decrease in the CART‐immunoreactivity and phosphorylated ERK‐expression in the hippocampus following MK‐801 treatment was observed. We conclude that, inhibition of NMDAR decreases CART‐signaling in hippocampus. CART, via ERK activation, may alleviate MK‐801‐induced cognitive deficits and positive symptoms related to schizophrenia. Support or Funding Information This work was supported by Department of Biotechnology (DBT), Government of India. The travel expenses to attain Experimental Biology supported by ‘IBRO Travel grant’. 1 Effect of temporal delay and MK‐801 on the social recognition taskAnimals were treated with saline/aCSF (A,B) or MK‐801 (C,D,E,F) and subjected to social recognition task at 30min or 24h intra‐trial interval (ITI). Data represented as mean exploration time (sec) or relative discrimination±SEM. The data was analysed by using t‐test (exploration time) or one way ANOVA followed by Bonferroni's multiple comparison test (relative discrimination).*p<0.05,**p<0. 01 vs respective saline+aCSF2 Effect of CART on the social recognition taskDifferent doses of CART (A,B,C,D) alone or in combination with MK‐801 and/or U0126 (E,F), infused intracerebroventricularly (icv), and kept with novel (A,B,E,F) or same (C,D) juvenile rats for 5 min. The data was analysed by using student's t‐test (exploration time) or one way ANOVA discrimination). *p<0.05, **p<0.01, ***p<0.001 vs respective saline+aCSF; # p<0.05 vs CART.3 Immunohistochemical evaluation of phosphorylated ERK (pERK) and CART in the dentate gyrus (DG)pERK‐(A,B,C,D) and CART‐immunoreactive (ir) neurons (E,F,G) in the DG of brain isolated from naïve (A, E) or 10‐min after exposure to novel juvenile rats and infused with aCSF (B, F), MK‐801 (C, G) or CART (D). Morphometric analysis given in (I,J). The bar values are shown as the mean±SEM for 5 rats. *p<0.01 vs naïve group, # p<0.001 vs aCSF, $ p<0.001 vs per se MK‐801. Scale bar=100 μm.