Modulation Of Nicotinic Acetylcholine Receptors Research Articles

Raman spectroscopy and one-dimensional convolutional neural network modeling as a real-time monitoring tool for in vitro transaminase-catalyzed synthesis of a pharmaceutically relevant amine precursor.

Raman spectroscopy has been used to measure the concentration of a pharmaceutically relevant model amine intermediate for positive allosteric modulators of nicotinic acetylcholine receptor in a ω-transaminase-catalyzed conversion. A model based on a one-dimensional convolutional neural network was developed to translate raw data augmented Raman spectra directly into substrate concentrations, with which the conversion from ketone to amine by ω-transaminase could be determined over time. The model showed very good predictive capabilities, with R2 values higher than 0.99 for the spectra included in the modeling and 0.964 for an independent dataset. However, the model could not extrapolate outside the concentrations specified by the model. The presented work shows the potential of Raman spectroscopy as a real-time monitoring tool for biocatalytic reactions.

Investigating the role of nicotinic acetylcholine receptors in menthol's effects in mice

The use of menthol in tobacco products has been linked to an increased likelihood of developing nicotine dependence. The widespread use of menthol can be attributed to its unique sensory characteristics; however, emerging evidence suggests that menthol also alters sensitivity to nicotine through modulation of nicotinic acetylcholine receptors (nAChRs). Nicotinic subunits, such as β2 and α5, are of interest due to their implications in nicotine reward, reinforcement, intake regulation, and aversion. This study, therefore, examined the in vivo relevance of β2 and α5 nicotinic subunits on the pharmacological and behavioral effects of menthol. Data suggests that the α5 nicotinic subunit modulates menthol intake in mice. Overall, deletion or a reduction in function of the α5 subunit lessened aversion to menthol. α5 KO mice and mice possessing the humanized α5 SNP, a variant that confers a nicotine dependence phenotype in humans, demonstrated increased menthol intake compared to their WT counterparts and in a sex-related fashion for α5 SNP mice. We further reported that the modulatory effects of the α5 subunit do not extend to other aversive tastants like quinine, suggesting that deficits in α5* nAChR signaling may not abolish general sensitivity to the aversive effects of other noxious chemicals. Further probing into the role of α5 in other pharmacological properties of menthol revealed that the α5 subunit does not modulate the antinociceptive properties of menthol in mice and suggests that the in vivo differences observed are likely not due to the direct effects of menthol on α5-containing nAChRs in vitro.

Synthesis of α3β4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3β4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3β4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3β4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3β4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3β4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

Discovery of a Novel Class of Benzimidazole-Based Nicotinic Acetylcholine Receptor Modulators: Positive and Negative Modulation Arising from Overlapping Allosteric Sites.

Here, we present the discovery of a novel class of benzimidazole-based allosteric modulators of nicotinic acetylcholine receptors (nAChRs). The modulators were developed based on a compound (1) exhibiting positive modulatory activity at α4β2 nAChR in a compound library screening by functional characterization of 100 analogues of 1 at nAChRs. Two distinct series of positive and negative allosteric modulators (PAMs and NAMs, respectively) comprising benzimidazole as a shared structural moiety emerged from this SAR study. The PAMs mediated weak modulation of α4β2 and α6β2β3, whereas the NAMs exhibited essentially equipotent inhibition of α4β2, α6β2β3, α6β4β3, and α3β4 nAChRs, with analogue 9j [2-(2,4-dichlorophenoxy)-1,3-dimethyl-1-H-benzo[d]imidazole-3-ium] displaying high-nanomolar and low-micromolar IC50 values at the β2- and β4-containing receptor subtypes, respectively. We propose that the PAMs and NAMs act through overlapping sites in the nAChR, and these findings thus underline the heterogenous modes of modulation that can arise from a shared allosteric site in the receptor.

Neurophysiological action of centrally-acting spider toxin polypeptides derived from Hadronyche versuta and Tegenaria agrestis venoms

Established dogma concerning the action of insecticidal arthropod-derived peptides (e.g., scorpion toxins), was that they acted on the peripheral nervous system and were excluded from the central nervous system (CNS) by barrier systems. Initial evidence for a CNS-directed toxicological effect following parenteral administration was for a novel peptide from the Hobo spider, Tegeneria agrestis. This toxin was inactive on peripheral sensory and motor nerves, but had a potent excitatory effect on the CNS of larval Musca domestica. Recently, a commercialized formulation of GS-omega/kappa-Hxtx-Hv1a (HXTX), derived from the venom of the Australian blue mountain funnel web spider (Hadronyche versuta) was introduced for use in agriculture by Vestaron Corp. Its primary mode of action was found to be central neuroexcitation via positive allosteric modulation of nicotinic acetylcholine receptors (nAchR) of cockroach neurons. In the present study, this peptide showed hyperexcitation followed by a decrease in firing of the Drosophila melanogaster larval CNS that was prevented by co-exposure to 100 nM α-bungarotoxin (α-BGTX), a classical nAchR noncompetitive antagonist. This effect was mirrored in isobologram analysis, which showed clear antagonism between the two toxins when injected into adult houseflies. Interestingly, U1-agatoxin-Ta1b-QA derived from Tegeneria agrestis (VST-7304) had a similar biphasic action, but showed increased nerve discharge when co-exposed with 100 nM α-BGTX, and had additive effects when injected together with α-BGTX in isobologram analyses. Binary mixtures of HXTX or VST-7304 with 30 nM nicotine showed clear evidence of synergized nerve block, which was also observed for mixtures of HXTX and VST-7304. Taken together, these data suggest that HXTX and VST-7304 have somewhat different and complementary modes of action.

The sulfoximine insecticide sulfoxaflor exposure reduces the survival status and disrupts the intestinal metabolism of the honeybee Apis mellifera.

Honeybees (Apis mellifera) are indispensable pollinators in agricultural production, biodiversity conservation, and nutrients provision. The abundance and diversity of honeybees have been rapidly diminishing, possibly related to the extensive use of insecticides in ecosystems. Sulfoxaflor is a novel sulfoximine insecticide that, like neonicotinoids, acts as a competitive modulator of nicotinic acetylcholine receptors (nAChR) in insects. However, few studies have addressed the negative effects of sulfoxaflor on honeybees at environmentally relevant concentrations. In the present study, adult workers were fed a 50% (w/v) of sugar solution containing different concentrations (0, 0.05, 0.5 and 2.0mg/L) of sulfoxaflor for two weeks consecutively. The survival rates, food intake, and body weight of the honeybees significantly decreased after continuous exposure at higher doses (0.5 and 2.0mg/L) of sulfoxaflor when compared with the control. The change in the metabolites in the honeybee gut was determined using high-throughput non-targeted metabolomics on day 14 after sulfoxaflor treatment. The results revealed that 24 and 105 metabolites changed after exposure to 0.5 and 2.0mg/L sulfoxaflor, respectively, compared with that of the control groups. A total of 12 changed compounds including pregenolone and glutathione were detected as potential biomarkers, which were eventually found to be enriched in pathways of the steroid hormone biosynthesis (p=0.0001) and glutathione metabolism (p=0.021). These findings provide a new perspective on the physiological influence of sulfoxaflor stress in honeybees.

Novel α7 nicotinic acetylcholine receptor modulators as potential antitussive agents

A novel series of α7 nicotinic acetylcholine receptor (nAChR) modulators was designed and evaluated for antitussive activity in an in vivo guinea pig model of chemically induced cough. Compound 16 at all tested doses (9.5, 3 and 1 mg/kg) significantly (p < 0.01) reduced the cumulative number of coughs and showed similar results to a positive control (codeine at 30 mg/kg). Among three different administration routes (intraperitoneal, oral and inhalation), compound 16 exerted a significant antitussive effect in guinea pigs at an inhaled dose as low as 0.4 mg/kg (p < 0.05). α7 nAChR modulators may provide a novel, non-narcotic approach to therapy in patients with acute and chronic cough.

Effects of chronic exposure to the new insecticide sulfoxaflor in combination with a SDHI fungicide in a solitary bee

The recent EU ban of the three most widely used neonicotinoids (imidacloprid, thiamethoxam and clothianidin) to all outdoors applications has stimulated the introduction of new insecticides into the market. Sulfoxaflor is a new systemic insecticide that, like neonicotinoids, acts as a modulator of nicotinic acetylcholine receptors. In agro-environments, bees can be exposed to this compound via contaminated pollen and nectar for long periods of time. Therefore, it is important to assess the potential effects of chronic exposure to sulfoxaflor, alone and in combination with fungicides, on pollinators. In this study, we tested the effects of chronic exposure to two field concentrations of sulfoxaflor (20 and 100 ppb) alone and in combination with four concentrations of the fungicide fluxapyroxad (7500, 15,000, 30,000 and 60,000 ppb) on syrup consumption and longevity in females of the solitary bee Osmia bicornis L. Exposure to 20 ppb of sulfoxaflor, alone and in combination with the fungicide, stimulated syrup consumption, but did not affect longevity. In contrast, syrup consumption decreased in bees exposed to 100 ppb, all of which died after 2–6 days of exposure. We found no evidence of synergism between the two compounds at any of the two sulfoxaflor concentrations tested. Comparison of our findings with the literature, confirms that O. bicornis is more sensitive to sulfoxaflor than honey bees. Our results highlight the need to include different bee species in risk assessment schemes.

Octopamine receptor agonists synergistically increase the selected pesticides’ toxicity in Rhopalosiphum padi: Perspectives for reducing pesticide use, emergence of resistant strains and environmental impacts

Worldwide, the bird cherry-oat aphid, Rhopalosiphum padi, (R. padi) affects wheat, sorghum, and other grain crops, and conventional pesticides to control this aphid negatively affects the surrounding environment. Therefore, knowing the entomotoxicity of different chemical compounds against R. padi is an important step to control these pests. Thus, we aimed to evaluate the toxicity of different nicotinic acetylcholine receptor modulators (thiamethoxam, imidacloprid, acetamiprid, and sulfoxaflor) and the octopamine receptor agonists’ (ORAs hereon) synergistic effect (chlordimeform and amitraz) on the selected pesticides’ toxicity against R. padi adults. We found that chlordimeform was more effective than amitraz (LC50: 144.01 and 238.33 µg/mL, respectively), after 24-h of exposure. Sulfoxaflor was the most toxic pesticide (LC50 values were 4.61 and 0.44 µg/mL), whereas we identified acetamiprid as the least potent one (LC50 values were 111.82 and 88.69 µg/ mL). Thiamethoxam was the most effective neonicotinoid pesticide among those we used. Chlordimeform and amitraz had synergized effects with the surveyed pesticides, with amitraz showing the highest synergistic ratio. These findings indicate that ORAs are promising tools to increase the selected pesticides’ effectiveness on R. padi control, which may contribute to the decrease in the use of generic pesticides, the emergence of resistant strains, and, consequently, their impacts on the environment

Expression and Roles of Lynx1, a Modulator of Cholinergic Transmission, in Skeletal Muscles and Neuromuscular Junctions in Mice.

Lynx1 is a glycosylphosphatidylinositol (GPI)-linked protein shown to affect synaptic plasticity through modulation of nicotinic acetylcholine receptor (nAChR) subtypes in the brain. Because of this function and structural similarity to α-bungarotoxin, which binds muscle-specific nAChRs with high affinity, Lynx1 is a promising candidate for modulating nAChRs in skeletal muscles. However, little is known about the expression and roles of Lynx1 in skeletal muscles and neuromuscular junctions (NMJs). Here, we show that Lynx1 is expressed in skeletal muscles, increases during development, and concentrates at NMJs. We also demonstrate that Lynx1 interacts with muscle-specific nAChR subunits. Additionally, we present data indicating that Lynx1 deletion alters the response of skeletal muscles to cholinergic transmission and their contractile properties. Based on these findings, we asked if Lynx1 deletion affects developing and adult NMJs. Loss of Lynx1 had no effect on NMJs at postnatal day 9 (P9) and moderately increased their size at P21. Thus, Lynx1 plays a minor role in the structural development of NMJs. In 7- and 12-month-old mice lacking Lynx1, there is a marked increase in the incidence of NMJs with age- and disease-associated morphological alterations. The loss of Lynx1 also reduced the size of adult muscle fibers. Despite these effects, Lynx1 deletion did not alter the rate of NMJ reinnervation and stability following motor axon injury. These findings suggest that Lynx1 is not required during fast remodeling of the NMJ, as is the case during reformation following crushing of motor axons and development. Instead, these data indicate that the primary role of Lynx1 may be to maintain the structure and function of adult and aging NMJs.

α7 nicotinic acetylcholine receptor modulation of accumbal dopamine release covaries with novelty seeking.

Heightened novelty-seeking phenotypes are associated with a range of behavioural traits including susceptibility to drug use. These relationships are recapitulated in preclinical models, where rats that exhibit increased exploratory activity in novel environments (high responders-HR) acquire self-administration of psychostimulants more rapidly compared to rats that display low novelty exploration (low responders-LR). Dopamine release dynamics in the nucleus accumbens (NAc) covaries with response to novelty, and differences in dopaminergic signalling are thought to be a major underlying driver of the link between novelty seeking and drug use vulnerability. Accumbal dopamine release is controlled by local microcircuits including modulation through glutamatergic and nicotinic acetylcholine receptor (nAChR) systems, but whether these mechanisms contribute to disparate dopamine signalling across novelty phenotypes is unclear. Here, we used ex vivo voltammetry in the NAc of rats to determine if α7 nAChRs contribute to differential dopamine dynamics associated with individual differences in novelty exploration. We found that blockade of α7 nAChRs attenuates tonic dopamine release evoked by low-frequency stimulations across phenotypes but that phasic release is decreased in LRs while HRs are unaffected. These stimulation frequency- and phenotype-dependent effects result in a decreased dynamic range of release exclusively in LRs. Furthermore, we found that differential α7 modulation of dopamine release in LRs is dependent on AMPA but not NMDA receptors. These results help to form an understanding of the local NAc microcircuitry and provide a potential mechanism for covariance of dopamine dynamics and sensitivity to the reinforcing effects of drugs of abuse.

Nicotinic acetylcholine receptor modulator insecticides act on diverse receptor subtypes with distinct subunit compositions.

Insect nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of many insecticides, including neonicotinoids, which are the most widely used insecticides in the world. However, the development of resistance in pests and the negative impacts on bee pollinators affect the application of insecticides and have created a demand for alternatives. Thus, it is very important to understand the mode of action of these insecticides, which is not fully understood at the molecular level. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunit mutants to eleven insecticides acting on nAChRs. Our results showed that there are several subtypes of nAChRs with distinct subunit compositions that are responsible for the toxicity of different insecticides. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. Moreover, spinosyns may act exclusively on the α6 homomeric pentamers but not any other nAChRs. Behavioral assays using thermogenetic tools further confirmed the bioassay results and supported the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for the management of resistance and the development of novel insecticides targeting these important ion channels.

Dextran Sodium Sulphate-Induced Gastrointestinal Injury Further Aggravates the Impact of Galantamine on the Gastric Myoelectric Activity in Experimental Pigs

Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5–7%) are the most common side effects. The aim of this study was to assess the effect of galantamine on porcine gastric myoelectric activity without (Group A) and with (Group B) dextran sodium sulphate (DSS)-induced gastrointestinal injury. Galantamine hydrobromide was administrated to twelve pigs as a single intragastric dose (24 mg). Gastric myoelectric activity was investigated by electrogastrography (EGG). Basal (15 min before galantamine administration) and study recordings after galantamine administration (300 min) were evaluated using a running spectral analysis. Results were expressed as dominant frequency of gastric slow waves and power analysis (areas of amplitudes). Altogether, 3780 one-minute EGG recordings were evaluated. In Group A, power was steady from basal values for 180 min, then gradually decreased till 270 min (p = 0.007). In Group B, there was a rapid gradual fall from basal values to those after 120 min (p = 0.007) till 300 min (p ˂ 0.001). In conclusion, galantamine alone revealed an unfavourable effect on porcine myoelectric activity assessed by gastric power. It can be a plausible explanation of galantamine-associated dyspepsia in humans. DSS caused further profound decrease of EGG power. That may indicate that underlying inflammatory, ischaemic or NSAIDs-induced condition of the intestine in humans can have aggravated the effect of galantamine on gastric myoelectric activity.

Machine learning and pharmacophore‐based prediction of allosteric modulators of Nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors are important members of the ligand-gated ion channel family. They participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. Recent experimental results of electrophysiological studies indicate that apigenin tested on the function of the a7-subunit of the human nicotinic acetylcholine (a7-nACh) receptor caused a potentiation of currents induced by acetylcholine and works as positive allosteric modulator (PAM). Mechanism of action by which apigenin interact with the nicotinic acetylcholine (a7-nAChR) receptor is not fully understood. Using computational modeling techniques, such as pharmacophore search, molecular docking and molecular dynamics we have identified location of inter-subunit binding for apigenin in transmembrane region. Using machine learning methodologies, we identified several novel apigenin analogs that may work as positive allosteric modulators.

Toxicity of the insecticide sulfoxaflor alone and in combination with the fungicide fluxapyroxad in three bee species

The sulfoximine insecticide sulfoxaflor is regarded as a potential substitute for neonicotinoids that were recently banned in the EU due to their side effects on bees. Like neonicotinoids, sulfoxaflor acts as a competitive modulator of nicotinic acetylcholine receptors. In agricultural environments, bees are commonly exposed to combinations of pesticides, and neonicotinoids are known to interact synergistically with fungicides. The objective of our study is to assess the acute oral toxicity of sulfoxaflor alone and in combination with a single dose of fluxapyroxad, a succinate dehydrogenase inhibitor (SDHI) fungicide, in three bee species: Apis mellifera, Bombus terrestris and Osmia bicornis. Because synergism may be dose-dependent, we tested a range of sulfoxaflor doses. Synergistic effects were assessed using three different approaches: Bliss criterion of drugs independence, ratio test comparing LD50s and model deviation ratio. Osmia bicornis was the most sensitive species to sulfoxaflor and both O. bicornis and A. mellifera showed significant synergism between the insecticide and the fungicide. For the most part, these synergistic effects were weak and only occurred at early assessment times and intermediate sulfoxaflor doses. The potential ecological relevance of these effects should be confirmed in field and/or cage studies. Overall, our laboratory results demonstrate that sulfoxaflor is somewhat less toxic than the recently banned neonicotinoids imidacloprid, thiamethoxam and clothianidin, but much more toxic than other neonicotinoids (acetamiprid, thiacloprid) still in use in the EU at the time this study was conducted.

Survival rate and changes in foraging performances of solitary bees exposed to a novel insecticide

Solitary bees are among the most important pollinators worldwide however population declines especially in croplands has been noticed. The novel pesticide sulfoxaflor is a competitive modulator of nicotinic acetylcholine receptors (nAChR) in insects. While there is evidence of a negative impact of neonicotinoids on bees of several social organization levels, our overall knowledge on the impact of sulfoxaflor on bees is poor. Here we present for the first time a study showing effects of field realistic doses of sulfoxaflor on solitary bees. Bees submitted to long term exposure of field realistic doses of sulfoxaflor (5 µg dm-3, 10 µg dm-3, 50 µg dm-3) and control were observed regarding their survival rate. Moreover, we recorded metrics related to flower visitation and flight performance. We discover that the highest field realistic dose is lethal to Osmia bicornis along five days of exposure. The effect of sulfoxaflor reduces the outcome of foraging, important features for fruit and seed production of cross-pollinated plant species. Bees exposed to pesticide visited flowers mostly walking rather than flying. Flight performance was also impaired by the pesticide.

Three-dimensional Quantitative Structure-activity Relationship (3DQSAR) and Molecular Docking Study of 2-((pyridin-3-yloxy)methyl) Piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders.

Comparative molecular field analysis (CoMFA) of 27 analogues of 2-((pyridin-3-yloxy)methyl)piperazine derivatives was carried out using software Tripos SYBYL X. Optimal r2 (0.854) and q2 (0.541) values were obtained for the developed 3D-QSAR model. The contour plots obtained from CoMFA analysis have shown 13.84% steric contribution and 66.14% electrostatic contribution towards an anti-inflammatory activity. The homology model of the receptor protein, α7 nicotinic acetylcholine, was generated in SWISS MODELLER using auto template mode and was analysed for the quality using Procheck, QMEAN Z-score, Anolea and GROMOS plots. The QMEAN score for the model was observed to be - 3.862. The generated model of alpha 7 nicotinic acetylcholine receptor was used for docking study of 27 piperazine analogues using Auto-Dock 4.2.5.1. The dock score obtained from docking analysis was then correlated with experimental pIC50 values for in-silico validation of the developed CoMFA model and a good correlation was obtained with correlation coefficient (r2) value of -0.7378. The present investigation suggests an optimal 3D-QSAR with CoMFA model for further evaluating new chemical entities based on piperazine skeleton.

Activation of Somatostatin Interneurons by Nicotinic Modulator Lypd6 Enhances Plasticity and Functional Recovery in the Adult Mouse Visual Cortex.

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period: to rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through the enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.SIGNIFICANCE STATEMENT The decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical somatostatin (SST) interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors, enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.

Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation. SIGNIFICANCE STATEMENT: Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.

Exploring the ameliorative role of α7 neuronal nicotinic acetylcholine receptor modulation in epilepsy and associated comorbidities in post-PTZ-kindled mice

AimThe present study aimed to explore the ameliorative role of alpha7 (α7) neuronal nicotinic acetylcholine receptor (nAChR) modulation in epilepsy and associated comorbidities in postpentylenetetrazole (PTZ)-kindled mice. Material and methodsThe subconvulsive dose of PTZ (35 mg/kg, i.p.) was used to induce kindling-associated epileptogenesis in mice. After successful kindling, animals were treated intraperitoneally with saline, phenytoin (35 mg/kg), valproate (300 mg/kg), choline chloride (α7 agonist; 400 mg/kg and 800 mg/kg), and methyllycaconitine citrate (α7 antagonist; 3.5 mg/kg and 7.0 mg/kg) for 10 days. All the groups except naive were exposed to PTZ injections on day 3, 6, and 9 of treatment to assess seizure severity score. Epilepsy-associated comorbid depression was evaluated by tail suspension test, sucrose preference test, and plasma corticosterone levels, whereas epilepsy-associated memory deficit condition was assessed by step-through paradigm, Morris water maze, and nitrite levels. Neurochemical perturbations related to epilepsy and associated depression and memory deficit were measured by high-performance liquid chromatography (HPLC). ResultsPost-PTZ-kindled mice displayed significant depressive behavior and memory impairment as compared with naive mice as evidenced by corresponding behavioral and biochemical observations. Methyllycaconitine citrate treatment was unable to produce any ameliorative effect in diseased condition. Choline administration dose dependently ameliorated depression, memory impairment, and seizure severity in post-PTZ-kindled mice. The behavioral findings of the study were concurred with neurochemical and biochemical findings. ConclusionIn conclusion, the present study demonstrated the amelioration of epilepsy, comorbid depression, and memory deficit by α7 nAChR agonist choline chloride in PTZ-kindled mice model.