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.2012 Mar;37(4):1057-66.
doi: 10.1038/npp.2011.298. Epub 2011 Nov 30.

Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator

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Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator

Francois Gastambide et al. Neuropsychopharmacology.2012 Mar.

Abstract

Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.

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Figures

Figure 1
Figure 1
Performance of both saline- (white bars) and MAM-treated rats (gray bars) in the attentional set-shifting task (N=8 per group). Graph bars represent the mean±SEM of the number of errors made to reach the criterion of six correct consecutive trials in each test discrimination (a) and the average number of perseverativevs regressive errors made within the first two reversal learning discriminations (b). Symbols:#p<0.001vs the saline-treated group at the IDS discrimination;*p<0.05 and**p<0.01vs the saline-treated group within the same discrimination (a) or error type category (b).
Figure 2
Figure 2
Performance of both saline- (white bars) and PCP-treated rats (gray bars) in the attentional set-shifting task (N=12 per group). Graph bars represent the mean±SEM of the number of errors made to reach the criterion of six correct consecutive trials in each test discrimination (a) and the average number of perseverativevs regressive errors made within the first two reversal learning discriminations (b). Symbols:#p<0.001vs the saline-treated group at the IDS discrimination;*p<0.05 and**p<0.01vs the saline-treated group within the same discrimination (a) or error type category (b).
Figure 3
Figure 3
Performance of both saline- (white bars) and MAM-treated rats (gray bars) in the attentional set-shifting task after an administration of either vehicle (blank bars) or LSN2463359 (striped bars) (N=9–10 per group). Graph bars represent the mean±SEM of the number of errors made to reach the criterion in each test discrimination (a) and the average number of perseverativevs regressive errors made within the first two reversal learning discriminations (b). Symbols:#p<0.001vs the saline/veh-treated group at the IDS discrimination;*p<0.05 and**p<0.01vs the saline/veh-treated group within the same discrimination (a) or error type category (b); °p<0.05, °°p<0.01, °°°p<0.001vs the MAM/veh-treated group within the same discrimination (a) or error type category (b).
Figure 4
Figure 4
Performance of both saline- (white bars) and PCP-treated rats (gray bars) in the attentional set-shifting task after an administration of either vehicle (blank bars) or LSN2463359 (striped bars) (N=8 per group). Graph bars represent the mean±SEM of the number of errors made to reach the criterion in each test discrimination (a) and the average number of perseverativevs regressive errors made within the first two reversal learning discriminations (b). Symbols:#p<0.001vs the saline/veh-treated group at the IDS discrimination;*p<0.05 and**p<0.01vs the saline/veh-treated group within the same discrimination (a) or error type category (b).
Figure 5
Figure 5
: (a-h) Photomicrographs of parvalbumin (PV) (a-d)- and mGlu5 (e-h)- immunostained sections from saline (a, c, e, g)- and MAM (b, d, f, h)-treated animals, aged 3 month-old. Scale bar =500 μm. (i-j) Graph bars express the mean±SEM of PV-positive neurons per mm3 (i) and mGlu5-immunoreactivity per mm2 (j) measured in the orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC) of saline- (white bars) and MAM-treated animals (gray bars).*p<0.05;**p<0.01vs the saline-treated controls.
Figure 6
Figure 6
Graph bars express the mean±SEM of the number of mGlu5-positive pixels expressed by area measure units within cortical (a, b) and sub-cortical (c-e) regions of saline- (white bars) and MAM-treated animals (gray bars).*p<0.05;**p<0.01vs the saline-treated controls.
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References

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