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Biochemical and Biophysical Research... Jul 2021In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical...
In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal.
Topics: Animals; Female; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nicotine; Optogenetics; Raphe Nuclei; Receptors, Nicotinic; Serotonergic Neurons; Serotonin; Substance Withdrawal Syndrome
PubMed: 34038754
DOI: 10.1016/j.bbrc.2021.05.052 -
Pharmacology, Biochemistry, and Behavior Jul 2021Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for...
Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for understanding the addictive properties and health-risks associated with ECIG use; however, there is not a standard dosing regimen used across research laboratories. The main objective was to determine how vapor puff durations, administration session length, and flavored e-liquid alter general and mood-disorder related behaviors while providing a foundation of vapor administration parameters. Adult male and female C57BL/6 mice were exposed to several nicotine-free unflavored vapor puff durations (1, 3, 6, or 10 s) and vapor administration session lengths (10 and 30 min) then measured on the following assays: locomotor activity (LMA), tail suspension test (TST), and light-dark test. The effects of mecamylamine and the time-course of vapor-induced depression of LMA also were assessed. Additionally, mice were exposed to flavored (strawberry and adventurers tobacco blend) vapor inhalation and measured on locomotor activity, tail suspension test, and light-dark test. Following both 10 and 30 min vapor administration session, there was a puff duration-dependent decrease in distance traveled, time in center, and rearing. The vapor-induced depression of LMA was not mediated by nicotine or nicotinic acetylcholine receptor (nAChR) activation and lasted 60-90 min. The 10 s puff duration produced an anxiogenic-like effect in the light-dark test by decreasing the time spent in the light side. Vapor inhalation did not significantly alter TST behavior. No significant effects of sex or flavor were found. The anxiogenic-like effects of nicotine-free vapor inhalation are concerning as many adolescents vape nicotine-free flavored e-liquid, and there is an association between ECIGs and mood disorders. Additionally, these studies demonstrate that vapor puff duration, but not vapor administration session length, is an important variable to consider during research design as it can become a confounding variable and alter baseline behaviors.
Topics: Administration, Inhalation; Adolescent; Animals; Anxiety; Behavior, Animal; E-Cigarette Vapor; Electronic Nicotine Delivery Systems; Female; Flavoring Agents; Humans; Locomotion; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Antagonists; Receptors, Nicotinic; Sex Factors; Time Factors; Vaping
PubMed: 34019915
DOI: 10.1016/j.pbb.2021.173207 -
Nicotine & Tobacco Research : Official... Nov 2021Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is...
INTRODUCTION
Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is unknown if there are sex differences in the reward-enhancing effects of nicotine self-administration and if the rewarding effects of nicotine change over time.
METHODS
Rats were prepared with catheters and intracranial self-stimulation (ICSS) electrodes to investigate the effects of nicotine and saline self-administration on reward function. A decrease in thresholds in the ICSS procedure reflects an enhancement of reward function. The ICSS parameters were determined before and after the self-administration sessions from days 1 to 10, and after the self-administration sessions from days 11 to 15.
RESULTS
During the first 10 days, there was no sex difference in nicotine intake, but during the last 5 days, the females took more nicotine than the males. During the first 10 days, nicotine self-administration did not lower the brain reward thresholds but decreased the response latencies. During the last 5 days, nicotine lowered the reward thresholds and decreased the response latencies. An analysis with the 5-day averages (days 1-5, 6-10, and 11-15) showed that the reward enhancing and stimulatory effects of nicotine increased over time. There were no sex differences in the reward-enhancing and stimulatory effects of nicotine. The nicotinic receptor antagonist mecamylamine diminished the reward-enhancing and stimulatory effects of nicotine.
CONCLUSION
These findings indicate that the rewarding effects of nicotine self-administration increase over time, and there are no sex differences in the reward-enhancing effects of nicotine self-administration in rats.
IMPLICATIONS
This study investigated the rewarding effect of nicotine and saline self-administration in male and female rats. The self-administration of nicotine, but not saline, enhanced brain reward function and had stimulatory effects. The rewarding effects of nicotine increased over time in the males and the females. Despite that the females had a higher level of nicotine intake than the males, the reward-enhancing effects of nicotine self-administration were the same. These findings suggest that in new tobacco and e-cigarette users, nicotine's rewarding effects might increase quickly, and a higher level of nicotine use in females might not translate into greater rewarding effects.
Topics: Animals; Electronic Nicotine Delivery Systems; Female; Male; Nicotine; Rats; Rats, Wistar; Reward; Self Stimulation
PubMed: 33987656
DOI: 10.1093/ntr/ntab097 -
Nicotine & Tobacco Research : Official... Feb 2022Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and... (Review)
Review
INTRODUCTION
Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and unpleasant side effects such as nausea and dizziness.
AIMS AND METHODS
Here we review the sensory effects of nicotine and the underlying neurobiological processes.
RESULTS AND CONCLUSIONS
Nicotine elicits oral irritation and pain via the activation of neuronal nicotinic acetylcholine receptors (nAChRs) expressed by trigeminal nociceptors. These nociceptors excite neurons in the trigeminal subnucleus caudalis (Vc) and other brainstem regions in a manner that is significantly reduced by the nAChR antagonist mecamylamine. Vc neurons are excited by lingual application of nicotine and exhibit a progressive decline in firing to subsequent applications, consistent with desensitization of peripheral sensory neurons and progressively declining ratings of oral irritation in human psychophysical experiments. Nicotine also elicits a nAChR-mediated bitter taste via excitation of gustatory afferents. Nicotine solutions are avoided even when sweeteners are added. Studies employing oral self-administration have yielded mixed results: Some studies show avoidance of nicotine while others report increased nicotine intake over time, particularly in adolescents and females. Nicotine is consistently reported to increase human pain threshold and tolerance levels. In animal studies, nicotine is antinociceptive when delivered by inhalation of tobacco smoke or systemic infusion, intrathecally, and by intracranial microinjection in the pedunculopontine tegmentum, ventrolateral periaqueductal gray, and rostral ventromedial medulla. The antinociception is thought to be mediated by descending inhibition of spinal nociceptive transmission. Menthol cross-desensitizes nicotine-evoked oral irritation, reducing harshness that may account for its popularity as a flavor additive to tobacco products.
IMPLICATIONS
Nicotine activates brain systems underlying reward and antinociception, but at the same time elicits aversive sensory effects including oral irritation and pain, bitter taste, and other unpleasant side effects mediated largely by nicotinic acetylcholine receptors (nAChRs). This review discusses the competing aversive and antinociceptive effects of nicotine and exposure to tobacco smoke, and the underlying neurobiology. An improved understanding of the interacting effects of nicotine will hopefully inform novel approaches to mitigate nicotine and tobacco use.
Topics: Adolescent; Animals; Female; Humans; Mecamylamine; Nicotine; Receptors, Nicotinic; Nicotiana; Tobacco Products; Tobacco Use
PubMed: 33955474
DOI: 10.1093/ntr/ntab086 -
Progress in Neuro-psychopharmacology &... Dec 2021Nicotine withdrawal syndrome is a major clinical problem. Animal models with sufficient predictive validity to support translation of pre-clinical findings to clinical...
BACKGROUND
Nicotine withdrawal syndrome is a major clinical problem. Animal models with sufficient predictive validity to support translation of pre-clinical findings to clinical research are lacking.
AIMS
We evaluated the behavioural and neurochemical alterations in zebrafish induced by short- and long-term nicotine withdrawal.
METHODS
Zebrafish were exposed to 1 mg/L nicotine for 2 weeks. Dependence was determined using behavioural analysis following mecamylamine-induced withdrawal, and brain nicotinic receptor binding studies. Separate groups of nicotine-exposed and control fish were assessed for anxiety-like behaviours, anhedonia and memory deficits following 2-60 days spontaneous withdrawal. Gene expression analysis using whole brain samples from nicotine-treated and control fish was performed at 7 and 60 days after the last drug exposure. Tyrosine hydroxylase (TH) immunoreactivity in pretectum was also analysed.
RESULTS
Mecamylamine-precipitated withdrawal nicotine-exposed fish showed increased anxiety-like behaviour as evidenced by increased freezing and decreased exploration. H-Epibatidine labeled heteromeric nicotinic acethylcholine receptors (nAChR) significantly increased after 2 weeks of nicotine exposure while I-αBungarotoxin labeled homomeric nAChR remained unchanged. Spontaneous nicotine withdrawal elicited anxiety-like behaviour (increased bottom dwelling), reduced motivation in terms of no preference for the enriched side in a place preference test starting from Day 7 after withdrawal and a progressive decrease of memory attention (lowering discrimination index). Behavioural differences were associated with brain gene expression changes: nicotine withdrawn animals showed decreased expression of chrna 4 and chrna7 after 60 days, and of htr2a from 7 to 60 days.The expression of c-Fos was significantly increased at 7 days. Finally, Tyrosine hydroxylase (TH) immunoreactivity increased in dorsal parvocellular pretectal nucleus, but not in periventricular nucleus of posterior tuberculum nor in optic tectum, at 60 days after withdrawal.
CONCLUSIONS
Our findings show that nicotine withdrawal induced anxiety-like behaviour, cognitive alterations, gene expression changes and increase in pretectal TH expression, similar to those observed in humans and rodent models.
Topics: Anhedonia; Animals; Anxiety; Brain; Emotions; Female; Gene Expression; Male; Mammals; Receptors, Nicotinic; Substance Withdrawal Syndrome; Time Factors; Tobacco Use Disorder; Tyrosine 3-Monooxygenase; Zebrafish
PubMed: 33905756
DOI: 10.1016/j.pnpbp.2021.110334 -
Journal of Psychopharmacology (Oxford,... Oct 2021Animal models are critical to improve our understanding of the neuronal mechanisms underlying nicotine withdrawal. Nicotine dependence in rodents can be established by... (Review)
Review
BACKGROUND
Animal models are critical to improve our understanding of the neuronal mechanisms underlying nicotine withdrawal. Nicotine dependence in rodents can be established by repeated nicotine injections, chronic nicotine infusion via osmotic minipumps, oral nicotine intake, tobacco smoke exposure, nicotine vapor exposure, and e-cigarette aerosol exposure. The time course of nicotine withdrawal symptoms associated with these methods has not been reviewed in the literature.
AIM
The goal of this review is to discuss nicotine withdrawal symptoms associated with the cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure in rats and mice. Furthermore, age and sex differences in nicotine withdrawal symptoms are reviewed.
RESULTS
Cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure leads to nicotine withdrawal symptoms such as somatic withdrawal signs, changes in locomotor activity, anxiety- and depressive-like behavior, learning and memory deficits, attention deficits, hyperalgesia, and dysphoria. These withdrawal symptoms are most pronounced within the first week after cessation of nicotine exposure. Anxiety- and depressive-like behavior, and deficits in learning and memory may persist for several months. Adolescent (4-6 weeks old) rats and mice display fewer nicotine withdrawal symptoms than adults (>8 weeks old). In adult rats and mice, females show fewer nicotine withdrawal symptoms than males. The smoking cessation drugs bupropion and varenicline reduce nicotine withdrawal symptoms in rodents.
CONCLUSION
The nicotine withdrawal symptoms that are observed in rodents are similar to those observed in humans. Tobacco smoke and e-cigarette aerosol contain chemicals and added flavors that enhance the reinforcing properties of nicotine. Therefore, more valid animal models of tobacco and e-cigarette use need to be developed by using tobacco smoke and e-cigarette aerosol exposure methods to induce dependence.
Topics: Animals; Disease Models, Animal; Electronic Nicotine Delivery Systems; Humans; Mice; Nicotine; Rats; Sex Factors; Smoking Cessation; Smoking Cessation Agents; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 33888006
DOI: 10.1177/02698811211005629 -
Scientific Reports Apr 2021Context affects the salience and visibility of image elements in visual scenes. Collinear flankers can enhance or decrease the perceptual and neuronal sensitivity to...
Context affects the salience and visibility of image elements in visual scenes. Collinear flankers can enhance or decrease the perceptual and neuronal sensitivity to flanked stimuli. These effects are mediated through lateral interactions between neurons in the primary visual cortex (area V1), in conjunction with feedback from higher visual areas. The strength of lateral interactions is affected by cholinergic neuromodulation. Blockade of muscarinic receptors should increase the strength of lateral intracortical interactions, while nicotinic blockade should reduce thalamocortical feed-forward drive. Here we test this proposal through local iontophoretic application of the muscarinic receptor antagonist scopolamine and the nicotinic receptor antagonist mecamylamine, while recording single cells in parafoveal representations in awake fixating macaque V1. Collinear flankers generally reduced neuronal contrast sensitivity. Muscarinic and nicotinic receptor blockade equally reduced neuronal contrast sensitivity. Contrary to our hypothesis, flanker interactions were not systematically affected by either receptor blockade.
Topics: Animals; Contrast Sensitivity; Macaca mulatta; Male; Muscarinic Antagonists; Neurons; Nicotinic Antagonists; Photic Stimulation; Receptors, Muscarinic; Receptors, Nicotinic; Visual Cortex
PubMed: 33863988
DOI: 10.1038/s41598-021-88044-7 -
International Journal of Molecular... Mar 2021Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in...
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca content and lower frequency of spontaneous Ca signals in SGCE MSNs. Blocking of voltage-gated Ca channels by verapamil was less efficient in suppressing KCl-induced Ca peaks of SGCE MSNs. Ca amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.
Topics: Acetylcholine; Action Potentials; Adult; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Cell Differentiation; Cells, Cultured; Corpus Striatum; Dendritic Spines; Dystonic Disorders; Female; Gene Expression; Glycine; Humans; Induced Pluripotent Stem Cells; Male; Mecamylamine; Middle Aged; Patch-Clamp Techniques
PubMed: 33808167
DOI: 10.3390/ijms22073565 -
Archives of Toxicology Jun 2021Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons.... (Comparative Study)
Comparative Study
Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca concentration ([Ca]) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca] signaling at 10-100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1-10 µM) blunted the signaling response of nicotine. The pesticides (at 3-30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.
Topics: Calcium; Cell Line; Cell Line, Tumor; Dopaminergic Neurons; Dose-Response Relationship, Drug; Humans; Neonicotinoids; Neuroblastoma; Patch-Clamp Techniques; Pesticides; Receptors, Nicotinic; Signal Transduction
PubMed: 33778899
DOI: 10.1007/s00204-021-03031-1 -
BMC Biology Mar 2021Attentional modulation in the visual cortex of primates is characterized by multiplicative changes of sensory responses with changes in the attentional state of the...
BACKGROUND
Attentional modulation in the visual cortex of primates is characterized by multiplicative changes of sensory responses with changes in the attentional state of the animal. The cholinergic system has been linked to such gain changes in V1. Here, we aim to determine if a similar link exists in macaque area MT. While rhesus monkeys performed a top-down spatial attention task, we locally injected a cholinergic agonist or antagonist and recorded single-cell activity.
RESULTS
Although we confirmed cholinergic influences on sensory responses, there was no additional cholinergic effect on the attentional gain changes. Neither a muscarinic blockage nor a local increase in acetylcholine led to a significant change in the magnitude of spatial attention effects on firing rates.
CONCLUSIONS
This suggests that the cellular mechanisms of attentional modulation in the extrastriate cortex cannot be directly inferred from those in the primary visual cortex.
Topics: Acetylcholine; Animals; Attention; Cholinergic Agonists; Cholinergic Antagonists; Macaca mulatta; Male; Mecamylamine; Scopolamine; Visual Cortex; Visual Perception
PubMed: 33726757
DOI: 10.1186/s12915-021-00993-7