Simultaneous activation of mGlu and muscarinic receptors reverses MK-801-induced cognitive decline in rodents.

The activity of an allosteric agonist of muscarinic M receptor, VU0357017, and a positive allosteric modulator (PAM) of M receptor, VU0238429, were investigated alone or in combination with the mGlu receptor PAM, LY487379 using the following behavioural tests: prepulse inhibition (PPI), novel object recognition (NOR), and spatial delayed alternation (SDA). VU0357017 (10 and 20 mg/kg) and VU0238429 (5 and 10 mg/kg) reversed deficits in PPI while VU0238429 (2.5 and 5 mg/kg) was effective in SDA. The simultaneous administration of subeffective doses of M or M activators (5, 1, or 0.25 mg/kg) with LY487379 (0.5 mg/kg) induced the same effect as that observed for the active dose of each compound. Selective M or M receptor blockers antagonized the effect exerted by these combinations, and pharmacokinetic studies confirmed independent transport through the blood-brain barrier. The expression of both receptors (M and M) was established in brain structures involved in cognition (neocortex, hippocampus, and entorhinal cortex) in both the rat and the mouse brains by immunofluorescence staining. Specifically, double neuronal staining of mGlu-M and mGlu-M receptors was observed in many areas of the rat brain, while the number of double-stained mGlu-M receptors was moderate in the mouse brain with no mGlu-M colocalization. Finally, the combined administration of subeffective doses of the compounds did not alter prolactin levels or motor coordination, in contrast to the compounds given alone at the highest dose or in combination with standard neuroleptics.