Pathophysiology of nAChRs: Limbic circuits and related disorders

Mineur, Yann S.; Soares, Alexa R.; Etherington, Ian M.; Abdulla, Zuhair I.; Picciotto, Marina

doi:10.1016/j.phrs.2023.106745

Cited by 14 publications

(7 citation statements)

References 166 publications

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“…These findings suggest that some aspects of the inflammatory reflex do not involve an M1-mediated ACh pathway. Perhaps other muscarinic or nicotinic isoforms contribute (Yeomans 2012 ; Wills and Kenny 2021 ; Mineur et al 2023 ; Fontana et al 2023 ). Alternatively, the CLP-induced difference in IL-6 may be mediated by a non-cholinergic neural pathway.…”

Section: Discussionmentioning

confidence: 99%

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Abraham,

Nedeljkovic-Kurepa,

Fernandes

et al. 2024

Mol Med

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Background The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. Results At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILβ+ neutrophils and ILβ+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline—treated and untreated post-CLP mice. Conclusion Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.

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Section: Discussionmentioning

confidence: 99%

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Abraham,

Nedeljkovic-Kurepa,

Fernandes

et al. 2024

Mol Med

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“…Understanding the scope of expression of nicotinic acetylcholine receptors (nAChRs) within hippocampal interneurons would lend great insight for cognitive therapies used in Alzheimer’s Disease [ 1 , 2 ], Attention-Deficit Hyperactivity Disorder [ 3 ], Autism Spectrum Disorder [ 4 ], and Post-Traumatic Stress Disorder [ 5 ]. The GABAergic interneurons are controlled by nAChRs found on their dendrites, soma, and on the axon terminals [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Single-cell quantitative expression of nicotinic acetylcholine receptor mRNA in rat hippocampal interneurons

Jackson,

Burgon,

Thompson

et al. 2024

PLoS ONE

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Hippocampal interneurons are a very diverse population of cells. Using single-cell quantitative PCR to analyze rat CA1 hippocampal interneurons, we quantified neuronal nicotinic acetylcholine receptor (nAChR) mRNA subunit expression and detailed possible nAChR subtype combinations for the α2, α3, α4, α5, α7, β2, β3, and β4 subunits. We also compared the expression detected in the stratum oriens and the stratum radiatum hippocampal layers. We show that the majority of interneurons in the CA1 of the rat hippocampus contain detectable levels of nAChR subunit mRNA. Our results highlight the complexity of the CA1 nAChR population. Interestingly, the α3 nAChR subunit is one of the highest expressed subunit mRNAs in this population, while the α4 is one of the least likely subunits to be detected in CA1 interneurons. The β2 nAChR subunit is the highest expressed beta subunit mRNA in these cells. In addition, Pearson’s correlation coefficient values are calculated to identify significant differences between the nAChR subunit combinations expressed in the CA1 stratum oriens and the stratum radiatum. Statistical analysis also indicates that there are likely over 100 different nAChR subunit mRNA combinations expressed in rat CA1 interneurons. These results provide a valid avenue for identifying nAChR subtype targets that may be effective hippocampus-specific pharmacological targets.

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“…Anxiety is associated with different mechanisms, and one of them is that of nicotinic acetylcholine receptors (nAChRs) which are pentameric ion channels, and they can be heteromeric or homomeric subtypes depending on their subunit composition (α2–α10 and β2–β4) and stoichiometry [ 6 ]. The nAChRs family plays an important role in regulating emotional behaviors [ 7 ], and some evidence has shown that nAChRs are involved in anxiety, depression and nicotine addiction [ 6 ]. The α4β2 subtypes, which are the major nAChRs present in the central nervous system (CNS) [ 6 , 7 ] have been proposed as the principal subtypes involved in anxiety and nicotine addiction; however, another nAChR subtype could contribute to these disorders.…”

Section: Introductionmentioning

confidence: 99%

“…The nAChRs family plays an important role in regulating emotional behaviors [ 7 ], and some evidence has shown that nAChRs are involved in anxiety, depression and nicotine addiction [ 6 ]. The α4β2 subtypes, which are the major nAChRs present in the central nervous system (CNS) [ 6 , 7 ] have been proposed as the principal subtypes involved in anxiety and nicotine addiction; however, another nAChR subtype could contribute to these disorders. The nAChR subtypes have been studied in different animal models such as non-human primates, cats, frogs, rats, mice, and zebrafish, associated with different behaviors such as memory loss and drug abuse, among others, and play a key role in the anxiolytic activity of nicotine [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Behavioral Study of 3- and 5-Halocytisine Derivatives in Zebrafish Using the Novel Tank Diving Test (NTT)

Farías-Cea,

Leal,

Hödar-Salazar

et al. 2023

IJMS

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Anxiety is a serious mental disorder, and recent statistics have determined that 35.12% of the global population had an anxiety disorder during the COVID-19 pandemic. A mechanism associated with anxiolytic effects is related to nicotinic acetylcholine receptor (nAChR) agonists, principally acting on the α4β2 nAChR subtype. nAChRs are present in different animal models, including murine and teleosteos ones. Zebrafish has become an ideal animal model due to its high human genetic similarities (70%), giving it high versatility in different areas of study, among them in behavioral studies related to anxiety. The novel tank diving test (NTT) is one of the many paradigms used for studies on new drugs related to their anxiolytic effect. In this work, an adult zebrafish was used to determine the behavioral effects of 3- and 5-halocytisine derivatives, using the NTT at different doses. Our results show that substitution at position 3 by chlorine or bromine decreases the time spent by the fish at the bottom compared to the control. However, the 3-chloro derivative at higher doses increases the bottom dwelling time. In contrast, substitution at the 5 position increases bottom dwelling at all concentrations showing no anxiolytic effects in this model. Unexpected results were observed with the 5-chlorocytisine derivative, which at a concentration of 10 mg/L produced a significant decrease in bottom dwelling and showed high times of freezing. In conclusion, the 3-chloro and 3-bromo derivatives show an anxiolytic effect, the 3-chlorocytisine derivative being more potent than the 3-bromo derivative, with the lowest time at the bottom of the tank at 1mg/L. On the other hand, chlorine, and bromine at position 5 produce an opposite effect.

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Pathophysiology of nAChRs: Limbic circuits and related disorders

Cited by 14 publications

References 166 publications

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture

Single-cell quantitative expression of nicotinic acetylcholine receptor mRNA in rat hippocampal interneurons

Behavioral Study of 3- and 5-Halocytisine Derivatives in Zebrafish Using the Novel Tank Diving Test (NTT)

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