Modulation of Nicotinic Receptor Activity in the Central Nervous System

Albuquerque, Edson X.; Santos, Máriton D.; Alkondon, Manickavasagom; Pereira, Edna F. R.; Maelicke, Alfred

doi:10.1097/00002093-200108001-00004

Cited by 66 publications

(35 citation statements)

References 46 publications

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“…We have shown previously that the galantamine antiinflammatory mechanism is centrally mediated and requires the α7nAChR (13). Moreover, in addition to being an acetylcholinesterase inhibitor, galantamine is a positive allosteric modulator of nicotinic receptors, including α7nAChR (38). Therefore, it is possible that a central, nicotinic receptor-mediated cholinergic appetite modulation is implicated in the food intake suppressing effect of galantamine.…”

Section: Discussionmentioning

confidence: 99%

Galantamine Alleviates Inflammation and Other Obesity-Associated Complications in High-Fat Diet-Fed Mice

Satapathy

Ochani

Dancho

et al. 2011

Mol Med

103

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Section: Discussionmentioning

confidence: 99%

Galantamine Alleviates Inflammation and Other Obesity-Associated Complications in High-Fat Diet-Fed Mice

Satapathy

Ochani

Dancho

et al. 2011

Mol Med

103

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“…A different approach would be to administer a nicotinic positive allosteric modulator (PAM) that can reinforce the endogenous cholinergic neurotransmission without directly stimulating the target receptors (for review, see Maelicke, 2000;Albuquerque et al, 2001). Several PAMs have been identified that increase the potency and/or maximal efficacy of agonists for the ␣7 nAChR; however, none of these agents has been shown to modify neuronal or circuit level activity in vivo (Krause et al, 1998;Zwart et al, 2002;Chimienti et al, 2003;Conroy et al, 2003;Zbarsky et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Hurst¹,

Hajós²,

Raggenbass³

et al. 2005

J. Neurosci.

422

473

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Several lines of evidence suggest a link between the ␣7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the ␣7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human ␣7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by ␣4␤2, ␣3␤4, and ␣9␣10 nAChRs. PNU-120596 increased the channel mean open time of ␣7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of ␣7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances ␣7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.

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“…Acetylcholine, the major endogenous cholinergic neurotransmitter, modulates neuronal activity through agonist effects on muscarinic and nicotinic receptors. Reduced expression of nicotinic acetylcholine receptors has been associated with reduced performance in attention, learning and memory tasks in animals and normal humans and appears to be one of the markers of the pathogenesis of Alzheimer's disease (AD) (Albuquerque et al, 2001;Gattu et al, 1997). Degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contribute significantly to the deterioration in cognitive function seen in patients with AD ('cholinergic hypothesis of AD') (Bartus et al, 1982;Francis et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…There are two common pharmacologic mechanisms used to increase activation of cholinergic receptors: (1) directly through administration of cholinergic agonists such as nicotine, and (2) indirectly through administration of acetylcholinesterase inhibitors (AChEIs), such as donepezil. AChEIs inhibit the breakdown of the major endogenous cholinergic agonist acetylcholine, and therefore increase the amount of acetylcholine in the synaptic cleft to bind to muscarinic and nicotinic receptors, which enhances neuronal transmission (Albuquerque et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

Psychoactive Drugs and Pilot Performance: A Comparison of Nicotine, Donepezil, and Alcohol Effects

Mumenthaler

Yesavage

Taylor

et al. 2003

Neuropsychopharmacol

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The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine) ¼ 0.80; ES (donepezil) ¼ 1.02; ES (alcohol acute) ¼ À3.66; ES (alcohol 8 h) ¼ À0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.

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Modulation of Nicotinic Receptor Activity in the Central Nervous System

Cited by 66 publications

References 46 publications

Galantamine Alleviates Inflammation and Other Obesity-Associated Complications in High-Fat Diet-Fed Mice

Galantamine Alleviates Inflammation and Other Obesity-Associated Complications in High-Fat Diet-Fed Mice

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Psychoactive Drugs and Pilot Performance: A Comparison of Nicotine, Donepezil, and Alcohol Effects

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