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Psychopharmacology Sep 2022The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working...
RATIONALE
The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working memory (WM), the underlying mechanism remains unclear. It is widely accepted that WM consists of multiple functional modules, one storing short-term memory and the other manipulating and utilizing it. A recently developed visual search task and a relevant model can be used to assess multiple components of WM during administration of acetylcholine receptor (AChR)-related substances.
OBJECTIVES
The effects of systemic administration of AChR-related agents on WM and eye movements were examined during the oculomotor foraging task.
METHODS
Three monkeys performing the task received an intramuscular injection of saline or the following AChR-related agents: nicotine (24 or 56 μg/kg), mecamylamine (nicotinic AChR antagonist, 1.0 mg/kg), oxotremorine (muscarinic AChR agonist, 3.0 µg/kg), and scopolamine (muscarinic AChR antagonist, 20 μg/kg). The task was to find a target among 15 identical objects by making eye movements within 6 s. The data were analyzed according to the foraging model that incorporated three parameters.
RESULTS
Nicotine and mecamylamine significantly increased the utility but not the capacity of short-term memory, while muscarinic AChR-related agents did not alter any WM parameters. Further regression analyses with a mixed-effect model showed that the beneficial effect of nicotine on memory utility remained after considering eye movement variability, but the beneficial effect of mecamylamine disappeared.
CONCLUSIONS
Nicotine improves visual search, mainly by increasing the utility of short-term memory, with minimal changes in oculomotor parameters.
Topics: Animals; Haplorhini; Macaca; Mecamylamine; Memory, Short-Term; Muscarinic Antagonists; Nicotine; Nicotinic Antagonists; Receptors, Muscarinic
PubMed: 35802143
DOI: 10.1007/s00213-022-06186-6 -
Cells May 2022Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by intestinal dysmotility. Changes in intestinal microbiota (dysbiosis) can lead to...
Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by intestinal dysmotility. Changes in intestinal microbiota (dysbiosis) can lead to alterations in neuro-muscular functions in the gut. Toll-like receptors (TLRs) 2 and 4 recognize intestinal bacteria and are involved in the motor response induced by gastrointestinal (GI) neurotransmitters. Acetylcholine (ACh) is a well-known neurotransmitter involved in the regulation of GI motility. This study aimed to evaluate the role of TLR2 and TLR4 in the intestinal motor-response induced by ACh in the mouse ileum, as well as the expression and function of the muscarinic and nicotinic ACh receptors. Muscle contractility studies showed that the contractions induced by ACh were significantly lower in TLR2 and TLR4 with respect to WT mice. In WT mice, the contractions induced by ACh were reduced in the presence of AF-DX AF-DX 116 (a muscarinic ACh receptor (mAChR) M2 antagonist), 4-DAMP (a mAChR M3 antagonist), mecamylamine (a nicotinic AChR receptor (nAChR) α3β4 antagonist) and α-bungarotoxin (a nAChR α7 antagonist). In TLR2 mice, the contractions induced by ACh were increased by AF-DX 116 and mecamylamine. In TLR4 mice, the contractions induced by ACh were reduced by α-bungarotoxin and 4-DAMP. The mRNA and protein expressions of M3 and α3 receptors were diminished in the ileum from TLR2 and TLR4 with respect to WT mice. However, the levels of mRNA and protein of β4 were diminished only in TLR4 but not in TLR2 mice. In conclusion, our results show that TLR2 and TLR4 modulates the motor responses to ACh in the mouse ileum. TLR2 acts on muscarinic M2 and M3 and nicotinic α3β4 ACh receptors, while TLR4 acts on muscarinic M3 and nicotinic α3β4 and α7 ACh receptors.
Topics: Acetylcholine; Animals; Bungarotoxins; Cholinergic Agents; Gastrointestinal Motility; Ileum; Mecamylamine; Mice; Muscarinic Antagonists; RNA, Messenger; Receptors, Muscarinic; Receptors, Nicotinic; Toll-Like Receptor 2; Toll-Like Receptor 4
PubMed: 35681486
DOI: 10.3390/cells11111791 -
ELife May 2022Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process...
Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.
Topics: Animals; Cholinergic Agents; Corpus Striatum; Interneurons; Mice; Neurons; Nicotine; gamma-Aminobutyric Acid
PubMed: 35579422
DOI: 10.7554/eLife.75829 -
Neuropsychopharmacology Reports Jun 2022Cessation of smoking induces nicotine withdrawal symptoms such as anxiety, depression, and dysphoria, which could lead to smoking relapse. In the present study, we...
AIM
Cessation of smoking induces nicotine withdrawal symptoms such as anxiety, depression, and dysphoria, which could lead to smoking relapse. In the present study, we examined the role of noradrenergic transmission within the ventral bed nucleus of the stria terminalis (vBNST) on nicotine withdrawal-induced aversive behavior.
METHODS
Nicotine dependence in rats was established by subcutaneous implantation with a nicotine-filled osmotic minipump on day 1. Nicotine withdrawal was precipitated by administration of the nicotine receptor antagonist, mecamylamine (3.0 mg/kg, s.c.), on day 15. Nicotine withdrawal-induced intra-vBNST noradrenaline release and aversive behavior were examined by in vivo microdialysis and a conditioned place aversion (CPA) test, respectively.
RESULTS
Intra-vBNST noradrenaline release was significantly increased during nicotine withdrawal. Nicotine withdrawal induced aversive behavior, which was attenuated by intra-vBNST injection of the β-adrenoceptor antagonist, timolol.
CONCLUSIONS
These results suggest that enhanced noradrenergic transmission via β-adrenoceptors in the vBNST plays a crucial role in nicotine withdrawal-induced aversive behavior.
Topics: Animals; Nicotine; Norepinephrine; Rats; Rats, Sprague-Dawley; Septal Nuclei; Substance Withdrawal Syndrome
PubMed: 35437943
DOI: 10.1002/npr2.12252 -
Frontiers in Cellular Neuroscience 2022Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which...
Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and CF3-N,N-diethyl-'-phenyl-piperazine (CF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by CF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures CF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1β. The ATP-mediated release of IL-1β by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of CF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements CF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, CF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and CF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. CF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1β. Compared to phosphocholine, CF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of CF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.
PubMed: 35431807
DOI: 10.3389/fncel.2022.779081 -
Human Psychopharmacology Sep 2022Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens....
OBJECTIVE
Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints.
METHODS
Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC).
RESULTS
Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment.
CONCLUSIONS
The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.
Topics: Aged; Cholinergic Agents; Cholinergic Antagonists; Cognition; Estradiol; Estrogens; Female; Humans; Postmenopause; Scopolamine; Self Report
PubMed: 35212023
DOI: 10.1002/hup.2838 -
BMC Complementary Medicine and Therapies Jan 2022Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to...
BACKGROUND
Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to evaluate the efficacy of immature Rubus occidentalis extract(iROE) on acid-induced hyperalgesia, investigate the mechanism involved, and compare the antihyperalgesic effect of immature and mature ROEs.
METHODS
In adult male Sprague-Dawley rats, chronic muscle pain was induced via two injections of acidic saline into one gastrocnemius muscle. To evaluate the dose response, the rats were injected intraperitoneally with 0.9% saline or iROE (10, 30, 100, or 300 mg/kg) following hyperalgesia development. To evaluate the mechanism underlying iROE-induced analgesia, the rats were injected intraperitoneally with saline, yohimbine 2 mg/kg, dexmedetomidine 50 μg/kg, prazosin 1 mg/kg, atropine 5 mg/kg, mecamylamine 1 mg/kg, or naloxone 5 mg/kg 24 h after hyperalgesia development, followed by iROE 300 mg/kg administration. To compare immature versus mature ROE, the rats were injected with mature ROE 300 mg/kg and immature ROE 300 mg/kg after hyperalgesia development. For all experiments, the mechanical withdrawal threshold(MWT) was evaluated using von Frey filaments before the first acidic saline injection, 24 h after the second injection, and at various time points after drug administration. Data were analysed using multivariate analysis of variance(MANOVA) and the linear mixed-effects model(LMEM). We compared the MWT at each time point using analysis of variance with the Bonferroni correction.
RESULTS
The iROE 300 mg/kg injection resulted in a significant increase in MWT compared with the control, iROE 30 mg/kg, and iROE 100 mg/kg injections at ipsilateral and contralateral sites. The iROE injection together with yohimbine, mecamylamine, or naloxone significantly decreased the MWT compared with iROE alone, whereas ROE together with dexmedetomidine significantly increased the MWT. According to MANOVA, the effects of immature and mature ROEs were not significantly different; however, the LMEM presented a significant difference between the two groups.
CONCLUSIONS
Immature R. occidentalis showed antihyperalgesic activity against acid-induced chronic muscle pain, which may be mediated by the α-adrenergic, nicotinic cholinergic, and opioid receptors. The iROE displayed superior tendency regarding analgesic effect compared to mature ROE.
Topics: Animals; Behavior, Animal; Hyperalgesia; Male; Musculoskeletal Pain; Phytotherapy; Plant Preparations; Plant Senescence; Rats; Rats, Sprague-Dawley; Rubus; Saline Solution
PubMed: 35016667
DOI: 10.1186/s12906-021-03491-z -
Neuroscience Letters Jan 2022Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock...
Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 μg) and IT phentolamine hydrochloride (10 μg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 μg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 μg), ondansetron (10 μg), mecamylamine (50 μg), antalarmin (24 μg), aSVG30 (12 μg), and SSR149415 (50 μg).
Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Stress, Physiological; Urinary Bladder
PubMed: 34929317
DOI: 10.1016/j.neulet.2021.136401 -
Frontiers in Molecular Biosciences 2021The cholinergic anti-inflammatory pathway plays an important role in controlling inflammation. This study investigated the effects of varenicline, an α7 nicotinic...
The cholinergic anti-inflammatory pathway plays an important role in controlling inflammation. This study investigated the effects of varenicline, an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on inflammatory cytokine levels, cell proliferation, and migration rates in a lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 murine macrophage cell lines. The cells were treated with increasing concentrations of varenicline, followed by LPS incubation for 24 h. Prior to receptor-mediated events, anti-inflammatory effects of varenicline on different cytokines and chemokines were investigated using a cytokine array. Nicotinic AChR-mediated effects of varenicline were investigated by using a non-selective nAChR antagonist mecamylamine hydrochloride and a selective α7nAChR antagonist methyllycaconitine citrate. TNFα, IL-1β, and IL-6 levels were determined by the ELISA test in cell media 24 h after LPS administration and compared with those of dexamethasone. The rates of cellular proliferation and migration were monitored for 24 h after drug treatment using a real-time cell analysis system. Varenicline decreased LPS-induced cytokines and chemokines including TNFα, IL-6, and IL-1β via α7nAChRs to a similar level that observed with dexamethasone. Varenicline treatment decreased LPS-induced cell proliferation, without any nAChR involvement. On the other hand, the LPS-induced cell migration rate decreased with varenicline via α7nAChR. Our data suggest that varenicline inhibits LPS-induced inflammatory response by activating α7nAChRs within the cholinergic anti-inflammatory pathway, reducing the cytokine levels and cell migration.
PubMed: 34712695
DOI: 10.3389/fmolb.2021.721533 -
International Journal of Molecular... Oct 2021A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants....
A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated.
Topics: Animals; Antioxidants; Cell Membrane Permeability; Gastrointestinal Motility; Intestinal Mucosa; Jejunal Diseases; Jejunum; Male; Melatonin; Rats; Rats, Wistar; Receptors, Melatonin; Receptors, Nicotinic; Surface-Active Agents
PubMed: 34639101
DOI: 10.3390/ijms221910762