Pharmacological consequences of cholinergic plus serotonergic manipulations

Riekkinen, Paavo; Sirviö, Jouni; Valjakka, Antti; Miettinen, Reijo

doi:10.1016/0006-8993(91)90654-e

Cited by 69 publications

(14 citation statements)

References 21 publications

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“…A variety of studies involving anatomic or pharmacologic lesions of serotonin (5-HT) neurons have shown effects suggesting interactions with ACh functioning (Riekkinen et al 1991). Other work has shown that the selective 5-HT 3 antagonist ondansetron stimulates release of cortical ACh and can enhance cognitive performance in rodents (Carey et al 1992) and primates (Barnes 1990).…”

Section: Serotoninmentioning

confidence: 97%

Nicotinic acetylcholine involvement in cognitive function in animals

Levin¹,

Simon²

1998

Psychopharmacology

646

388

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Nicotinic cholinergic systems are involved with several important aspects of cognitive function including attention, learning and memory. Nicotinic cholinergic receptors are located in many regions of the brain, including areas important for cognitive function such as the hippocampus and frontal cortex. Nicotinic agonists have been found in rodent and non-human primate studies to improve performance on a variety of memory tasks. In a complementary fashion, nicotinic antagonists such as mecamylamine impair working memory function. In humans, similar effects have been seen. Nicotinic agonist treatment can improve attention, learning and memory and nicotinic antagonist treatment can cause deficits. To define the neural substrates of nicotinic involvement in cognitive function, three areas of investigation are underway. 1) Critical neuroanatomic loci for nicotinic effects are beginning to be determined. The hippocampus, frontal cortex and midbrain dopaminergic nuclei have been found to be important sites of action for nicotinic involvement in memory function. 2) Nicotinic receptor subtype involvement in cognitive function is being studied. There has been considerable recent work identifying nicotinic receptor subunit conformation including alpha and beta subunits. Nicotinic receptor subtypes appear to be associated with different functional systems; however, much remains to be done to determine the precise role each subtype plays in terms of cognitive function. 3) Nicotinic interactions with other transmitter systems are being assessed. Nicotine receptors interact in important ways with other systems to affect cognitive functioning, including muscarinic ACh, dopamine, norepinepherine, serotonin, glutamate, and other systems. Nicotinic function in clinical populations and potential for therapeutics has been investigated for Alzheimer's disease, Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder. Areas which need to receive greater attention are the exact anatomical location and the specific receptor subtypes critically involved in nicotine's effects. In addition, more work needs to be done to develop and determine the efficacy and safety of novel nicotinic ligands for use in the long-term treatment of human cognitive disorders.

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Section: Serotoninmentioning

confidence: 97%

Nicotinic acetylcholine involvement in cognitive function in animals

Levin¹,

Simon²

1998

Psychopharmacology

646

388

View full text Add to dashboard Cite

show abstract

“…The important therapeutic implications of cholinergic-5-HT interactions in learning and memory have been reviewed (Cassel and Jeltsch 1995). Interestingly, 5-HT appears to participate in the modulation of activity of septal efferents to the hippocampal formation Riekkinen et al 1991;Milner and Veznedaroglu 1993), which are of considerable importance to mnemonic processes and AD neuropathology. This evidence combined with the documented serotonergic loss in AD (Yamamoto andHirano 1985: Zweig et al 1988) may indeed indicate that ligands at 5-HT receptors have the potential to improve neuronal function (and the cognitive decline) of AD.…”

Section: Introductionmentioning

confidence: 99%

Enhanced delayed matching performance in younger and older macaques administered the 5-HT 4 receptor agonist, RS 17017

et al. 1998

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Recent evidence indicates that the 5-HT4 subtype of serotonin receptor may modulate central cholinergic activity in regions of the mammalian CNS important to memory such as the frontal cortex, hippocampus and amygdala. These receptors could represent targets for drugs designed for the symptomatic therapy of Alzheimer's disease (AD) and other disorders of memory. In the present study, the binding activity of RS 17017 (previously described as a selective 5-HT4 agonist) was assessed across a number of neurotransmitter receptors and binding sites, pharmacokinetic data were obtained, and the compound was evaluated in macaques for mnemonic effects via a computer-assisted delayed matching-to-sample task (DMTS). Binding data confirmed the 5-HT4 selectivity of the compound, while pharmacokinetic results revealed low oral bioavailability, but a large volume of distribution of the compound. Significant and reproducible improvements in DMTS accuracy were observed after oral administration of the compound across a dose-effect series in both younger and older monkeys. The results suggest that RS 17017 offers a potential for memory enhancement in disorders involving cognitive decline, and are consistent with a role for central 5-HT4 receptors in memory. Improvements in DMTS performance in aged monkeys may have particular implications for neurodegenerative conditions such as AD, whereas positive results in the younger monkeys indicate that RS 17017 (or similar compounds) may have additional potential in the therapeutics of memory disorders not necessarily associated with advanced age.

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“…For example, a reduction of brain serotonin concentrations by injection of 5,7-dihydroxytryptamine (5,7-DHT) into the median raphe nucleus (Riekkinen Jr et al 1991) or after systemic administration of p-chloroamphetamine (pCA) or p-chlorophenylalanine (pCPA) (Riekkinen and Riekkinen Jr 1995) aggravated the acquisition deficit of water maze task induced by scopolamine. These acetylcholine-serotonin interactions may be of clinical importance, since cholinergic as well as serotonergic neurons are damaged in Alzheimer's disease (Reinikainen et al 1988(Reinikainen et al , 1990Cross 1990).…”

Section: Introductionmentioning

confidence: 99%

Blockade of muscarinic, rather than nicotinic, receptors impairs attention, but does not interact with serotonin depletion

et al. 2000

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5-HT system is not essential for the modulation of attention, but it is important in the modulation of response control. Central muscarinic receptors are important in the modulation of attention, whereas central nicotinic receptors may be more essential in response control. The results do not support there being an interaction between the serotonergic and the cholinergic systems in the modulation of attention.

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Pharmacological consequences of cholinergic plus serotonergic manipulations

Cited by 69 publications

References 21 publications

Nicotinic acetylcholine involvement in cognitive function in animals

Nicotinic acetylcholine involvement in cognitive function in animals

Enhanced delayed matching performance in younger and older macaques administered the 5-HT 4 receptor agonist, RS 17017

Blockade of muscarinic, rather than nicotinic, receptors impairs attention, but does not interact with serotonin depletion

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