Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans

Abstract

Functional abnormalities in muscarinic and nicotinic receptors are associated with a number of disorders including Alzheimer's disease and schizophrenia. While the contribution of muscarinic receptors in modulating cognition is well established in humans, the effects of nicotinic receptors and the interactions and possible synergistic effects between muscarinic and nicotinic receptors have not been well characterized in humans. The current study examined the effects of selective and simultaneous muscarinic and nicotinic receptor antagonism on a range of cognitive processes. The study was a double-blind, placebo-controlled, repeated measures design in which 12 healthy, young volunteers completed cognitive testing under four acute treatment conditions: placebo (P); mecamylamine (15 mg) (M); scopolamine (0.4 mg i.m.) (S); mecamylamine (15 mg)/scopolamine (0.4 mg i.m.) (MS). Muscarinic receptor antagonism with scopolamine resulted in deficits in working memory, declarative memory, sustained visual attention and psychomotor speed. Nicotinic antagonism with mecamylamine had no effect on any of the cognitive processes examined. Simultaneous antagonism of both muscarinic and nicotinic receptors with mecamylamine and scopolamine impaired all cognitive processes impaired by scopolamine and produced greater deficits than either muscarinic or nicotinic blockade alone, particularly on working memory, visual attention and psychomotor speed. These findings suggest that muscarinic and nicotinic receptors may interact functionally to have synergistic effects particularly on working memory and attention and suggests that therapeutic strategies targeting both receptor systems may be useful in improving selective cognitive processes in a number of disorders.

Towards a muscarinic hypothesis of schizophrenia

“…21,28 A deficit in the function of the cholinergic system is thus likely to result in cognitive impairment. As neurocognitive impairment is frequently associated with schizophrenia, 1,2 and has been shown to be worsened by exposure to muscarinic antagonists, 29,30 an involvement of the cholinergic system in the pathophysiology of this illness seems possible.…”

“…Some of these shortcomings of IQNB may be overcome with newly developed SPECT-and PET-ligands that bind selectively to specific subtypes of the muscarinic receptor. 103,104 Neuropsychopharmacological studies Muscarinic receptor antagonists (anticholinergics) such as atropine and scopolamine cause cognitive dysfunction in healthy controls 29 and, at higher doses, can induce delirium as well as vivid hallucinations in healthy controls. 105 Despite these potential effects, treatment of subjects with schizophrenia with anticholinergics has been a common practice for many years to alleviate motor side effects caused by first-generation antipsychotics.…”

Acetylcholine Deficiency in Caenorhabditis elegans Induced by Hyperthermia Can Be Compensated by ACh-esterase Inhibition or Activation of GAR-3 mAChRs

“…However it is possible that role of separate types of synaptic transmission in the whole nervous system dysfunction produced by heat stress can be different. Cholinergic synaptic transmission plays extremely important role in the large majority of functions of human and animals' organisms including thermoregulation (Conti-Tronconi & Raffery, 1982;Ellis et al, 2006;Erskine et al, 2004;Feiro & Gould, 2005;Gomeza et al, 1999;Lanzafame, Christopoulos, & Mitchelson, 2003). Therefore it is possible that cholinergic system plays important role in the response of whole nervous system to hyperthermia including its dysfunctions and compensatory responses.…”

Gαq-Coupled Muscarinic Acetylcholine Receptors Enhance Nicotinic Acetylcholine Receptor Signaling inCaenorhabditis elegansMating Behavior

“…Many behavioral circuits coexpress nAChRs and mAChRs (Miller et al, 1992;Raizen et al, 1995;Weeks et al, 1997;Kim et al, 2001;Bany et al, 2003;Steger and Avery, 2004). Using agonists and antagonists for different receptor types, effects of nicotinic and muscarinic receptors signaling have been described in organismal behaviors such as early visual processing, mice memory of conditioned fear, and human memory (Erskine et al, 2004;Feiro and Gould, 2005;Ellis et al, 2006). However, determining how different cholinergic signaling events regulate vertebrate behaviors is difficult because of the complexity of the vertebrate nervous system.…”