M4 Muscarinic receptor KO (Chrm4 tm1Jwe) Mouse

M4 Muscarinic Receptor Knockout: Activation of M4R may reduce the reinforcing effect of drugs of abuse, and contribute to the analgesic effects observed after administration of muscarinic agonists.

The five Muscarinic Acetylcholine (ACh) receptors are G-protein coupled receptors (M1R-M5R). M1R, M3R and M5R selectively couple to Gq/G11; M2R and M4R selectively couple to Gi/Go. M4R knockout mice are viable and fertile, and have no major morphological abnormalities.

Dopamine hyperactivity in subcortical areas such as the nucleus accumbens is a key feature associated with schizophrenia. M4 muscarinic receptors in the central nervous system are decreased in the basal ganglia and prefrontal cortex of patients with schizophrenia, and basal dopamine levels are increased in the nucleus accumbens of M4R knockout mice. These results suggest that M4R agonists may be clinically useful in the treatment of schizophrenia and other CNS disorders associated with hyperdopaminergia.

Most drugs of abuse trigger an increase in dopamine release in the nucleus accumbens. Stimulation of midbrain M4 autoreceptors are thought to decrease the activity of dopaminergic neurons in ventral tegmental area neurons, leading to reduced dopamine release in the nucleus accumbens. Activation of central M4R may reduce the reinforcing effects of drugs of abuse. Analysis of M4R knockout mice also has shown that M4Rs contribute to the analgesic effects observed after administration of muscarinic agonists.