M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission:: relevance to the pathophysiology and treatment of related central nervous system pathologies

Dopaminergic dysfunction is an important pathogenetic factor for brain pathologies such as Parkinson's disease, ADHD, schizophrenia, and addiction as well as for metabolic disorders and anorexia. Dopaminergic neurons projecting from the midbrain to forebrain regions, such as the nucleus accumbens and the prefrontal cortex, regulate motor and cognitive functions and coordinate the patterned response of the organism to sensory, affective, and rewarding stimuli. In this study, we showed that dopaminergic neurotransmission is highly dependent on M-4 cholinergic muscarinic receptor function. Using in vivo microdialysis, we found elevated dopamine (DA) basal values and enhanced DA response to psychostimulants in the nucleus accumbens of M-4 knockout mice. We also demonstrated impaired homeostatic control of cholinergic activity that leads to increased basal acetylcholine efflux in the midbrain of these animals. Thus, loss of M-4 muscarinic receptor control of cholinergic function effectuates a state of dopaminergic hyperexcitability. This may be responsible for pathological conditions, in which appetitive motivation as well as affective and cognitive processing is impaired. We propose that M-4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.