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Fitoterapia Jun 2016In screening a library of plant extracts from ~1000 species native to the Southeastern United States, Lobelia cardinalis was identified as containing nicotinic...
In screening a library of plant extracts from ~1000 species native to the Southeastern United States, Lobelia cardinalis was identified as containing nicotinic acetylcholine receptor (nicAchR) binding activity which was relatively non-selective for the α4β2- and α7-nicAchR subtypes. This nicAchR binding profile is atypical for plant-derived nicAchR ligands, the majority of which are highly selective for α4β2-nicAchRs. Its potential therapeutic relevance is noteworthy since agonism of α4β2- and α7-nicAchRs is associated with anti-inflammatory and neuroprotective properties. Bioassay-guided fractionation of L. cardinalis extracts led to the identification of lobinaline, a complex binitrogenous alkaloid, as the main source of the unique nicAchR binding profile. Purified lobinaline was a potent free radical scavenger, displayed similar binding affinity at α4β2- and α7-nicAchRs, exhibited agonist activity at nicAchRs in SH-SY5Y cells, and inhibited [(3)H]-dopamine (DA) uptake in rat striatal synaptosomes. Lobinaline significantly increased fractional [(3)H] release from superfused rat striatal slices preloaded with [(3)H]-DA, an effect that was inhibited by the non-selective nicAchR antagonist mecamylamine. In vivo electrochemical studies in urethane-anesthetized rats demonstrated that lobinaline locally applied in the striatum significantly prolonged clearance of exogenous DA by the dopamine transporter (DAT). In contrast, lobeline, the most thoroughly investigated Lobelia alkaloid, is an α4β2-nicAchR antagonist, a poor free radical scavenger, and is a less potent DAT inhibitor. These previously unreported multifunctional effects of lobinaline make it of interest as a lead to develop therapeutics for neuropathological disorders that involve free radical generation, cholinergic, and dopaminergic neurotransmission. These include neurodegenerative conditions, such as Parkinson's disease, and drug abuse.
Topics: Alkaloids; Animals; Cell Line; Corpus Striatum; Dopamine; High-Throughput Screening Assays; Lobelia; Male; Nicotinic Antagonists; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Synaptosomes; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 27105955
DOI: 10.1016/j.fitote.2016.04.013 -
PloS One 2016Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased...
Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.
Topics: Alkaloids; Animals; Azocines; Drug Evaluation, Preclinical; Food Preferences; Male; Mecamylamine; Nicotinic Agonists; Nicotinic Antagonists; Nucleus Accumbens; Quinolizines; Rats, Wistar; Receptors, Nicotinic; Sucrose; Varenicline
PubMed: 27028298
DOI: 10.1371/journal.pone.0150270 -
Journal of Psychopharmacology (Oxford,... Mar 2024Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new...
BACKGROUND
Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders.
AIM
These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine.
METHODS
The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded.
RESULTS
The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets.
CONCLUSION
These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.
Topics: Humans; Rats; Animals; Nicotine; Mecamylamine; Mifepristone; Smoking; Receptors, Glucocorticoid; Tobacco Use Disorder; Substance Withdrawal Syndrome; Rats, Wistar; Self Administration; Dose-Response Relationship, Drug
PubMed: 38332661
DOI: 10.1177/02698811241230255 -
Neuropharmacology Nov 2019The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of...
The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of acetylcholine (ACh) systems in this pathway have not been explored. Thus, this study assessed ACh levels and gene expression of α- and β-containing nicotinic acetylcholine receptor (nAChR) subunits in the IPN of female and male rats following nicotine treatment and withdrawal. Rats were prepared with a pump that delivered nicotine for 14 days, and naïve controls received a sham surgery. In Study 1, rats were prepared with a probe in the IPN, and ACh levels were measured following saline and then mecamylamine administration. In Study 2, separate groups of naïve control or nicotine-treated rats received saline or mecamylamine and physical signs and anxiety-like behavior were assessed using elevated plus maze (EPM) procedures. The IPN was then dissected and mRNA levels were assessed using RT-qPCR methods. Nicotine treatment increased ACh levels to a larger extent in females than males. Nicotine withdrawal produced a similar increase in physical signs; however, females displayed greater anxiety-like behavior than males. In females, gene expression of α5 increased following nicotine treatment and withdrawal. In males, α7 increased following nicotine treatment and α2 and α3 increased during nicotine withdrawal. Both females and males displayed an increase in β3 and β4 during nicotine withdrawal. In females, anxiety-like behavior was correlated with α4, α5, and β2 gene expression in the IPN. These results suggest that sex differences in withdrawal are modulated via cholinergic systems in the IPN.
Topics: Animals; Anxiety; Behavior, Animal; Female; Gene Expression; Interpeduncular Nucleus; Male; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; RNA, Messenger; Rats; Receptors, Nicotinic; Sex Factors; Substance Withdrawal Syndrome; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 31325431
DOI: 10.1016/j.neuropharm.2019.107714 -
Acta Pharmacologica Sinica Oct 2018Neuronal nicotinic acetylcholine receptors containing α6 subunits (α6-nAChRs) show highly restricted distribution in midbrain neurons associated with pleasure, reward,...
Neuronal nicotinic acetylcholine receptors containing α6 subunits (α6-nAChRs) show highly restricted distribution in midbrain neurons associated with pleasure, reward, and mood control, suggesting an important impact of α6-nAChRs in modulating mesolimbic functions. However, the function and pharmacology of α6-nAChRs remain poorly understood because of the lack of selective agonists for α6-nAChRs and the challenging heterologous expression of functional α6-nAChRs in mammalian cell lines. In particular, the α6 subunit is commonly co-expressed with α4-nAChRs in the midbrain, which masks α6-nAChR (without α4) function and pharmacology. In this study, we systematically profiled the pharmacology and function of α6-nAChRs and compared these properties with those of α4β2 nAChRs expressed in the same cell line. Heterologously expressed human α6/α3 chimeric subunits (α6 N-terminal domain joined with α3 trans-membrane domains and intracellular loops) with β2 and β3 subunits in the human SH-EP1 cell line (α6-nAChRs) were used. Patch-clamp whole-cell recordings were performed to measure these receptor-mediated currents. Functionally, the heterologously expressed α6-nAChRs exhibited excellent function and showed distinct nicotine-induced current responses, such as kinetics, inward rectification and recovery from desensitization, compared with α4β2-nAChRs. Pharmacologically, α6-nAChR was highly sensitive to the α6 subunit-selective antagonist α-conotoxin MII but had lower sensitivity to mecamylamine and dihydro-β-erythroidine. Nicotine and acetylcholine were found to be full agonists for α6-nAChRs, whereas epibatidine and cytisine were determined to be partial agonists. Heterologously expressed α6-nAChRs exhibited pharmacology and function distinct from those of α4β2-nAChRs, suggesting that α6-nAChRs may mediate different cholinergic signals. Our α6-nAChR expression system can be used as an excellent cell model for future investigations of α6-nAChR function and pharmacology.
Topics: Amino Acid Sequence; Cell Line; Humans; Kinetics; Nicotinic Agonists; Nicotinic Antagonists; Patch-Clamp Techniques; Receptors, Nicotinic
PubMed: 29795357
DOI: 10.1038/aps.2017.209 -
The Journal of Pharmacology and... Aug 2020Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular...
Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are key regulators of both the abuse and neurotoxic potential of structurally and behaviorally related agents, the impact of MDPV on these transporters was investigated. Results revealed that a single in vivo MDPV administration rapidly (within 1 hour) and reversibly increased both rat striatal DAT and VMAT-2 activity, as assessed via [H]DA uptake in synaptosomes and synaptic vesicles, respectively, prepared from treated rats. There was no evidence of an MDPV-induced increase in plasmalemmal membrane DAT surface expression. Plasma concentrations of MDPV increased dose-dependently as assessed 1 hour after 2.5 and 5.0 mg/kg (s.c.) administration and returned to levels less than 10 ng/ml by 18 hours after 2.5 mg/kg (s.c.). Neither pretreatment with a D1 receptor (SCH23390), a D2 receptor (eticlopride), nor a nicotinic receptor (mecamylamine) antagonist attenuated the MDPV-induced increase in DAT activity. In contrast, eticlopride pretreatment attenuated both the MDPV-induced increase in VMAT-2-mediated DA uptake and an associated increase in cytoplasmic-associated vesicle VMAT-2 immunoreactivity. SCH23390 did not attenuate the MDPV-induced increase in VMAT-2 activity. Repeated MDPV injections did not cause persistent DAergic deficits, as assessed 7 to 8 days later. The impact of MDPV on striatal and hippocampal serotonergic assessments was minimal. Taken together, these data contribute to a growing pharmacological rubric for evaluating the ever-growing list of designer cathinone-related stimulants. The profile of MDPV compared with related psychostimulants is discussed. SIGNIFICANCE STATEMENT: Pharmacological characterization of the synthetic cathinone, 3,4-methylenedioxypyrovalerone (MDPV; commonly referred to as a "bath salt"), is critical for understanding the abuse liability and neurotoxic potential of this and related agents. Accordingly, the impact of MDPV on monoaminergic neurons is described and compared with that of related psychostimulants.
Topics: Animals; Benzodioxoles; Body Temperature; Central Nervous System Stimulants; Designer Drugs; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Female; Male; Neostriatum; Pyrrolidines; Rats; Rats, Sprague-Dawley; Substance-Related Disorders; Vesicular Monoamine Transport Proteins; Synthetic Cathinone
PubMed: 32385092
DOI: 10.1124/jpet.119.264895 -
EvoDevo 2019Nicotinic and muscarinic acetylcholine receptors likely evolved in the cnidarian-bilaterian common ancestor. Both receptor families are best known for their role at...
BACKGROUND
Nicotinic and muscarinic acetylcholine receptors likely evolved in the cnidarian-bilaterian common ancestor. Both receptor families are best known for their role at chemical synapses in bilaterian animals, but they also have described roles as non-neuronal signaling receptors within the bilaterians. It is not clear when either of the functions for nicotinic or muscarinic receptors evolved. Previous studies in cnidarians suggest that acetylcholine's neuronal role existed prior to the cnidarian-bilaterian divergence, but did not address potential non-neuronal functions. To determine the origins of neuronal and non-neuronal functions of nicotinic acetylcholine receptors, we investigated the phylogenetic position of cnidarian acetylcholine receptors, characterized the spatiotemporal expression patterns of nicotinic receptors in , and compared pharmacological studies in to the previous work in other cnidarians.
RESULTS
Consistent with described activity in other cnidarians, treatment with acetylcholine-induced tentacular contractions in the cnidarian sea anemone Phylogenetic analysis suggests that the genome encodes 26 nicotinic (nAChRs) and no muscarinic (mAChRs) acetylcholine receptors and that nAChRs independently radiated in cnidarian and bilaterian linages. The namesake nAChR agonist, nicotine, induced tentacular contractions similar to those observed with acetylcholine, and the nAChR antagonist mecamylamine suppressed tentacular contractions induced by both acetylcholine and nicotine. This indicated that tentacle contractions are in fact mediated by nAChRs. Nicotine also induced the contraction of radial muscles, which contract as part of the peristaltic waves that propagate along the oral-aboral axis of the trunk. Radial contractions and peristaltic waves were suppressed by mecamylamine. The ability of nicotine to mimic acetylcholine responses, and of mecamylamine to suppress acetylcholine and nicotine-induced contractions, supports a neuronal function for acetylcholine in cnidarians. Examination of the spatiotemporal expression of nAChRs () during development and in juvenile polyps identified that are expressed in neurons, muscles, gonads, and large domains known to be consistent with a role in developmental patterning. These patterns are consistent with nAChRs functioning in both a neuronal and non-neuronal capacity in
CONCLUSION
Our data suggest that nAChR receptors functioned at chemical synapses in to regulate tentacle contraction. Similar responses to acetylcholine are well documented in cnidarians, suggesting that the neuronal function represents an ancestral role for nAChRs. Expression patterns of nAChRs are consistent with both neuronal and non-neuronal roles for acetylcholine in cnidarians. Together, these observations suggest that both neuronal and non-neuronal functions for the ancestral nAChRs were present in the cnidarian-bilaterian common ancestor. Thus, both roles described in bilaterian species likely arose at or near the base of nAChR evolution.
PubMed: 31700598
DOI: 10.1186/s13227-019-0136-3 -
The Journal of Pharmacology and... Aug 2018Evidence suggests that the 42, but not the 7, subtype of the nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine...
Evidence suggests that the 42, but not the 7, subtype of the nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine and related drugs. However, the importance of other nAChR subtypes remains unclear. The present studies were conducted to examine the involvement of nAChR subtypes by determining the effects of selected nicotinic agonists and antagonists in squirrel monkeys either 1) responding for food reinforcement or 2) discriminating the nicotinic agonist (+)-epibatidine (0.001 mg/kg) from vehicle. In food-reinforcement studies, nicotine, (+)-epibatidine, varenicline and cytisine all produced dose-dependent decreases in rates of food-maintained responding. The rate-decreasing effects of nicotine were antagonized by mecamylamine (nonselective), not appreciably altered by dihydro--erythroidine (42 selective), and exacerbated by the nicotinic partial agonists, varenicline and cytisine. Results from discrimination studies show that non-nicotinic drugs did not substitute for (+)-epibatidine, and that except for lobeline, the nicotinic agonists produced either full [(+)-epibatidine, (-)-epibatidine, and nicotine] or partial (varenicline, cytisine, anabaseine, and isoarecolone) substitution for (+)-epibatidine. In interaction studies with antagonists differing in selectivity, (+)-epibatidine discrimination was substantively antagonized by mecamylamine, slightly attenuated by hexamethonium (peripherally restricted) or dihydro--erythroidine, and not altered by methyllycaconitine (7 selective). Varenicline and cytisine enhanced (+)-epibatidine's discriminative-stimulus effects. Correlational analysis revealed a close correspondence between relative behavioral potencies of nicotinic agonists in both studies and their published relative binding affinities at 42 and 34, but not 7 nAChR, subtypes. Collectively, these results are consistent with the idea that the 42 and 34, but not 7 nAChR subtypes play a role in the behavioral effects of nicotinic agonists.
Topics: Animals; Behavior, Animal; Drug Interactions; Male; Nicotinic Agonists; Nicotinic Antagonists; Protein Isoforms; Receptors, Nicotinic; Reinforcement, Psychology
PubMed: 29784663
DOI: 10.1124/jpet.118.248070 -
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 -
In Vivo (Athens, Greece) 2020Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its...
BACKGROUND/AIM
Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its receptor inhibitors, and Pinus halepensis bark extract in relation to known antioxidants were investigated.
MATERIALS AND METHODS
Primary mouse keratinocytes were exposed to cigarette smoke in the presence and absence of Pinus halepensis bark extract (1 μg/ml), rutin (50 μM) and ascorbic acid (250 μM), nicotine (1 μM) with or without mecamylamine (5 μM) and α-bungarotoxin (0.1 μM). Keratinocyte viability and oxidative stress were evaluated by MTT and fluorescence assays.
RESULTS
Pinus halepensis bark extract decreased the oxidative stress and increased the viability of keratinocytes, and moreover, these effects were more pronounced compared to the mixture of rutin and L-ascorbic acid. Nicotine significantly enhanced the viability potentiation of the beneficial effect induced by Pinus halepensis bark extract. Mecamylamine and α-bungarotoxin showed no specific effect.
CONCLUSION
Pinus halepensis bark extract in combination with nicotine may successfully reverse skin damage induced by cigarette smoke.
Topics: Animals; Keratinocytes; Mice; Nicotine; Oxidative Stress; Pinus; Plant Bark; Plant Extracts; Smoking
PubMed: 32606153
DOI: 10.21873/invivo.11978