-
Journal of the Experimental Analysis of... May 2022Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be... (Review)
Review
Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be described by two primary components, termed directional and activational motivation, both of which can be examined and dissociated using effort-choice tasks. The directional component refers to motivated behavior directed towards reinforcing stimuli and away from aversive stimuli. Behaviors characterized by increased vigor, persistence, and work output are considered to reflect activational components of motivation. Disruption of DA signaling has been shown to decrease activational components of motivation, while leaving directional features intact. Facilitation of DA release promotes the activational aspects of motivated behavior. In this review, we discuss cholinergic and DA regulation of motivated behaviors. We place emphasis on effort-choice processes and the ability of effort-choice tasks to examine and dissociate changes of motivated behavior in the context of substance use and mood disorders. Furthermore, we consider how altered cholinergic transmission impacts motivated behavior across disease states, and the possible role of cholinergic dysregulation in the etiology of these illnesses. Finally, we suggest that treatments targeting cholinergic activity may be useful in ameliorating motivational disruptions associated with substance use and comorbid substance use and mood disorders.
Topics: Cholinergic Agents; Dopamine; Humans; Mood Disorders; Motivation; Nucleus Accumbens; Substance-Related Disorders
PubMed: 35286712
DOI: 10.1002/jeab.747 -
Arthritis Research & Therapy Mar 2015The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally... (Review)
Review
The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
Topics: Animals; Arthritis, Rheumatoid; Autonomic Pathways; Cholinergic Agents; Cholinergic Fibers; Cholinergic Neurons; Disease Progression; Female; Humans; Immune System; Inflammation; Male; Mice; Receptors, Cholinergic; Sensitivity and Specificity
PubMed: 25889979
DOI: 10.1186/s13075-015-0597-2 -
Tijdschrift Voor Psychiatrie 2023Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation... (Review)
Review
BACKGROUND
Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation of these receptors can offer new treatment options.
AIM
To provide an overview of current research on the role of cholinergic M and M receptors in the development and treatment of psychoses, with special attention to the development of new drugs such as xanomeline and emraclidine.
METHOD
To obtain an overview, we searched for English-language studies published in PubMed, Embase, and PsycInfo up until June 1, 2023. We examined the role and effects of M and/or M agonists in schizophrenia. Additionally, we consulted clinical trial registers.
RESULTS
Our search strategy resulted in nine published articles on five clinical studies. These studies revealed that reduced presence of M receptors, primarily in the frontal cortex, and M receptors, primarily in the basal ganglia, are associated with psychoses. M and M receptors modulate dopaminergic activity in the ventral tegmentum and striatum through various pathways. Several M and/or M agonists, partial agonists, and positive allosteric modulators (PAMs) have been developed. Drugs exhibiting agonistic activity on M and/or M receptors, such as xanomeline-trospium (phase 2 and 3 studies) and emraclidine (phase 1b studies), have shown positive effects on cognitive and potentially negative symptoms in patients with schizophrenia.
CONCLUSION
M and/or M receptor agonists show potential as new treatment strategies for individuals with psychotic disorders. Although initial studies with xanomeline-trospium and emraclidine have shown positive results, further research is needed to assess their long-term efficacy, safety, and tolerability before these new medications can be evaluated.
Topics: Humans; Muscarinic Agonists; Psychotic Disorders; Receptor, Muscarinic M1; Receptor, Muscarinic M4
PubMed: 37947466
DOI: No ID Found -
Brain : a Journal of Neurology Jun 2022This scientific commentary refers to ‘Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke’ by O’Sullivan...
This scientific commentary refers to ‘Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke’ by O’Sullivan (https://doi.org/10.1093/brain/awac070).
Topics: Cholinergic Agents; Cognition; Hippocampus; Humans; Stroke
PubMed: 35438715
DOI: 10.1093/brain/awac142 -
Progress in Retinal and Eye Research Sep 2019The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye... (Review)
Review
The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.
Topics: Acetylcholine; Choline; Cholinergic Agents; Cytidine Diphosphate Choline; Glaucoma; Humans; Neuroprotective Agents; Retinal Ganglion Cells; Signal Transduction; Visual Cortex
PubMed: 31242454
DOI: 10.1016/j.preteyeres.2019.06.003 -
Neuroscience Sep 2018In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups... (Review)
Review
In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups of cholinergic projection neurons and interneurons distributed across the central nervous system. It has been more than forty years since it was discovered that cholinergic transmission profoundly modifies the perception of pain. Directly activating cholinergic receptors or extending the action of endogenous acetylcholine via pharmacological blockade of acetylcholine esterase reduces pain in rodents as well as humans; conversely, inhibition of muscarinic cholinergic receptors induces nociceptive hypersensitivity. Here, we aim to review the considerable progress in our understanding of peripheral, spinal and brain contributions to cholinergic modulation of pain. We discuss the distribution of cholinergic neurons, muscarinic and nicotinic receptors over the central nervous system and the synaptic and circuit-level modulation by cholinergic signaling. AchRs profoundly regulate nociceptive transmission at the level of the spinal cord via pre- as well as postsynaptic mechanisms. Moreover, we attempt to provide an overview of how some of the salient regions in the pain network spanning the brain, such as the primary somatosensory cortex, insular cortex, anterior cingulate cortex, the medial prefrontal cortex and descending modulatory systems are influenced by cholinergic modulation. Finally, we critically discuss the clinical relevance of cholinergic signaling to pain therapy. Cholinergic mechanisms contribute to several both conventional as well as unorthodox forms of pain treatments, and reciprocal interactions between cholinergic and opioidergic modulation impact on the function and efficacy of both opioids and cholinomimetic drugs.
Topics: Animals; Autonomic Nervous System; Central Nervous System; Cholinergic Agents; Cholinergic Neurons; Humans; Pain
PubMed: 28890048
DOI: 10.1016/j.neuroscience.2017.08.049 -
Respiratory Medicine May 2016Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing... (Comparative Study)
Comparative Study Review
BACKGROUND
Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.
METHODS
As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies.
RESULTS
Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting β2-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting β2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler(®) 18 μg/Respimat(®) 5 μg).
CONCLUSIONS
The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments.
Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Tiotropium Bromide
PubMed: 27109805
DOI: 10.1016/j.rmed.2016.02.012 -
International Journal of Molecular... Feb 2024Commercially available 2-deoxy-D-ribose was used to synthesize the appropriate oxolane derivative-(2,3)-2-(hydroxymethyl)oxolan-3-ol-by reduction and...
Commercially available 2-deoxy-D-ribose was used to synthesize the appropriate oxolane derivative-(2,3)-2-(hydroxymethyl)oxolan-3-ol-by reduction and dehydration/cyclization in an acidic aqueous solution. Its monotosyl derivative, as a result of the quaternization reaction, allowed us to obtain eight new muscarine-type derivatives containing a quaternary nitrogen atom and a hydroxyl group linked to the oxolane ring. Their structure was fully confirmed by the results of NMR, MS and IR analyses. The crystal structure of the pyridinium derivative showed a high similarity of the conformation of the oxolane ring to previously published crystal structures of muscarine. Two reference strains of Gram-negative bacteria ( ATCC 25922 and ATCC 27853), two reference strains of Gram-positive staphylococci ( ATCC 25923 and ATCC 29213) and four reference strains of pathogenic yeasts of the genus spp. ( SC5314, DSM 11226, DSM 6128 and DSM 5784) were selected for the evaluation of the antimicrobial potential of the synthesized compounds. The derivative containing the longest (decyl) chain attached to the quaternary nitrogen atom turned out to be the most active.
Topics: Muscarine; Salts; Microbial Sensitivity Tests; Nitrogen; Ammonium Compounds; Anti-Bacterial Agents
PubMed: 38397044
DOI: 10.3390/ijms25042368 -
Journal of Neurochemistry Sep 2021Cholinergic signaling is crucial in cognitive processes, and degenerating cholinergic projections are a pathological hallmark in dementia. Use of cholinesterase... (Review)
Review
Cholinergic signaling is crucial in cognitive processes, and degenerating cholinergic projections are a pathological hallmark in dementia. Use of cholinesterase inhibitors is currently the main treatment option to alleviate symptoms of Alzheimer's disease and has been postulated as a therapeutic strategy in acute brain damage (stroke and traumatic brain injury). However, the benefits of this treatment are still not clear. Importantly, cholinergic receptors are expressed both by neurons and by astrocytes and microglia, and binding of acetylcholine to the α7 nicotinic receptor in glial cells results in anti-inflammatory response. Similarly, the brain fine-tunes the peripheral immune response over the cholinergic anti-inflammatory axis. All of these processes are of importance for the outcome of acute and chronic neurological disease. Here, we summarize the main findings about the role of cholinergic signaling in brain disorders and provide insights into the complexity of molecular regulators of cholinergic responses, such as microRNAs and transfer RNA fragments, both of which may fine-tune the orchestra of cholinergic mRNAs. The available data suggest that these small noncoding RNA regulators may include promising biomarkers for predicting disease course and assessing treatment responses and might also serve as drug targets to attenuate signaling cascades during overwhelming inflammation and to ameliorate regenerative capacities of neuroinflammation.
Topics: Acetylcholine; Animals; Central Nervous System Diseases; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Humans; RNA; Signal Transduction
PubMed: 33638173
DOI: 10.1111/jnc.15332 -
Hearing Research Mar 2021Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in... (Review)
Review
Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in complex acoustic settings and negatively impacts the ability to accurately analyze the auditory scene. This is in part due to an inability to focus auditory attention on a particular stimulus source while simultaneously filtering out other sound stimuli. The present review examines the impact of aging on two neurotransmitter systems involved in accurate temporal processing and auditory gating in auditory thalamus (medial geniculate body; MGB), a critical brain region involved in the coding and filtering of auditory information. The inhibitory neurotransmitter GABA and its synaptic receptors (GABARs) are key to maintaining accurate temporal coding of complex sounds, such as speech, throughout the central auditory system. In the MGB, synaptic and extrasynaptic GABARs mediate fast phasic and slow tonic inhibition respectively, which in turn regulate MGB neuron excitability, firing modes, and engage thalamocortical oscillations that shape coding and gating of acoustic content. Acoustic coding properties of MGB neurons are further modulated through activation of tegmental cholinergic afferents that project to MGB to potentially modulate attention and help to disambiguate difficult to understand or novel sounds. Acetylcholine is released onto MGB neurons and presynaptic terminals in MGB activating neuronal nicotinic and muscarinic acetylcholine receptors (nAChRs, mAChRs) at a subset of MGB afferents to optimize top-down and bottom-up information flow. Both GABAergic and cholinergic neurotransmission is significantly altered with aging and this review will detail how age-related changes in these circuits within the MGB may impact coding of acoustic stimuli.
Topics: Acoustic Stimulation; Aged; Aging; Cholinergic Agents; Geniculate Bodies; Humans; Synaptic Transmission; Thalamus; gamma-Aminobutyric Acid
PubMed: 32703637
DOI: 10.1016/j.heares.2020.108003