CART alleviates MK-801 induced schizophrenic dementia-like symptoms

Clozapine, an antipsychotic agent, inhibited ketamine-induced long-term memory impairment in mice (Antonio et al., 2016) and increased serum CART level in the schizophrenic patients (Wysokinski and Kloszewska, 2014).  Herein, exogenously administered CART (icv) promoted social cognition suggesting reversal of schizophrenic dementia-like condition induced by MK-801.  The social recognition memory was tested in these experiments using the novel juvenile rats.  We may add that, rodents can generally remember a companion after a single encounter of interaction time as short as 2-min (Kogan et al., 2000; Riedel et al., 2009).  The hippocampus is believed to encode some unique configuration of features that form a polymodal representation of the interacting mouse (Kogan et al., 2000).  Therefore social recognition memory showed by the animals may not only be dependent on the familiarity but also the novelty discrimination ability of the animals, which may be supported by CART.

These data concur with the immunohistochemical profile seen in different groups.  Interaction with the juvenile increased the expression of the peptide in VTA, PFC and AcbSh (see paragraph above).  Although MK-801 per se (no juvenile interaction) did not produce any change in CART-immunoreactivity, MK-801 pre-treatment, followed by juvenile interaction, suppressed the juvenile interaction induced increase in CART expression.  These results implicate CART system activation in schizophrenic dementia-like condition.

Previous studies reported CART neuronal projections from ARC and LH to VTA and AcbSh (Dellavechia-Adams et al., 2002; Bharne et al., 2015; Somalwar et al., 2017).  However, neurons of ARC and LH did not show any change in CART expression following juvenile interaction and/or MK-801 treatment.  We speculate that, CART synthesis in these nuclear groups may not be involved in the cognitive processes under investigation.

CART neurons communicate with the dopamine neurons of the VTA projecting to PFC

The dopamine neurons of the VTA are known to project to PFC, and the importance of this circuit in cognition and schizophrenic dementia is well established (Goldman-Rakic, 1992; Gao and Goldman-Rakic, 2003).  With a view to finding out if these dopamine-containing neuronal cell bodies receive CARTergic inputs, Di-I was administered in the PFC.  Retrogradely labeled dopamine neurons in the VTA were found to receive CART fiber terminals.  This pattern of connectivity suggests that CART might modulate dopaminergic VTA-PFC circuit, which in turn may influence cognition.  The role of CART in the modulation of the VTA-AcbSh reward pathway has been highlighted in earlier studies (Dellavechia-Adams et al., 2002; Philpot et al., 2005; Somalwar et al., 2017).

Elucidation of PFC dopamine receptor in CART’s action

A wealth of data emphasize the role of D1 receptors in the PFC in working memory deficits associated with schizophrenia (Goldman-Rakic et al., 2000; Abi-Dargham et al., 2002; Rinaldi et al., 2007).  D1 receptors are also implicated in the social cognition (Di Cara et al., 2007).  Therefore we tested the involvement of D1 receptors in the PFC in the procognitive action of CART.  Administration of D1 receptor antagonist directly in the PFC attenuated the procognitive effect of CART, thereby suggesting that the action of CART is dependent on the normal mesocortical dopamine system. 

CART reversed the hyperactivity in MK-801 induced schizophrenia-like condition

Central administration of CART reversed the hyperactivity seen in the MK-801 model of schizophrenia.  Converging lines of evidences suggest that MK-801 induced hyperactivity may be attributed to increased sub-cortical dopamine and dysregulation of PFC dopamine system (Meyer-Lindenberg et al., 2002; Yoon et al., 2013).  The mesolimbic system regulates the locomotor activity (Wise, 1984; Wyvell and Berridge, 2000).  Although CART per se did not affect the overall locomotor activity in naïve animals, MK-801 induced hyperactivity was partially attenuated by CART treatment.  CART is reported to reverse the locomotor sensitivity following agents like dopamine, cocaine, amphetamine and caffeine (Jaworski et al., 2003; Job et al., 2014; Fu et al., 2016).  While we do not know the underlying mechanism, we speculate the CART mediated modulation of D1/D2 receptors in the Acb responsible for reduced locomotion (Moffett et al., 2011).

Conclusion

CART is known to regulate dopamine release in the brain and innervate dopaminergic mesocortical projections as observed in the present study.  Based on the current data, we conclude that the social cognitive deficits associated with schizophrenia-like condition may be reversed by CART acting via mesocortical dopamine system in the rodents.