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Schizophrenia Research Mar 2007Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting.
METHODS
Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner.
RESULTS
Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement.
CONCLUSIONS
1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.
Topics: Acute Disease; Adult; Cotinine; Demography; Depression; Female; Humans; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Prevalence; Psychotic Disorders; Receptors, Nicotinic; Recurrence; Schizophrenia; Severity of Illness Index; Smoking Cessation; Smoking Prevention; Substance Withdrawal Syndrome; Surveys and Questionnaires; Tobacco Use Disorder
PubMed: 17293085
DOI: 10.1016/j.schres.2006.12.007 -
British Journal of Pharmacology Dec 2014Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor...
BACKGROUND AND PURPOSE
Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission.
EXPERIMENT APPROACH
Perfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively.
KEY RESULTS
Periarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca(2+) -free medium.
CONCLUSION AND IMPLICATION
These results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves.
Topics: Acetylcholine; Adrenergic Neurons; Animals; Atropine; Axons; Calcitonin Gene-Related Peptide; Capsaicin; Cholinergic Agonists; Guanethidine; Hydrogen-Ion Concentration; Mecamylamine; Mesenteric Arteries; Muscarinic Antagonists; Nicotinic Antagonists; Protons; Rats; Ruthenium Red; Sympatholytics; Synaptic Transmission; Vasoconstriction; Vasodilation
PubMed: 25117291
DOI: 10.1111/bph.12878 -
Neurobiology of Learning and Memory Oct 2021Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2...
Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.
Topics: Aconitine; Animals; Conditioning, Operant; Dihydro-beta-Erythroidine; Female; Macaca mulatta; Male; Mecamylamine; Memory, Short-Term; Muscarinic Antagonists; Nicotinic Antagonists; Scopolamine
PubMed: 34425219
DOI: 10.1016/j.nlm.2021.107505 -
Psychopharmacology Sep 2022The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working...
RATIONALE
The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working memory (WM), the underlying mechanism remains unclear. It is widely accepted that WM consists of multiple functional modules, one storing short-term memory and the other manipulating and utilizing it. A recently developed visual search task and a relevant model can be used to assess multiple components of WM during administration of acetylcholine receptor (AChR)-related substances.
OBJECTIVES
The effects of systemic administration of AChR-related agents on WM and eye movements were examined during the oculomotor foraging task.
METHODS
Three monkeys performing the task received an intramuscular injection of saline or the following AChR-related agents: nicotine (24 or 56 μg/kg), mecamylamine (nicotinic AChR antagonist, 1.0 mg/kg), oxotremorine (muscarinic AChR agonist, 3.0 µg/kg), and scopolamine (muscarinic AChR antagonist, 20 μg/kg). The task was to find a target among 15 identical objects by making eye movements within 6 s. The data were analyzed according to the foraging model that incorporated three parameters.
RESULTS
Nicotine and mecamylamine significantly increased the utility but not the capacity of short-term memory, while muscarinic AChR-related agents did not alter any WM parameters. Further regression analyses with a mixed-effect model showed that the beneficial effect of nicotine on memory utility remained after considering eye movement variability, but the beneficial effect of mecamylamine disappeared.
CONCLUSIONS
Nicotine improves visual search, mainly by increasing the utility of short-term memory, with minimal changes in oculomotor parameters.
Topics: Animals; Haplorhini; Macaca; Mecamylamine; Memory, Short-Term; Muscarinic Antagonists; Nicotine; Nicotinic Antagonists; Receptors, Muscarinic
PubMed: 35802143
DOI: 10.1007/s00213-022-06186-6 -
Behavioural Brain Research Apr 2015This paper reviews the evidence for nicotine-induced acceleration of the internal clock when timing in the seconds-to-minutes timescale, and proposes an alternative...
This paper reviews the evidence for nicotine-induced acceleration of the internal clock when timing in the seconds-to-minutes timescale, and proposes an alternative explanation to this evidence: that nicotine reduces the threshold for responses that result in more reinforcement. These two hypotheses were tested in male Wistar rats using a novel timing task. In this task, rats were trained to seek food at one location after 8s since trial onset and at a different location after 16s. Some rats received the same reward at both times (group SAME); some received a larger reward at 16s (group DIFF). Steady baseline performance was followed by 3 days of subcutaneous nicotine administration (0.3mg/kg), baseline recovery, and an antagonist challenge (mecamylamine, 1.0mg/kg). Nicotine induced a larger, immediate reduction in latencies to switch (LTS) in group DIFF than in group SAME. This effect was sustained throughout nicotine administration. Mecamylamine pretreatment and nicotine discontinuation rapidly recovered baseline performance. These results support a response-threshold account of nicotinic disruption of timing performance, possibly mediated by nicotinic acetylcholine receptors. A detailed analysis of the distribution of LTSs suggests that anomalous effects of nicotine on LTS dispersion may be due to loss of temporal control of behavior.
Topics: Animals; Appetitive Behavior; Male; Mecamylamine; Neuropsychological Tests; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats, Wistar; Reward; Time Perception
PubMed: 25637907
DOI: 10.1016/j.bbr.2015.01.027 -
British Journal of Clinical Pharmacology May 2018Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.
METHODS
This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.
RESULTS
Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and β power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine.
CONCLUSIONS
Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.
Topics: Adolescent; Adult; Cognition; Cross-Over Studies; Double-Blind Method; Drug Interactions; Electroencephalography; Galantamine; Healthy Volunteers; Humans; Male; Mecamylamine; Middle Aged; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Reaction Time; Young Adult
PubMed: 29319910
DOI: 10.1111/bcp.13507 -
CNS & Neurological Disorders Drug... Mar 2010Alcohol use disorders (AUDs) are complex, and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy... (Review)
Review
Alcohol use disorders (AUDs) are complex, and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy approaches. Epidemiological studies have shown there is a high correlation between alcohol consumption and tobacco use, and the prevalence of smoking in alcoholics is as high as 80% compared to about 30% for the general population. Both preclinical and clinical data provide evidence that nicotine administration increases alcohol intake and non-specific nicotinic receptor antagonists reduce alcohol-mediated behaviors. As nicotine interacts specifically with the neuronal nicotinic acetylcholine receptor (nAChR) system, this suggests that nAChRs play an important role in the behavioral effects of alcohol. In this review, we discuss the importance of nAChRs for the treatment of AUDs and argue that the use of FDA approved nAChR ligands, such as varenicline and mecamylamine, approved as smoking cessation aids may prove to be valuable treatments for AUDs. We also address the importance of combining effective medications with behavioral therapy for the treatment of alcohol dependent individuals.
Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; Benzazepines; Brain; Humans; Mecamylamine; Neurons; Nicotinic Agonists; Nicotinic Antagonists; Quinoxalines; Receptors, Nicotinic; Tobacco Use Disorder; Varenicline
PubMed: 20201817
DOI: 10.2174/187152710790966597 -
British Journal of Clinical Pharmacology Aug 2017The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point... (Comparative Study)
Comparative Study Randomized Controlled Trial
AIMS
The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model.
METHODS
In this double-blind, placebo-controlled, four-way cross-over trial, 12 healthy male subjects received oral mecamylamine 10 and 20 mg, intravenous scopolamine 0.5 mg and placebo. Pharmacokinetics were analysed using non-compartmental analysis. Pharmacodynamic effects were measured with a multidimensional test battery that includes neurophysiological, subjective, (visuo)motor and cognitive measurements.
RESULTS
All treatments were safe and well tolerated. Mecamylamine had a t of 2.5 h and a C of 64.5 ng ml for the 20 mg dose. Mecamylamine had a dose-dependent effect decreasing the adaptive tracking performance and VAS alertness, and increasing the finger tapping and visual verbal learning task performance time and errors. Scopolamine significantly affected almost all pharmacodynamic tests.
CONCLUSION
This study demonstrated that mecamylamine causes nicotinic receptor specific temporary decline in cognitive functioning. Compared with the scopolamine model, pharmacodynamic effects were less pronounced at the dose levels tested; however, mecamylamine caused less sedation. The cognitive effects of scopolamine might at least partly be caused by sedation. Whether the mecamylamine model can be used for proof-of-pharmacology of nicotinic acetylcholine receptor agonists remains to be established.
Topics: Adult; Attention; Brain; Cognition; Cross-Over Studies; Double-Blind Method; Electroencephalography; Healthy Volunteers; Humans; Hypnotics and Sedatives; Learning; Male; Mecamylamine; Muscarinic Antagonists; Nicotine; Nicotinic Antagonists; Receptors, Muscarinic; Receptors, Nicotinic; Scopolamine; Time Factors; Young Adult
PubMed: 28217868
DOI: 10.1111/bcp.13268 -
British Journal of Pharmacology Dec 2020Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid...
BACKGROUND AND PURPOSE
Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown.
EXPERIMENTAL APPROACH
Transepithelial short circuit currents (I ) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca ] were studied on freshly dissociated mouse tracheal epithelial cells.
KEY RESULTS
Apical application of the nAChR agonist nicotine transiently increased I . The nicotine effect was abolished by the nAChR antagonist mecamylamine. α-Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A-85380 (α4β2 and α3β4) increased I . The antagonists dihydro-β-erythroidine (α4β2, α3β2, α4β4 and α3β4), α-conotoxin MII (α3β2) and α-conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine- and epibatidine-induced currents were unaltered in β2 mice, but in β4 mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca -ATPase inhibitor) or the ryanodine receptor antagonists JTV-519 and dantrolene there was a reduction in the nicotine-effect, indicating involvement of Ca release from intracellular stores. Additionally, the PKA inhibitor H-89 and the TMEM16A (Ca -activated chloride channel) inhibitor T16Ainh-A01 significantly reduced the nicotine-effect.
CONCLUSION AND IMPLICATIONS
α3β4 nAChRs are responsible for the nicotine-induced current changes via Ca release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A.
Topics: Acetylcholine; Animals; Dihydro-beta-Erythroidine; Mecamylamine; Mice; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Receptors, Nicotinic
PubMed: 32959891
DOI: 10.1111/bph.15270 -
Pharmacology, Biochemistry, and Behavior Dec 2009Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more... (Comparative Study)
Comparative Study
Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for beta2*, alpha7*, alpha6beta2*, and alpha3beta4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-beta-erythroidine (DHbetaE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHbetaE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis-picolinium analogs (N, N'-(3, 3'-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target alpha3beta4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that beta2* and potentially alpha3beta4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids.
Topics: Animals; Conditioning, Psychological; Dextromethorphan; Dihydro-beta-Erythroidine; Male; Mecamylamine; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic
PubMed: 19778551
DOI: 10.1016/j.pbb.2009.09.012