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Biochemical Pharmacology Oct 2013Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes... (Review)
Review
Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (α7 and α4β2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction.
Topics: Cholinergic Agents; Cognition; Cognition Disorders; Gene Expression Regulation; Humans; Receptors, Nicotinic
PubMed: 23928190
DOI: 10.1016/j.bcp.2013.07.021 -
Biological & Pharmaceutical Bulletin 2022Immune cells such as T and B cells, monocytes and macrophages all express most of the cholinergic components of the nervous system, including acetylcholine (ACh),...
Immune cells such as T and B cells, monocytes and macrophages all express most of the cholinergic components of the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase (AChE). Because of its efficient cleavage by AChE, ACh synthesized and released from immune cells acts only locally in an autocrine and/or paracrine fashion at mAChRs and nAChRs on themselves and other immune cells located in close proximity, leading to modification of immune function. Immune cells generally express all five mAChR subtypes (M-M) and neuron type nAChR subunits α2-α7, α9, α10, β2-β4. The expression pattern and levels of mAChR subtypes and nAChR subunits vary depending on the tissue involved and its immunological status. Immunological activation of T cells via T-cell receptor-mediated pathways and cell adhesion molecules upregulates ChAT expression, which facilitates the synthesis and release of ACh. At present, α7 nAChRs expressed in macrophages are receiving much attention because they play a central role in anti-inflammatory cholinergic pathways. However, it now appears that through modification of cytokine synthesis, G-coupled mAChRs play a prominent role in regulation of T cell proliferation and differentiation and B cell immunoglobulin class switching. It is anticipated that greater understanding of G-coupled mAChRs on immune cells will provide an opportunity to develop new and effective treatments for immunological disorders.
Topics: Acetylcholine; Acetylcholinesterase; Choline O-Acetyltransferase; Cholinergic Agents; Immunity; Receptors, Muscarinic
PubMed: 35650095
DOI: 10.1248/bpb.b21-01005 -
Biochemical Society Transactions Apr 2023Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the... (Review)
Review
Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders. This review reappraises the dopamine-acetylcholine balance hypothesis in light of recent evidence and describes how the Gαi/o coupled muscarinic M4 receptor acts in opposition to dopamine signaling in the basal ganglia. We highlight how M4 signaling can ameliorate or exacerbate movement disorders symptoms and physiological correlates of these symptoms in specific disease states. Furthermore, we propose future directions for investigation of this mechanisms to fully understand the potential efficacy of M4 targeting therapeutics in movement disorders. Overall, initial evidence suggest that M4 is a promising pharmaceutical target to ameliorate motor symptoms of hypo- and hyper-dopaminergic disorders.
Topics: Humans; Acetylcholine; Receptor, Muscarinic M4; Dopamine; Movement Disorders; Cholinergic Agents
PubMed: 37013974
DOI: 10.1042/BST20220525 -
Biochemical Pharmacology Oct 2015The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are... (Review)
Review
The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of "multitarget-directed ligands" (MTDLs), the development and/or identification of compounds that exhibit "multifunctional" activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), "repurposing" strategies for existing compounds that have other clinical indications, and novel "adjunctive" treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, "multifunctional" properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and the low affinity α7 nAChR.
Topics: Cholinergic Agents; Drug Discovery; Ligands; Mental Disorders; Receptors, Nicotinic
PubMed: 26231940
DOI: 10.1016/j.bcp.2015.07.027 -
The Journal of Physiology Jun 2019Persistent inward currents (PICs) in spinal motoneurons are long-lasting, voltage-dependent currents that increase excitability; they are dramatically potentiated by...
KEY POINTS
Persistent inward currents (PICs) in spinal motoneurons are long-lasting, voltage-dependent currents that increase excitability; they are dramatically potentiated by serotonin, muscarine, and noradrenaline (norepinephrine). Loss of these modulators (and the PIC) during sleep is hypothesized as a major contributor to REM sleep atonia. Reduced excitability of XII motoneurons that drive airway muscles and maintain airway patency is causally implicated in obstructive sleep apnoea (OSA), but whether XII motoneurons possess a modulator-sensitive PIC that could be a factor in the reduced airway tone of sleep is unknown. Whole-cell recordings from rat XII motoneurons in brain slices indicate that PIC amplitude increases ∼50% between 1 and 23 days of age, when potentiation of the PIC by 5HT , muscarinic, or α noradrenergic agonists peaks at <50%, manyfold lower than the potentiation observed in spinal motoneurons. α noradrenergic receptor activation produced changes in XII motoneuron firing behaviour consistent with PIC involvement, but indicators of strong PIC activation were never observed; in vivo experiments are needed to determine the role of the modulator-sensitive PIC in sleep-dependent reductions in airway tone.
ABSTRACT
Hypoglossal (XII) motoneurons play a key role in maintaining airway patency; reductions in their excitability during sleep through inhibition and disfacilitation, i.e. loss of excitatory modulation, is implicated in obstructive sleep apnoea. In spinal motoneurons, 5HT , muscarinic and α noradrenergic modulatory systems potentiate persistent inward currents (PICs) severalfold, dramatically increasing excitability. If the PICs in XII and spinal motoneurons are equally sensitive to modulation, loss of the PIC secondary to reduced modulatory tone during sleep could contribute to airway atonia. Modulatory systems also change developmentally. We therefore characterized developmental changes in magnitude of the XII motoneuron PIC and its sensitivity to modulation by comparing, in neonatal (P1-4) and juvenile (P14-23) rat brainstem slices, the PIC elicited by slow voltage ramps in the absence and presence of agonists for 5HT , muscarinic, and α noradrenergic receptors. XII motoneuron PIC amplitude increased developmentally (from -195 ± 12 to -304 ± 19 pA). In neonatal XII motoneurons, the PIC was only potentiated by α receptor activation (5 ± 4%). In contrast, all modulators potentiated the juvenile XII motoneurons PIC (5HT , 5 ± 5%; muscarine, 22 ± 11%; α , 18 ± 5%). These data suggest that the influence of the PIC and its modulation on XII motoneuron excitability will increase with postnatal development. Notably, the modulator-induced potentiation of the PIC in XII motoneurons was dramatically smaller than the 2- to 6-fold potentiation reported for spinal motoneurons. In vivo measurements are required to determine if the modulator-sensitive, XII motoneuron PIC is an important factor in sleep-state dependent reductions in airway tone.
Topics: Aging; Animals; Animals, Newborn; Brain; Female; Male; Motor Neurons; Muscarine; Norepinephrine; Rats, Sprague-Dawley; Serotonin
PubMed: 31038198
DOI: 10.1113/JP277572 -
Psychopharmacology May 2023The M/M preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
The M/M preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders.
OBJECTIVE
Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.
METHODS
Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed.
RESULTS
Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline's PK profile.
CONCLUSIONS
Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.
Topics: Humans; Muscarinic Agonists; Cholinergic Agents; Pyridines; Thiadiazoles; Receptors, Muscarinic
PubMed: 37036495
DOI: 10.1007/s00213-023-06362-2 -
International Journal of Molecular... Dec 2022Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic... (Review)
Review
Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer's disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.
Topics: Neurosteroids; Central Nervous System; Steroids; Hormones; Receptors, Muscarinic; Cholinergic Agents
PubMed: 36613951
DOI: 10.3390/ijms24010507 -
Nutrients Mar 2022A link between obesity and cerebral health is receiving growing recognition. Here, we investigate in the frontal cortex and hippocampus the potential involvement of...
A link between obesity and cerebral health is receiving growing recognition. Here, we investigate in the frontal cortex and hippocampus the potential involvement of cholinergic markers in brain alterations previously reported in rats with obesity induced by diet (DIO) after long-term exposure (17 weeks) to a high-fat diet (HFD) in comparison with animals fed with a standard diet (CHOW). The obesity developed after 5 weeks of HFD. Bodyweight, systolic blood pressure, glycemia, and insulin levels were increased in DIO rats compared to the CHOW group. Measurements of malondialdehyde (MDA) provided lipid peroxidation in HFD-fed rats. Western blot and immunohistochemical techniques were performed. Our results showed a higher expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in obese rats but not the VAChT expression in the frontal cortex after 17 weeks of HFD. Furthermore, the acetylcholinesterase (AChE) enzyme was downregulated in HFD both in the frontal cortex and hippocampus. In the brain regions analyzed, it was reported a modulation of certain cholinergic receptors expressed pre- and post-synaptically (alpha7 nicotinic receptor and muscarinic receptor subtype 1). Collectively, these findings point out precise changes of cholinergic markers that can be targeted to prevent cerebral injuries related to obesity.
Topics: Acetylcholinesterase; Animals; Brain; Cholinergic Agents; Diet, High-Fat; Obesity; Rats
PubMed: 35334899
DOI: 10.3390/nu14061243 -
Alcohol, Clinical & Experimental... Mar 2023Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune...
Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure.
BACKGROUND
Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits.
METHODS
Male and female rats underwent AIE (5.0 g/kg/day ethanol or water, i.g., 2 day-on/2 day-off from postnatal day (PND) 25-54), followed by a 2-week regimen of the anti-inflammatory compound indomethacin (4.0 g/kg/day, PND 56-69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning.
RESULTS
AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high-mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase-2 (COX-2 + IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co-labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE-induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats.
CONCLUSIONS
These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti-inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits.
Topics: Rats; Animals; Male; Female; Ethanol; Indomethacin; Reversal Learning; Hippocampus; Prosencephalon; Cholinergic Neurons; Neurogenesis; Cholinergic Agents; Immunity, Innate; Maze Learning
PubMed: 36799290
DOI: 10.1111/acer.15019 -
Translational Psychiatry Mar 2023Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational... (Review)
Review
Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational attainment and indices of life success in the general population. Previous attempts at drug development for cognitive enhancement have commonly attempted to remedy defects in transmitters systems putatively associated with the conditions of interest such as the glutamate system in schizophrenia. Recent studies of the genomics of cognitive performance have suggested influences that are common in the general population and in different neuropsychiatric conditions. Thus, it seems possible that transmitter systems that are implicated for cognition across neuropsychiatric conditions and the general population would be a viable treatment target. We review the scientific data on cognition and the muscarinic cholinergic receptor system (M1 and M4) across different diagnoses, in aging, and in the general population. We suggest that there is evidence suggesting potential beneficial impacts of stimulation of critical muscarinic receptors for the enhancement of cognition in a broad manner, as well as the treatment of psychotic symptoms. Recent developments make stimulation of the M1 receptor more tolerable, and we identify the potential benefits of M1 and M4 receptor stimulation as a trans-diagnostic treatment model.
Topics: Humans; Receptor, Muscarinic M4; Cognition; Psychotic Disorders; Receptor, Muscarinic M1; Cholinergic Agents
PubMed: 36973270
DOI: 10.1038/s41398-023-02400-x