Muscarinic Receptor Pharmacology and Circuitry for the Modulation of Cognition

Abstract

The muscarinic cholinergic system constitutes an important part of the neuronal circuitry that modulates normal cognition. Muscarinic receptor antagonists are well known to produce or exacerbate impairments in attention, learning, and memory. Conversely, both direct-acting muscarinic receptor agonists and indirect-acting muscarinic cholinergic agonists, such as acetylcholinesterase inhibitors, have shown cognition-enhancing properties, including improvements in normal cognitive function, reversal of cognitive deficits induced by muscarinic receptor antagonists, and attenuation of cognitive deficits in psychiatric and neurological disorders, such as Alzheimer's disease and schizophrenia. However, until recently, the lack of small molecule ligands that antagonize or activate specific muscarinic acetylcholine receptor (mAChR) subtypes with high selectivity has been a major obstacle in defining the relative contributions of individual mAChRs to different aspects of cognitive function and for the development of novel therapeutic agents. These limitations may be potentially overcome by the recent discovery of novel mAChR subtype-selective compounds, notably allosteric agonists and positive allosteric modulators, which exhibit greater selectivity for individual mAChR subtypes than previous mAChR orthosteric agonists. In preclinical studies, these novel ligands have shown promising efficacy in several models for the enhancement of cognition. In this chapter, we will review the muscarinic cholinergic circuitry and pharmacology of mAChR agonists and antagonists relevant to the modulation of different aspects of cognition in animals and clinical populations.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Results with nicotine and caffeine are unpublished but collected with identical procedures. drugs in ICSS procedures are warranted (Conn et al, 2009;Bubser et al, 2012;Jones et al, 2012).…”

Effects of Selective Activation of M₁ and M₄ Muscarinic Receptors on Object Recognition Memory Performance in Rats

“…Yet an unanswered question is how each of the 5 mAChR subtypes influences memory, a question that has important implications for understanding how ACh modulates memory systems generally and for developing drug therapies to treat memory dysfunction specifically [2]. M 1 and M 4 receptors have much higher expression levels in the CNS relative to the PNS [3] and are densely expressed in memory circuitry, including the hippocampus, striatum and amygdala [4].…”

The nootropic properties of the tetrapeptide acetyl-(D-lys)-lys-arg-arg-amide (KK-1) on the model of scopolamine-induced alzheimer’s disease in rats

“…Вона може реалізовува-тися також завдяки підвищен-ню афінітету АХ до централь-них М-ХР. Такий механізм при-таманний низці алостеричних агоністів та позитивних ало-стеричних модуляторів холінер-гічного рецепторного комплек-су, які мають ряд переваг перед інгібіторами АХЕ (вищу фарма-кологічну активність) та пря-мими мускариновими агоніста-ми (кращий профіль безпеки) [8,24]. Оскільки скополамін є неселективним блокатором М-ХР, невідомо, за посередництва яких саме їх підтипів реалізується ноотропна активність пептиду КК-1.…”