Metabotropic
glutamate 5 (mGlu₅) receptors are known to functionally interact with
N-methyl-d-aspartate (
NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of
schizophrenia. We have previously described a novel mGlu₅ positive allosteric modulator (PAM),
LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive
NMDA receptor antagonist, SDZ 220,581. In addition,
LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute
phencyclidine (PCP) model. In the present study, the interactions between this mGlu₅ PAM and the
NMDA receptor were explored further by assessing the effects of
LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive
NMDA receptor antagonists PCP and
MK-801, the competitive
NMDA receptor antagonist SDZ 220,581 and the GluN2B selective
NMDA receptor antagonist,
Ro 63-1908.
LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the
drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by
Ro 63-1908. In contrast,
LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and
MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task,
LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu₅ and
NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of
NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for
schizophrenia. Positive allosteric modulators of the mGlu₅ receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled '
Cognitive Enhancers'.