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Pharmacological Studies on the Roles of M1 Muscarinic Acetylcholine Receptors in the Cognitive Function of the Rodent Brain

萬代, 敬生 筑波大学 DOI:10.15068/0002005700

2022.11.25

概要

The neurotransmitter acetylcholine (ACh) is involved in cognitive function. Cholinergic neurotransmission dysfunction has been implicated in cognitive decline in various disorders, such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). On the other hand, acetylcholinesterase inhibitors (AChEIs), such as donepezil and rivastigmine, ameliorate cognitive impairment in patients with AD and DLB by increasing ACh levels in the synaptic cleft. In addition, xanomeline, a muscarinic ACh receptor agonist, robustly improved cognitive impairment in patients with AD and schizophrenia. Thus, muscarinic receptors are considered to play a key role in cognitive functions. However, because most muscarinic ACh receptor subtypes are expressed in the brain regions that are critical for cognitive functions, it is unclear which subtypes are important for these functions. Recently, it was reported that knockout of M1 muscarinic ACh receptor (M1R) in mice caused cognitive impairment, suggesting that M1R is mainly involved in the regulation of cognitive functions. To gain further insight into the roles of M1R in cognitive functions of the rodent brain, an investigation of the impact of selective M1R activation on cognitive functions is important. In addition, the development of selective M1R activators can be a new therapeutic agent for the treatment of cognitive deficits associated with cholinergic hypofunction. In the first chapter, I characterized the in vitro and in vivo profiles of two M1R positive allosteric modulators (PAMs), T-495 and MK-7622, to confirm whether these compounds are suitable as a tool to investigate the impact of M1R activation on cognitive functions. Both T-495 and MK-7622 were highly selective M1R PAMs in vitro, and oral administration of T-495 and MK-7622 specifically activated M1R in the rodent brains. In rats, T-495 ameliorated scopolamine-induced memory deficits at a 100-fold lower dose than that required for the induction of diarrhea. In contrast, MK-7622 showed memory improvement and induction of diarrhea at an equal dose. Thus, T-495 was an ideal tool to investigate the impact of M1R activation on cognitive functions. Using T-495, I evaluated the effects of M1R activation on cognitive deficits in a more disease-relevant model. M1R activation reversed memory deficits in the contextual fear conditioning test and Y-maze task in a mouse model of DLB and Parkinson’s disease with dementia. In the second chapter, to investigate the brain regions activated by muscarinic receptors activators, I assessed c-Fos expression, which has been used widely as a marker of activated neural populations. Surprisingly, donepezil, which improved scopolamine-induced memory deficits, did not increase the number of c-Fos positive cells. On the other hand, xanomeline and TAK-071, a highly selective M1R PAM, significantly increased the number of c-Fos-positive cells in the brain regions critical for cognitive functions, including cortical areas, hippocampal formation, the amygdala, and nucleus accumbens. In conclusion, the present study found that activation of M1R enhanced cognitive functions through neural activation in rodents. These findings contribute to an understanding of the roles of M1R in cognitive functions. In addition, these results demonstrate that highly selective M1R PAMs can be a novel therapeutic agent for the treatment of cognitive impairment in neurodegenerative and neuropsychiatric diseases, such as AD, DLB, and schizophrenia.

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