Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice

Background: Muscarinic or 5-HT_1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits.

Methods: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT_1A receptor agonist (F15599) alone or in combinations with VU0357017 (M₁ receptor allosteric agonist), VU0152100 (M₄ receptor positive allosteric modulator), and VU0238429 (M₅ receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the Animals.

Results: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptor activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT_1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained Animals. No effects of the compounds were observed in non-trained mice.

Conclusion: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptor activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptor activators reverse MK-801-induced 5-HT_1A and GAD₆₅ dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

5-HT(1A); GAD(65); Morris water maze; Muscarinic receptors; Novel object recognition; Schizophrenia; Spatial learning.