Determining the mechanisms and therapeutic potential of novel cholinergic antipsychotics

About This Grant

PROJECT SUMMARY/ABSTRACT Excess dopamine in the dorsal striatum is thought to be a key driver of schizophrenia. Accordingly, there is a strong corre- lation between the potency of antipsychotic drugs and their affinity for D2 dopamine receptors (D2Rs). However, tradi- tional D2R-binding drugs are not effective for psychosis in ~30% of patients, do not address cognitive and negative symp- toms, and have many adverse effects. Recently, several new therapies have emerged that do not interact with D2Rs. These include promising drugs like xanomeline, an agonist of M1 and M4 acetylcholine receptors. One promise of this new drug class is its potential to work for more patients and address more symptoms than traditional antipsychotics. Capitalizing on this novel therapeutic mechanism requires a deeper understanding of how the drug class works. Recently, our lab used in vivo imaging to determine how two of these drugs (xanomeline and the M4 receptor selective modulator VU0467154) compare to more traditional antipsychotics. Paradoxically, we found that clinical antipsychotic efficacy was more strongly associated with the normalization of activity in striatal neurons that express D1 rather than D2 dopamine receptors (Yun et al., 2023). This was true for both traditional antipsychotics and the newer cholinergic receptor agonists—suggesting the two drug classes may have partly overlapping end effects in the brain. In parallel to these imaging studies, we developed two approaches to selectively activate (either transiently or persistently) dopamine projections to the dorsal striatum. Both approaches affect behavioral processes related to the symptoms of schizophrenia and are compatible with in vivo record- ing. Here will combine these models with in vivo imaging or microdialysis to understand the mechanism-of-action of novel cholinergic antipsychotics and use behavioral testing to explore the range of symptoms for which they may be ef- fective. Specifically, we will use dual-color in vivo imaging to simultaneously record striatal acetylcholine transmission and calcium activity in D1 or D2 receptor-expressing spiny-projection neurons (SPNs). After determining how acetylcho- line relates to D1-/D2-SPN activity and how each relates to locomotor activity, we will activate nigrostriatal dopamine neurons and observe the effects on acetylcholine and D1-/D2-SPN activity. After determining these effects, we will ask how different cholinergic receptor agonists or modulators (xanomeline, M1 agonist, M4 agonist, or an M1 positive allo- steric modulator) affect the relationship between acetylcholine and D1-/D2-SPN activity under normal and hyperdopamin- ergic conditions. The drugs we will test will allow us to directly compare receptor-specific agonism and positive allosteric modulation in isolation or in combination. Next, we will use the same drugs with our animal model of persistent nigrostri- atal dopamine neuron activation. We will use in vivo microdialysis to determine how striatal neurochemistry is altered in these animals and how different cholinergic drugs affect these changes. Finally, we will use behavior (working memory, social exploration, and auditory perception) to determine whether different cholinergic drug types normalize different be- havioral processes in this animal model. Altogether we expect these experiments will advance this new therapeutic strat- egy for psychosis by elucidating the mechanistic basis for its effects on striatal activity, neurochemistry, and behavior. In doing so, we hope to catalyze the development of better and more comprehensive treatments for psychotic disorders.