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Neuropsychopharmacology : Official... Feb 2022A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic...
A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.
Topics: Animals; GABAergic Neurons; Interpeduncular Nucleus; Male; Mecamylamine; Mice; Nicotine; Substance Withdrawal Syndrome
PubMed: 34326477
DOI: 10.1038/s41386-021-01107-1 -
Behavioural Pharmacology Sep 2021An attempt to determine the receptor selective nature of some of nicotine's behavioral effects was undertaken through the evaluation of the ability of two nicotinic...
An attempt to determine the receptor selective nature of some of nicotine's behavioral effects was undertaken through the evaluation of the ability of two nicotinic α4β2*-selective receptor agonists to produce nicotine-like effects and modify rates of responding in a discrimination assay and in an aversive stimulus assay. A group of eight rats was trained to discriminate the presence of 1 mg/kg nicotine base. Another group of 4-6 rats was trained to report the aversive effects of nicotine by selecting a lever that produced one food pellet over a second lever that produced two food pellets and an intravenous injection of nicotine. Ispronicline and metanicotine, two α4β2*-selective receptor agonists, increased selection of the nicotine-appropriate lever in a dose-related manner, up to a maximum of approximately 75%. The α4β2*-selective receptor antagonist, dihydro-beta-erythroidine blocked both the discriminative stimulus effects and the rate-suppressing effects of ispronicline, metanicotine, and small, but not large doses of nicotine. The nonselective antagonist, mecamylamine, antagonized the discriminative stimulus effects of each of the three nicotine agonists as well as the rate-decreasing effects of nicotine and metanicotine. Mecamylamine did not modify the rate-decreasing effects of ispronicline. Both ispronicline and metanicotine as well as nicotine were avoided in the drug + food vs. food choice situation. The receptor-selective nature of ispronicline and metanicotine was hereby confirmed in a behavioral assay, as were earlier reports that the discriminative stimulus effects of relatively small doses of nicotine are likely mediated by activity at the α4β2* nicotine receptor.
Topics: Animals; Behavior, Animal; Cognition; Dihydro-beta-Erythroidine; Dose-Response Relationship, Drug; Drug Monitoring; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pyridines; Rats; Receptors, Nicotinic
PubMed: 34320519
DOI: 10.1097/FBP.0000000000000644 -
Neurotherapeutics : the Journal of the... Jul 2021Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy...
Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1-25 mg kg) or repeatedly (10 mg kg) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.
Topics: Analgesics, Non-Narcotic; Animals; Antineoplastic Agents, Phytogenic; Azepines; Carbolines; Dose-Response Relationship, Drug; Male; Neuralgia; Neuroprotective Agents; Paclitaxel; Rats; Rats, Sprague-Dawley; Treatment Outcome
PubMed: 34312766
DOI: 10.1007/s13311-021-01069-8 -
Respiratory Physiology & Neurobiology Nov 2021Effects of acetylcholine (ACh) on respiratory activity have been an intriguing theme especially in relation to central chemoreception and the control of hypoglossal...
Effects of acetylcholine (ACh) on respiratory activity have been an intriguing theme especially in relation to central chemoreception and the control of hypoglossal nerve activity. We studied the effects of ACh on hypoglossal and phrenic (C4) nerve activities and inspiratory and pre-inspiratory neurons in the rostral ventrolateral medulla in brainstem-spinal cord preparations from newborn rats. ACh application increased respiratory rhythm, decreased inspiratory hypoglossal and C4 nerve burst amplitude, and enhanced pre-inspiratory hypoglossal activity. ACh induced membrane depolarization of pre-inspiratory neurons that might be involved in facilitation of respiratory rhythm by ACh. Effects of ACh on hypoglossal and C4 nerve activity were partially reversed by a nicotinic receptor blocker, mecamylamine. Further application of a muscarinic receptor antagonist, oxybutynin, resulted in slight increase of hypoglossal (but not C4) burst amplitude. Thus, ACh induced different effects on hypoglossal and C4 nerve activity in the brainstem-spinal cord preparation.
Topics: Acetylcholine; Animals; Animals, Newborn; Brain Stem; Chemoreceptor Cells; Hypoglossal Nerve; Intralaminar Thalamic Nuclei; Motor Neurons; Phrenic Nerve; Rats; Rats, Wistar; Respiratory Physiological Phenomena; Spinal Cord
PubMed: 34229065
DOI: 10.1016/j.resp.2021.103737 -
Drug and Alcohol Dependence Sep 2021Establishing preclinical models of the development of nicotine withdrawal following acute nicotine exposure could inform tobacco addiction-related research, treatment,...
BACKGROUND
Establishing preclinical models of the development of nicotine withdrawal following acute nicotine exposure could inform tobacco addiction-related research, treatment, and policy. To this end, this lab has previously reported that rats exhibit withdrawal-like elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) following acute nicotine exposure. The goal of this study was to provide further pharmacological characterization of ICSS as a measure of spontaneous and antagonist-precipitated withdrawal from acute nicotine.
METHODS AND RESULTS
Rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (1.0 mg/kg, s.c.), suggesting a modest spontaneous withdrawal effect (Experiment 1). In Experiment 2, the antidepressant bupropion (5.0 mg/kg, i.p.), which is used to treat tobacco addiction and attenuates nicotine withdrawal in both humans and rodents, blocked elevations in ICSS thresholds induced by a single injection of nicotine (0.5 mg/kg, s.c.) followed ≈ 2 h later by the non-selective, non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (3.0 mg/kg, s.c.). In Experiment 3a, s.c. administration of the competitive, relatively selective α4ß2 nAChR antagonist dihydro-beta-erythroidine (DHßE) (5.6 mg/kg, but not 3.0 mg/kg) following each of 5 daily injections of nicotine (0.5 mg/kg, s.c.) elevated ICSS thresholds. Mecamylamine (3.0 mg/kg, s.c.) also elevated ICSS thresholds when administered following all 5 daily nicotine injections (0.5 mg/kg, s.c., Experiment 3b).
CONCLUSIONS
These findings provide further characterization of elevations in ICSS thresholds as a measure of withdrawal from acute nicotine exposure. Further use of these models may be useful for understanding the early development of nicotine withdrawal.
Topics: Animals; Mecamylamine; Nicotine; Nicotinic Antagonists; Rats; Self Stimulation; Substance Withdrawal Syndrome
PubMed: 34216863
DOI: 10.1016/j.drugalcdep.2021.108870 -
Revue Des Maladies Respiratoires Sep 2021The effectiveness of the three validated smoking cessation medications, nicotine replacement therapy, varenicline and bupropion, may be insufficient, in hard-core... (Review)
Review
INTRODUCTION
The effectiveness of the three validated smoking cessation medications, nicotine replacement therapy, varenicline and bupropion, may be insufficient, in hard-core smokers.
OBJECTIVES
This systematic review investigates the efficacy of combinations of different medications in smoking abstinence and their tolerability.
RESULTS
Three randomized controlled trials (RCTs) compared the combined medications with varenicline and nicotine patches vs. varenicline; two found an increase in abstinence rates with the combined medications. In one study, the beneficial effect was only observed in heavy smokers. The four RCTs comparing the combined medications with varenicline and bupropion (vs. varenicline) demonstrated an increase in abstinence rates with the combined medications, most often in heavy smokers who are very dependent on tobacco. The results of the three RCTs comparing the combined medications with bupropion and nicotine replacement therapy vs. varenicline were discordant. Three studies included other molecules (mecamylamine, selegiline, sertraline, buspirone). Combined medications were well tolerated.
CONCLUSION
Combination treatments can achieve higher smoking abstinence rates than monotherapies, especially in smokers who have failed to quit (Hard-core smokers). Treatment with a combination of varenicline and nicotine replacement therapy is a therapeutic option in smoking cessation.
Topics: Bupropion; Humans; Nicotine; Smoking; Smoking Cessation; Varenicline
PubMed: 34215484
DOI: 10.1016/j.rmr.2021.05.012 -
Biological & Pharmaceutical Bulletin 2021Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the...
Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the medial prefrontal cortex (mPFC) is associated with memory, we examined the role of the mPFC in nicotine-induced enhancement of recognition memory using the novel object recognition test in male C57BL/6J mice. Systemic nicotine administration 10 min before training session significantly enhanced object recognition memory in test session that was performed 24 h after the training. Intra-mPFC infusion of mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, 5 min before nicotine administration blocked the effect of nicotine. Additionally, intra-mPFC infusion of dihydro-β-erythroidine, a selective α4β2 nAChR antagonist, or methyllycaconitine, a selective α7 nAChR antagonist, significantly suppressed the nicotine-induced object recognition memory enhancement. Finally, intra-mPFC infusion of nicotine 1 min before the training session augmented object recognition memory in a dose-dependent manner. These findings suggest that mPFC α4β2 and α7 nAChRs mediate the nicotine-induced object recognition memory enhancement.
Topics: Aconitine; Animals; Dihydro-beta-Erythroidine; Male; Mecamylamine; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Prefrontal Cortex; Receptors, Nicotinic; Recognition, Psychology; alpha7 Nicotinic Acetylcholine Receptor; Mice
PubMed: 34193682
DOI: 10.1248/bpb.b21-00314 -
Biomedicine & Pharmacotherapy =... Aug 2021There is substantial evidence that GABA agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue...
There is substantial evidence that GABA agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABA receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABA receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4β2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4β2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABA receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABA receptors to treat tobacco addiction in humans.
Topics: Animals; Baclofen; Behavior, Animal; Brain; Dopamine; GABA-B Receptor Antagonists; Male; Mecamylamine; Mice; Nicotine; Nicotinic Antagonists; Receptors, GABA-B; Receptors, Nicotinic; Substance Withdrawal Syndrome
PubMed: 34144406
DOI: 10.1016/j.biopha.2021.111786 -
Microorganisms May 2021Recently, we reported that nicotine plays a role in the failure of the macrophage in the clearance of subspecies (MAP) during infection in Crohn's disease smokers. We...
Recently, we reported that nicotine plays a role in the failure of the macrophage in the clearance of subspecies (MAP) during infection in Crohn's disease smokers. We also demonstrated that nicotine enhances macrophages cellular survival during MAP infection. Blocking α7 nicotinic acetylcholine receptor (α7nAChR) with the pharmacological antagonist-mecamylamine-subverted the anti-inflammatory effect of nicotine in macrophages. Yet, it is still unknown how α7nAChR is involved in the modulation of the macrophage response during MAP infection. Here, we studied the mechanistic role of nicotine-α7nAChR interaction in modulating NF-ĸB survival pathway, autophagy, and effect on cathelicidin production in MAP-infected macrophages using THP-1 cell lines. Our results showed that nicotine upregulated α7nAChR expression by 5-folds during MAP infection compared to controls. Bcl-2 expression was also significantly increased after nicotine exposure. Moreover, Nicotine inhibited autophagosome formation whereas infection with MAP in absence of nicotine has significantly increased LC-3b in macrophages. Nicotine also further upregulated NF-ĸB subunits expression including Rel-B and p100, and increased nuclear translocation of p52 protein. We also discovered that cathelicidin production was significantly suppressed in MAP-infected macrophages, treatment with nicotine showed no effect. Overall, the study provides new insight toward understanding the cellular role of nicotine through α7nAChR/NF-ĸB p100/p52 signaling pathway in inducing anti-apoptosis and macrophage survival during MAP infection in Crohn's disease smokers.
PubMed: 34070119
DOI: 10.3390/microorganisms9051086 -
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