M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS 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 M4 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 M4 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 M4 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 M4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.
Tzavara
Eleni T
ET
Eli Lilly and Co., Indianapolis, Indiana 46240-0510, USA.
Bymaster
Frank P
FP
Davis
Richard J
RJ
Wade
Mark R
MR
Perry
Kenneth W
KW
Wess
Jurgen
J
McKinzie
David L
DL
Felder
Chris
C
Nomikos
George G
GG
D000109:Acetylcholine / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D000661:Amphetamine; D012601:Scopolamine; D000109:Acetylcholine; D004298:Dopamine