The PET tracer [ 11 C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer’s disease

[ 11 C]MK-6884 is an M4R-specific PET tracer for quantifying target engagement in brain and providing insights into AD neuropathology.

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OF DYT1-TOR1A DYSTONIA

ABSTRACTTrihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is the preferred oral pharmaceutical for the treatment of DYT1-TOR1A dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. Using a mouse model of DYT1-TOR1A dystonia (Tor1a+/ΔE KI mice), we recently found that THP normalized striatal DA release, revealing a plausible mechanism of action for this compound. However, the exact mAChR subtypes that mediate this effect remain unclear. In this study we used a combination of a newly developed M4 subtype-selective mAChR antagonist and cell-type specific mAChR KO mice to determine which mAChR subtypes mediate the DA enhancing effects of THP. We determined that THP and the M4 subtype-selective mAChR antagonist enhance striatal DA release by blocking M4 mAChR on striatal cholinergic interneurons in Tor1a+/ΔE KI mice. However, in Tor1a+/+ mice THP increases striatal DA release through a combination of M1 and M4 mAChR, which reveals an alteration in M1 mAChR function in Tor1a+/ΔE KI mice. Taken together these data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that M4-subtype selective mAChR antagonists may be more efficacious therapeutics for DYT1-TOR1A dystonia.SIGNIFICANCE STATEMENTTrihexyphenidyl, a non-selective muscarinic receptor antagonist, is the preferred oral therapeutic for DYT1-TOR1A dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved therapeutics. We recently found that trihexyphenidyl rescues the deficit in both striatal dopamine release and steady-state extracellular striatal dopamine concentrations in a mouse model of DYT1-TOR1A dystonia. However, the precise muscarinic receptor subtype(s) that mediate these effects are unknown. We used a newly developed M4 muscarinic receptor subtype-selective antagonist along with M1 and M4 muscarinic receptor knockout mice to determine the precise muscarinic receptor subtypes that mediate the dopamine-enhancing effects of trihexyphenidyl.

Olanzapine: A potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics

Designer receptors exclusively activated by designer drugs (DREADDs) derived from muscarinic receptors not only are a powerful tool to test causality in basic neuroscience but also are potentially amenable to clinical translation. A major obstacle, however, is that the widely used agonist clozapineN-oxide undergoes conversion to clozapine, which penetrates the blood-brain barrier but has an unfavorable side effect profile. Perlapine has been reported to activate DREADDs at nanomolar concentrations but is not approved for use in humans by the Food and Drug Administration or the European Medicines Agency, limiting its translational potential. Here, we report that the atypical antipsychotic drug olanzapine, widely available in various formulations, is a potent agonist of the human M4 muscarinic receptor-based DREADD, facilitating clinical translation of chemogenetics to treat central nervous system diseases.