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Scientific Reports Sep 2018Repeated nicotine administration has been associated with increased paradoxical sleep in rats and antinociceptive properties, whereas paradoxical sleep deprivation (PSD)...
Repeated nicotine administration has been associated with increased paradoxical sleep in rats and antinociceptive properties, whereas paradoxical sleep deprivation (PSD) elicits pronociceptive and inflammatory responses. Thus, we aimed to evaluate the effect of repeated nicotine administration and its withdrawal combined with PSD on pain sensitivity and inflammatory markers. Sixty adult male Wistar rats were subjected to repeated injections of saline (SAL) or nicotine (NIC) for 12 days or 7 days of nicotine followed by acute mecamylamine administration on day 8 to precipitate nicotine abstinence (ABST). On day 9, the animals were submitted to PSD for 72 h or remained in control condition (CTRL); on day 12, thermal pain threshold was assessed by the hot plate test. PSD significantly decreased the latency to paw withdrawal in all groups compared to their respective controls. ABST-PSD animals presented higher levels of interleukin (IL)-6 compared to all groups, except ABST-CTRL. After adjustment for weight loss, IL-6, IL-4 and tumor necrosis factor alpha, ABST-PSD was associated with the lowest pain threshold. Nicotine and IL-4 levels were predictors of higher pain threshold. Hyperalgesia induced by PSD prevailed over the antinociceptive action of nicotine, while the association between PSD and ABST synergistically increased IL-6 concentrations and decreased pain threshold.
Topics: Animals; Hyperalgesia; Immunity; Interleukin-4; Interleukin-6; Male; Mecamylamine; Nicotine; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Sleep Deprivation; Sleep, REM; Tumor Necrosis Factor-alpha
PubMed: 30218019
DOI: 10.1038/s41598-018-32276-7 -
The Journal of Pharmacology and... Dec 2010Accumulating evidence suggests that acetylcholine nicotinic systems may contribute importantly to the abuse-related effects of d-methamphetamine (d-MA). The present...
Accumulating evidence suggests that acetylcholine nicotinic systems may contribute importantly to the abuse-related effects of d-methamphetamine (d-MA). The present study was conducted to compare the effects of indirect dopamine (DA) agonists (d-amphetamine, d-MA, and l-methamphetamine), full [(-)-nicotine, anabaseine, (+)-epibatidine, (-)-epibatidine, isoarecolone] and partial (varenicline) nicotinic agonists, and other cholinergic compounds (mecamylamine, dihydro-β-erythroidine hydrobromide, methyllycaconitine, atropine, scopolamine, rivastigmine, and donepezil) in rats trained to discriminate 0.3 mg/kg i.p. d-MA from saline. All indirect DA agonists fully substituted for d-MA in a dose-related manner. Among nicotinic agonists, only (-)-nicotine fully substituted for d-MA in a dose-dependent manner, whereas all other nicotinic agonists and, to a limited extent, muscarinic antagonists produced partial d-MA-like responding. Other cholinergic compounds failed to produce d-MA-like discriminative stimulus effects. In drug interaction studies, varenicline served to dose-dependently attenuate the d-MA-like effects of (-)-nicotine, whereas mecamylamine, but not varenicline, reduced the discriminative stimulus effects of the training dose of d-MA. Differences between (-)-nicotine and other nicotinic agonists may be related to their ability to activate the DA system. These results provide further evidence that nicotinic mechanisms may be useful neurochemical targets for the development of therapeutics for the management of monoaminergic stimulant abuse and addiction.
Topics: Animals; Behavior, Animal; Benzazepines; Cholinergic Agents; Cholinesterase Inhibitors; Conditioning, Operant; Dextroamphetamine; Discrimination Learning; Discrimination, Psychological; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Male; Mecamylamine; Methamphetamine; Muscarinic Antagonists; Nicotinic Agonists; Nicotinic Antagonists; Pentobarbital; Quinoxalines; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Varenicline
PubMed: 20847037
DOI: 10.1124/jpet.110.173773 -
Psychopharmacology Jul 2009Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm...
RATIONALE
Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown.
OBJECTIVES
To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice.
MATERIALS AND METHODS
Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-beta-erythroidine, and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry.
RESULTS
Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol.
CONCLUSIONS
Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol.
Topics: Alcoholic Intoxication; Animals; Darkness; Dopamine; Dose-Response Relationship, Drug; Ethanol; Immunohistochemistry; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Neurons; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic; Reward
PubMed: 19247637
DOI: 10.1007/s00213-009-1488-5 -
Neuropharmacology Oct 2013Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but...
Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.
Topics: Animals; Ataxia; Benzazepines; Cerebellum; Dose-Response Relationship, Drug; Gait; Male; Mecamylamine; Motor Activity; Nerve Degeneration; Neural Pathways; Niacinamide; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Olivary Nucleus; Postural Balance; Pyridines; Quinoxalines; Rats; Rotarod Performance Test; Varenicline
PubMed: 23711550
DOI: 10.1016/j.neuropharm.2013.05.016 -
Clinica Chimica Acta; International... Jun 2012Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment.
Simultaneous quantification of nicotine, cotinine, trans-3'-hydroxycotinine, norcotinine and mecamylamine in human urine by liquid chromatography-tandem mass spectrometry.
BACKGROUND
Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment.
METHODS
A simple, rapid and reliable liquid chromatography tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying nicotine, cotinine, trans-3'-hydroxycotinine, norcotinine and mecamylamine in human urine. Chromatography was performed on a Synergi PolarRP column with a gradient of 0.1% formic acid and 0.1% formic acid in acetonitrile at 0.25 ml/min with an 8-min total runtime. Analytes were monitored by positive mode electrospray ionization and multiple reaction monitoring mass spectrometry.
RESULTS
Linear dynamic ranges were 1-500 ng/ml for nicotine and norcotinine, 0.5-500 ng/ml for trans-3'-hydroxycotinine, 0.2-500 ng/ml for cotinine, and 0.1-100 ng/ml for mecamylamine; correlation coefficients were consistently greater than 0.99, and all calibrator concentrations were within 20% of target. Extensive endogenous and exogenous interferences were evaluated. At 3 concentrations spanning the linear dynamic range of the assay, mean extraction efficiencies from urine were 55.1-109.1% with analytical recovery (bias) 82.0-118.7% and total imprecision of 0.7-9.1%. Analytes were stable for 24h at room temperature, 72 h at 4 °C, 72 h in autosampler at 15 °C and after three freeze/thaw cycles.
CONCLUSION
This method is useful for monitoring mecamylamine, nicotine and nicotine metabolites in smoking cessation and other clinical nicotine research.
Topics: Calibration; Chromatography, Liquid; Cotinine; Humans; Mecamylamine; Nicotine; Sensitivity and Specificity; Smoking; Smoking Cessation; Tandem Mass Spectrometry
PubMed: 22394455
DOI: 10.1016/j.cca.2012.02.017 -
Journal of Cellular and Molecular... Nov 2012Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying...
Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10-30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3-1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca(2+) ] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.
Topics: Acetylcholinesterase; Animals; Arterioles; Atropine; Calcium; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Fluoxetine; HSP90 Heat-Shock Proteins; Male; Mecamylamine; Methysergide; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Reperfusion; Serotonin; Selective Serotonin Reuptake Inhibitors; Signal Transduction; Stroke; Vasodilation
PubMed: 22697296
DOI: 10.1111/j.1582-4934.2012.01596.x -
Neuropharmacology Oct 2021Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect...
Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect of this control is modulation of neuronal activity through cholinergic signaling. Nociceptive neurons in the dorsal horn express both nicotinic and muscarinic cholinergic receptors and activation of these receptors reduces pain in humans, while inhibition leads to nociceptive hypersensitivity. At a cellular level, acetylcholine (ACh) has diverse effects on excitability which is dependent on the receptor and neuronal subtypes involved. In the present study we sought to characterize the electrophysiological responses of specific subsets of lamina II interneurons from rat and marmoset spinal cord. Neurons were grouped by morphology and by action potential firing properties. Whole-cell voltage-clamp recordings from lamina II dorsal horn neurons of adult rats showed that bath applied acetylcholine increased, decreased or had no effect on spontaneous synaptic current activity in a cell-type specific manner. ACh modulated inhibitory synaptic activity in 80% of neurons, whereas excitatory synaptic activity was affected in less than 50% of neurons. In whole-cell current clamp recordings, brief somatic application of ACh induced cell-type specific responses in 79% of rat lamina II neurons, which included: depolarization and action potential firing, subthreshold membrane depolarization, biphasic responses characterized by transient depolarization followed by hyperpolarization and membrane hyperpolarization alone. Similar responses were seen in marmoset lamina II neurons and the properties of each neuron group were consistent across species. ACh-induced hyperpolarization was blocked by the muscarinic antagonist atropine and all forms of acetylcholine-induced depolarization were blocked by the nicotinic antagonist mecamylamine. The cholinergic system plays an important role in regulating nociception and this study contributes to our understanding of how circuit activity is controlled by ACh at a cellular level in primate and rodent spinal cord.
Topics: Acetylcholine; Action Potentials; Animals; Atropine; Callithrix; Excitatory Postsynaptic Potentials; Female; Interneurons; Male; Mecamylamine; Mice; Muscarinic Antagonists; Nerve Net; Nicotinic Antagonists; Nociception; Patch-Clamp Techniques; Posterior Horn Cells; Rats; Rats, Sprague-Dawley
PubMed: 34416268
DOI: 10.1016/j.neuropharm.2021.108755 -
Behavioural Brain Research Oct 2016Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. Nicotine, the main psychoactive component of tobacco, appears to...
Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. Nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. Nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance. These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Locomotion; Male; Mecamylamine; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY
PubMed: 27363925
DOI: 10.1016/j.bbr.2016.06.050 -
Psychopharmacology Apr 2016Processes of attention have a heritable component, suggesting that genetic predispositions may predict variability in the response to attention-enhancing drugs. Among...
RATIONALE
Processes of attention have a heritable component, suggesting that genetic predispositions may predict variability in the response to attention-enhancing drugs. Among lead compounds with attention-enhancing properties are nicotinic acetylcholine receptor (nAChR) agonists.
OBJECTIVES
This study aims to test, by comparing three rat strains, whether genotype may influence the sensitivity to nicotine in the 5-choice serial reaction time task (5-CSRTT), a rodent model of attention.
METHODS
Strains tested were Long Evans (LE), Sprague Dawley (SD), and Wistar rats. The 5-CSRTT requires responses to light stimuli presented randomly in one of five locations. The effect of interest was an increased percentage of responses in the correct location (accuracy), the strongest indicator of improved attention.
RESULTS
Nicotine (0.05-0.2 mg/kg s.c.) reduced omission errors and response latency and increased anticipatory responding in all strains. In contrast, nicotine dose-dependently increased accuracy in Wistar rats only. The nAChR antagonist mecamylamine (0.75-3 mg/kg s.c.) increased omissions, slowed responses, and reduced anticipatory responding in all strains. There were no effects on accuracy, which was surprising giving the clear improvement with nicotine in the Wistar group.
CONCLUSIONS
The findings suggest strain differences in the attention-enhancing effects of nicotine, which would indicate that genetic predispositions predict variability in the efficacy of nAChR compounds for enhancing attention. The absence of effect of mecamylamine on response accuracy may suggest a contribution of nAChR desensitization to the attention-enhancing effects of nicotine.
Topics: Animals; Attention; Dose-Response Relationship, Drug; Male; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Nicotinic; Species Specificity
PubMed: 26875755
DOI: 10.1007/s00213-016-4236-7 -
Scientific Reports Oct 2016Traditional uses and current results highlight the neuroprotective properties of Rosmarinus officinalis L. The compelling need for novel strategies able to relieve...
Traditional uses and current results highlight the neuroprotective properties of Rosmarinus officinalis L. The compelling need for novel strategies able to relieve neuropathic pain encouraged us to analyze different rosemary leaf extracts in rats following chronic constriction injury (CCI) of sciatic nerve. Ethanol, acetone, and the innovative ultrasound-hexane extractive methods were used to obtain: EE, AE, and for hexane extracts UREprel and URE. Extracts were characterized in terms of typical constituents and repeatedly administered to CCI-rats (13-days treatment, from the day of surgery). URE showed the best efficacy and potency in reducing hypersensitivity to noxious- and non-noxious stimuli and spontaneous pain. URE contained the higher quantity of the terpenoid carnosic acid (CA) and its efficacy was compared to pure CA. Histological analysis of the sciatic nerve revealed that URE prevented axon and myelin derangement, edema and inflammatory infiltrate. In the dorsal horn of the spinal cord, URE did not reduce astrocyte activation. Both the pain reliever and the neuroconservative effects of URE were significantly prevented by the nicotinic receptor (nAChR) antagonist mecamylamine. In conclusion, the hexane-ultrasound rosemary extract is able to reduce neuropathic hypersensitivity and protect nervous tissues. Effectiveness is mainly related to the terpenoid fraction by mechanisms involving nAChRs.
Topics: Abietanes; Analgesics, Non-Narcotic; Animals; Chemical Fractionation; Disease Models, Animal; Mecamylamine; Neuralgia; Neuroprotective Agents; Nicotinic Antagonists; Plant Extracts; Rats, Sprague-Dawley; Receptors, Nicotinic; Rosmarinus; Sciatic Nerve; Solvents; Spinal Cord; Terpenes
PubMed: 27713514
DOI: 10.1038/srep34832