General comments

Cortical hypodopaminergia results in memory deficits in psychotic patients (Brisch et al., 2014).  These cognitive deficits severely impact the schizophrenia prognosis and therapeutic outcome (Bowie and Harvey, 2006; Keefe, 2008). Restoration of normal mesolimbic dopamine level has been considered as an effective strategy to prevent cognitive deficits in schizophrenia (Brisch et al., 2014).  Early clues indicate that CART might promote dopamine release and exercise nootropic effects (Hubert et al., 2008; Upadhya et al., 2011; Bharne et al., 2016).  The present study tests the role of CART in restoring the cognitive functions in MK-801 model of schizophrenia.  While MK-801 produced hyperactivity and social cognitive deficits, intracerebral administration of CART alleviated the symptoms.  Direct administration of CART into the VTA produced distinct pro-cognitive effects, which were fully blocked by dopamine D1 receptor antagonist (SCH23390) given into the PFC.  Thus CART seems to exercise its pro-cognitive effects via the modulation of mesocortical circuits in rats inflicted with the schizophrenic dementia-like condition.

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Methodological considerations

According to the hypoglutamateric hypothesis, the schizophrenia-like symptoms are induced by inhibition of NMDA receptors, secondary activation of the mesolimbic dopaminergic system and hypoactive mesocortical dopamine projections (Mathé et al., 1999; Bubenikova-Valesova et al., 2008; Roenker et al., 2012).  Acute administration of MK-801 resulted in social cognitive deficits and schizophrenia-like symptoms in rodents as well as humans (Jentsch and Roth, 1999; Bubenikova-Valesova et al., 2008).  In addition, MK-801 is known to induce a significant decrease and increase in the burst firing of mesocortical and mesolimbic dopaminergic neurons, respectively (Grace and Bunney, 1983; Pawlowski et al., 1990; Murase et al., 1993).  

The cognitive deficits were assessed in a social recognition test.  It is an ethologically relevant test, non-aversive or rewarding paradigm based on the innate desire of animal to investigate the conspecific (Engelmann et al., 1995; Bielsky and Young, 2004).  Naïve animal recognize familiar juvenile, if ITI is less than 40-min (Engelmann et al., 1995), however, recognition memory was impaired at longer intervals (24-hr) (Bharne et al., 2016).  Therefore, we tested the retention or weakening of social recognition at 30-min (short-term memory) or 24-hr (long-term memory) ITI, respectively.  Resident rats exhibited a significant reduction in the interaction time for familiar juvenile at session-2(30-min) as compared to session-1.  On the other hand, the duration of social interaction with novel juvenile was similar across both the sessions.  These data suggest intact short-term memory in the control animals.  These observations also exclude the possibility of fatigue or lack of interest towards the juvenile animals during session-2(30-min).  However, the control animals showed similar interaction time for the novel as well as a familiar juvenile at 24-hr time-point, indicating impaired long-term social cognition.

CART modulates long-term social recognition memory in naïve rats

In the behavioural study, naïve (without MK-801) as well as CART treated animals showed a similar pattern of interaction with the juvenile at the 30-min time-point.  CART does not seem to potentiate the memory performance at this time-point; this may be due to the ceiling effect reported earlier (Bharne et al., 2016).  However, a different scenario emerged at 24-hr ITI.  CART treated resident rat, but not naïve, could recognize the familiar juvenile rat.  Since CART was administered prior to session-1 (training), we suggest that the peptide may promote social learning, which in turn might improve long-term social recognition.  Improved spatial learning, object recognition and synaptic plasticity following CART administration have already been reported (Upadhya et al., 2011; Jin et al., 2015; Bharne et al., 2016).  The immunohistochemical data support this notion.  Animals allowed to interact with the juvenile showed a significant increase in CART-immunoreactivity in the VTA, PFC and AcbSh.  However, CART mRNA in Acb and CART in LH and ARC did not alter (data not shown).  We suggest that learning episode may enhance turnover and anterograde transport of CART in the fibre terminals at the target nuclei like the VTA, PFC and AcbSh.

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