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Relief from increases in anxiety during nicotine withdrawal contributes to tobacco addiction. While a variety of anxiogenic stimuli elicit avoidance of the center of an open field (thigmotaxis) in rodents, effects of nicotine withdrawal on thigmotaxis have not been studied extensively. The goal of this study was to evaluate determinants of increases in thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats. We evaluated several variables implicated in severity of other measures of precipitated nicotine withdrawal: mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age. In Experiment 1, mecamylamine elicited increases in thigmotaxis in adult rats receiving a chronic nicotine infusion (3.2 mg/kg/day for >7 days) at only the highest mecamylamine dose tested (4.0 mg/kg). In Experiment 2, repeated administration of 4.0 mg/kg mecamylamine throughout the course of a 2-week chronic nicotine infusion (3.2 mg/kg/day) did not affect thigmotaxis when administered following 2 days of the infusion, but elicited significant increases in thigmotaxis at longer infusion durations. In Experiment 3, adolescents tested under the same protocol used in adults in Experiment 2 did not exhibit increased thigmotaxis at any point during the 2-week nicotine infusion, even though we used higher nicotine doses (4.7 or 6.4 mg/kg/day) to account for the faster metabolism of nicotine in adolescents compared to adults. Our findings provide the first systematic characterization of determinants of increases in thigmotaxis during precipitated nicotine withdrawal in rats. Further use of this model may be useful for characterizing the mechanisms underlying the anxiogenic component of nicotine withdrawal., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three-chamber social interaction, self-grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. LAY SUMMARY: The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism-related behavioral features. In addition, the brain of the autistic-like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311-1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc., (© 2020 International Society for Autism Research, Wiley Periodicals, LLC.)

Introduction: Tobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system., Methods: To investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks)., Results: During the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake., Conclusions: A brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence., Implications: These animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Female smokers are more likely to relapse than male smokers, but little is known about sex differences in nicotine withdrawal. Therefore, male and female rats were prepared with minipumps that contained nicotine or saline and sex differences in precipitated and spontaneous nicotine withdrawal were investigated. The intracranial self-stimulation (ICSS) procedure was used to assess mood states. Elevations in brain reward thresholds reflect a deficit in reward function. Anxiety-like behavior was investigated after the acute nicotine withdrawal phase in a large open field and the elevated plus maze test. The nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-treated rats but did not affect those of the saline-treated control rats. A low dose of mecamylamine elevated the brain reward thresholds of the nicotine-treated male rats but not those of the females. Mecamylamine also precipitated more somatic withdrawal signs in the nicotine-treated male than female rats. Minipump removal elevated the brain reward thresholds of the nicotine-treated rats for about 36 h but did not affect those of the saline-treated rats. There was no sex difference in the reward deficit during spontaneous nicotine withdrawal. In addition, the nicotine-treated male and female rats did not display increased anxiety-like behavior three to four days after minipump removal. In conclusion, these studies suggest that relatively low doses of a nicotinic receptor antagonist induce a greater reward deficit and more somatic withdrawal signs in male than female rats, but there is no sex difference in the reward deficit during spontaneous withdrawal., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cigarette smoking and resultant nicotine dependence remain major public health problems. Most smokers begin before the age of 18, yet preclinical models have insufficiently characterized the development of nicotine dependence in adolescence. To categorize the short-term effects of chronic nicotine administration throughout adolescence and adulthood, we exposed male Sprague Dawley rats to 14 days of continuously delivered nicotine (0, 1.2 or 4.8 mg/kg/d) using a subcutaneous osmotic minipump, starting between postnatal day 33 (p33) and p96. Next, to explore the effects of extended exposure to chronic nicotine, we exposed male Sprague Dawley rats to 42 days of continuous nicotine starting in adolescence (p33) or early adulthood (p68). Somatic and affective signs of precipitated withdrawal (PW) were observed after a mecamylamine (1.5 mg/kg, i.p.) challenge as compared to a saline injection. Short term nicotine exposure starting at p96, well within the adult period, elicited a significant increase in somatic PW as measured by a composite behavioral score. In contrast, adolescent exposure to nicotine elicited a unique behavioral profile, dependent on the starting age of exposure. Late adolescence exposure was characterized by scratching while adult exposure was characterized by facial tremors and yawns. Extended exposure to nicotine resulted in age specific characteristic nicotine withdrawal behaviors, including scratches, ptosis and locomotion, distinct from the short-term exposure. Thus, nicotine dependence severity, based on the expression of total somatic PW behaviors, is not observed until the adult period, and differences between adolescents and adults are observed using a more nuanced behavioral scoring approach. We conclude that age of nicotine initiation affects somatic withdrawal signs and their magnitude. These data serve as a foundation for understanding the underlying brain mechanisms of nicotine dependence and their development over adolescence and early adulthood., (Published by Elsevier Inc.)

Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the mecamylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi-effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlorisondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. Based on the current results, the therapeutic use of mecamylamine (i.e., for smoking or to alleviate green tobacco sickness) should be weighed against the potential for mecamylamine to produce interoceptive effects that overlap with another class of abused drugs (i.e., NMDA receptor agonists)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mecamylamine is a nicotinic acetylcholine receptor (nAChR) antagonist that was recently used in a clinical trial to treat alcohol use disorder (AUD) in both smokers and non-smokers. The current manuscript reports a reanalysis of data from this clinical trial in which we examine changes in smoking that occurred over the course of the trial. We focused on examining the effects of mecamylamine on smoking and the association between reductions in alcohol use and smoking. Participants were the subgroup of smokers who participated in the clinical trial of mecamylamine (10 mg/day) to treat their AUD (n = 76). Smoking was assessed prior to randomization and tracked throughout the course of the 12-week medication treatment phase. Participants were categorized as treatment responders or non-responders based on their changes in drinking over the course of the clinical trial. Participants showed a reduction in smoking over the course of the clinical trial, but there were no significant differences in smoking outcomes between the mecamylamine and placebo groups. Among moderate/high dependence smokers, those who successfully reduced drinking showed a significant reduction in cigarettes smoked per day over the clinical trial. Mecamylamine had no detectable effect on smoking outcomes. Reductions in alcohol use predicted more favorable smoking outcomes among moderate/high tobacco dependence smokers irrespective of medication condition. The reduction in smoking among patients who decreased their alcohol use responders highlights an opportunity for patients being treated for AUD to reduce their smoking., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system., Methods: In a four-way cross-over study, eyes-closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine-a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects-with co-administration of placebo, nicotine or galantamine., Results: Using machine learning to optimally contrast the effects of 30 mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (∼95% non-cross-validated, ∼70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16 mg of galantamine as well as administering 21 mg of nicotine transdermally., Conclusions: Our findings indicate that the mecamylamine challenge model jointly with the nAChR index-a measure of the nicotinic EEG profile-could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds., Significance: This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The aversive effect of nicotine withdrawal is greater in female versus male rats, and we postulate that this sex difference is mediated in the nucleus accumbens (NAc). Nicotine withdrawal induces decreases in NAc dopamine and increases in acetylcholine (ACh) levels in male rats. To our knowledge, these neurochemical markers of nicotine withdrawal have not been compared in female versus male rats. Given the role of amino acids in modulating NAc dopaminergic and cholinergic transmission, concomitant measures of gamma-aminobutyric acid (GABA) and glutamate levels were also compared across sex. Rats received continuous nicotine exposure for 14 days, and then NAc dialysate was collected during baseline and following administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal. Chronic nicotine exposure was associated with larger increases in baseline dopamine, GABA and glutamate levels in the NAc of female versus male rats, whereas baseline ACh was only increased in male rats. During withdrawal, both sexes displayed equivalent increases in NAc ACh levels. As expected, male rats displayed decreases in dopamine, coupled with increases in GABA and decreases in glutamate levels, suggesting the possibility of increased inhibitory tone in the NAc during withdrawal. Relative to males, female rats displayed larger decreases in NAc dopamine and related increases in GABAergic transmission. As female rats also showed elevated glutamate levels that persist during withdrawal, it is suggested that sex differences may arise from increased glutamatergic drive of inhibitory tone in the NAc. The findings provide a potential mechanism whereby the aversive effects of nicotine withdrawal are enhanced in female rats., (© 2017 Society for the Study of Addiction.)

Rationale: Recent preclinical data has implicated the α7 nicotinic acetylcholine receptor (nAChR) as a target in modulating nicotine reward. However, the role of the channel properties of the α7 nAChR in nicotine withdrawal is unknown., Objectives: This study aimed to investigate the impact of α7 nAChR pharmacological modulation on mecamylamine-precipitated nicotine withdrawal behaviors in mice by using positive allosteric modulators (PAMs)., Methods: The effect of the orthosteric α7 nAChR full agonist PNU282987 (1, 3, 9 mg/kg, s.c.), type I α7 PAM NS1738 (1 and 10 mg/kg; i.p.) and the type II α7 PAM PNU120596 (3 and 9 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured in mice undergoing mecamylamine-precipitated nicotine withdrawal. Mice were infused with 24 mg/kg/day nicotine or saline for 14 days using s.c. osmotic minipumps. Nicotine withdrawal signs were precipitated upon administration of the non-selective nAChR antagonist mecamylamine (3.5 mg/kg, i.p.)., Results: Anxiety-like behavior in nicotine withdrawn mice was only attenuated by PNU282987 in a dose-related fashion. Somatic signs were reduced by PNU282987 and NS1738. PNU120596 was the only compound that reversed precipitated nicotine withdrawal-induced hyperalgesia., Conclusions: Taken together, our results suggest that modulation of the α7 nAChR can play important roles in mecamylamine-precipitated nicotine withdrawal behaviors in mice. In addition, the effects of PAMs in this study suggest that endogenous acetylcholine/choline tone is sufficient to attenuate some aspects of precipitated nicotine withdrawal. These findings highlight a beneficial effect of using α7 nAChR PAMs in some aspects of precipitated nicotine withdrawal.

Inhaled cigarette smoke stimulated vagal bronchopulmonary C fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was performed to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by an equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed the following: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance reached a peak of 588 ± 205% (mean ± SE) in 10-40 s, which gradually returned to baseline after 1-5 min. 2) Pretreatment with either atropine (iv) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves. NEW & NOTEWORTHY Recent reports revealed that nicotine at high concentration activated transient receptor potential ankyrin 1 receptor (TRPA1) expressed in vagal bronchopulmonary sensory nerves. This study showed that inhalation of a single breath of nicotine aerosol consistently evoked acute bronchoconstriction that was mediated through the cholinergic reflex pathway and triggered by activation of nicotinic acetylcholine receptor, but not TRPA1, located in these nerves. This is new and important information considering the recent rapid and alarming rise in the prevalence of e-cigarette use for nicotine inhalation.

The capacity to adjust actions based on new information is a vital cognitive function. An animal's ability to adapt behavioral responses according to changes in reward value can be measured using a reinforcer devaluation task, wherein the desirability of a given object is reduced by decreasing the value of the associated food reinforcement. Elements of the neural circuits serving this ability have been studied in both rodents and nonhuman primates. Specifically, the basolateral amygdala, orbitofrontal cortex, nucleus accumbens, and mediodorsal thalamus have each been shown to play a critical role in the process of value updating, required for adaptive goal selection. As these regions receive dense cholinergic input, we investigated whether systemic injections of non-selective nicotinic or muscarinic acetylcholine receptor antagonists, mecamylamine and scopolamine, respectively, would impair performance on a reinforcer devaluation task. Here we demonstrate that in the presence of either a nicotinic or muscarinic antagonist, animals are able to shift their behavioral responses in an appropriate manner, suggesting that disruption of cholinergic neuromodulation is not sufficient to disrupt value updating, and subsequent goal selection, in rhesus macaques., (Published by Elsevier B.V.)

Background: In the gastrointestinal tract of several species, facilitating 5-HT 4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT 4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract., Methods: In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride., Key Results: Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808., Conclusions & Inferences: In the murine gastrointestinal tract, activation of 5-HT 4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species., (© 2017 John Wiley & Sons Ltd.)

In addition to the T2R bitter taste receptors, neuronal nicotinic acetylcholine receptors (nAChRs) have recently been shown to be involved in the bitter taste transduction of nicotine, acetylcholine and ethanol. However, at present it is not clear if nAChRs are expressed in enteroendocrine cells other than beta cells of the pancreas and enterochromaffin cells, and if they play a role in the synthesis and release of neurohumoral peptides. Accordingly, we investigated the expression and functional role of nAChRs in enteroendocrine STC-1 cells. Our studies using RT-PCR, qRT-PCR, immunohistochemical and Western blotting techniques demonstrate that STC-1 cells express several α and β nAChR subunits. Exposing STC-1 cells to nicotine acutely (24h) or chronically (4 days) induced a differential increase in the expression of nAChR subunit mRNA and protein in a dose- and time-dependent fashion. Mecamylamine, a non-selective antagonist of nAChRs, inhibited the nicotine-induced increase in mRNA expression of nAChRs. Exposing STC-1 cells to nicotine increased intracellular Ca2+ in a dose-dependent manner that was inhibited in the presence of mecamylamine or dihydro-β-erythroidine, a α4β2 nAChR antagonist. Brain-derived neurotrophic factor (BDNF) mRNA and protein were detected in STC-1 cells using RT-PCR, specific BDNF antibody, and enzyme-linked immunosorbent assay. Acute nicotine exposure (30 min) decreased the cellular content of BDNF in STC-1 cells. The nicotine-induced decrease in BDNF was inhibited in the presence of mecamylamine. We also detected α3 and β4 mRNA in intestinal mucosal cells and α3 protein expression in intestinal enteroendocrine cells. We conclude that STC-1 cells and intestinal enteroendocrine cells express nAChRs. In STC-1 cells nAChR expression is modulated by exposure to nicotine in a dose- and time-dependent manner. Nicotine interacts with nAChRs and inhibits BDNF expression in STC-1 cells., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

It is well known that the cerebellar fastigial nucleus (FN) is involved in cardiovascular modulation, and has direct evidence of cholinergic activity; however, whether and how acetylcholine (ACh) in the FN modulates blood pressure has not been investigated. In this study, we analyzed mean arterial pressure, maximal change in mean arterial pressure, and the reaction time of blood pressure changes after microinjection of cholinergic reagents into the FN in anesthetized rats. The results showed that ACh evoked a concentration-dependent (10, 30 and 100mM) effect on blood pressure down-regulation. The muscarinic ACh (mACh) receptor antagonist atropine, but not the nicotinic ACh (nACh) receptor antagonist mecamylamine, blocked the ACh-mediated depressor response. The mACh receptor agonist oxotremorine M, rather than nACh receptor agonist nicotine, mimicked the ACh-mediated blood pressure decrease in a dose-dependent manner (10, 30 and 100mM). These results indicate that cholinergic input in the cerebellar FN exerts a depressor effect on systemic blood pressure regulation, and such effects are substantially contributed by mACh rather than nACh receptors, although the precise mechanism concerning the role of mACh receptor in FN-mediated blood pressure modulation remains to be elucidated., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Although osmotic minipumps are a reliable method for inducing nicotine dependence in rodents, continuous nicotine administration does not accurately model the intermittent pattern of nicotine intake in cigarette smokers. Our objectives, therefore, were to investigate whether intermittent nicotine delivery via osmotic minipumps could induce dependence in rats, and to compare the magnitude and duration of withdrawal following forced abstinence from intermittent nicotine to that induced by continuous nicotine administration. In order to administer nicotine intermittently, rats were surgically implanted with saline-filled osmotic minipumps attached to polyethylene tubing that contained hourly unit doses of nicotine alternating with mineral oil to mimic "injections". Three doses of nicotine (1.2, 2.4, and 4.8mg/kg/day) and saline were administered for 14days using this method. In order to compare our intermittent delivery method with the more traditional continuous nicotine delivery, a second group of rats was implanted with minipumps attached to tubing that delivered continuous nicotine for 14days. Rats were administered a 1.5mg/kg subcutaneous (SC) mecamylamine challenge and observed for somatic signs of withdrawal on days 7, 14, 21, and 28 following minipump implantation. Fifteen somatic withdrawal signs were summed within a 50-minute observation period to obtain a composite Dependence Score. A generalized linear mixed-effects model revealed a significant Day×Dose×Method interaction. Amongst continuously-treated rats, only 4.8mg/kg/d nicotine resulted in dependence scores significantly greater than those of controls at 14days of exposure. In contrast, all intermittent nicotine groups showed significantly higher scores beginning at 7days of exposure and persisting beyond 7days of abstinence. In general, intermittent delivery produced a more robust withdrawal syndrome than continuous delivery, and did so at a lower dose threshold and with greater persistence after forced abstinence., (Published by Elsevier Inc.)

Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective symptoms, withdrawal-related cognitive deficits are considered to be a critical symptom that predict relapse. Therefore, delineating the cognitive mechanisms of nicotine withdrawal may likely provide gainful insights into the neurobiology of nicotine addiction. The present study was designed to examine the effects of nicotine withdrawal induced by mecamylamine, a non-specific nicotinic receptor (nAChR) antagonist, on cognitive control processes in mice using an operant strategy switching task. Brain-derived neurotrophic factor (BDNF) modulates synaptic transmission in frontostriatal circuits, and these circuits are critical for executive functions. Thus, we examined the effects of mecamylamine-precipitated nicotine withdrawal on prefrontal and striatal BDNF protein expression. Mice undergoing precipitated nicotine withdrawal required more trials to attain strategy switching criterion as compared to the controls. Error analysis indicated that impaired performance in these animals was mostly related to their inability to execute the new strategy. The striatal/prefrontal BDNF ratios robustly increased following precipitated nicotine withdrawal. Moreover, higher BDNF ratios were associated with longer task acquisition. Collectively, our findings illustrate that mecamylamine-induced nicotine withdrawal disrupts cognitive control processes and that these changes are possibly linked to perturbations in frontostriatal BDNF signaling., (Copyright © 2016 Elsevier Inc. All rights reserved.)

One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs., ((c) 2015 APA, all rights reserved).)

Objectives: To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment., Methods: Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout., Results: Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth., Conclusions: TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.

Rats display both conditioned flavor preference (CFP) for fructose, and conditioned flavor avoidance (CFA) following sweet adulteration with quinine. Previous pharmacological analyses revealed that fructose-CFP expression was significantly reduced by dopamine (DA) D1 or D2 antagonists, but not NMDA or opioid antagonists. Fructose-CFP acquisition was significantly reduced by DA D1, DA D2 or NMDA antagonists, but not opioid antagonists. Quinine-CFA acquisition was significantly enhanced and prolonged by DA D1, NMDA or opioid, but not DA D2 antagonists. Cholinergic interneurons and projections interact with DA systems in the nucleus accumbens and ventral tegmental area. Further, both muscarinic and nicotinic cholinergic receptor signaling have been implicated in sweet intake and development of food-related preferences. Therefore, the present study examined whether systemic administration of muscarinic (scopolamine: SCOP) or nicotinic (mecamylamine: MEC) cholinergic receptor antagonists mediated fructose-CFP expression, fructose-CFP acquisition and quinine-CFA acquisition. For fructose-CFP expression, rats were trained over 10 sessions with a CS+ flavor in 8% fructose and 0.2% saccharin and a CS- flavor in 0.2% saccharin. Two-bottle choice tests with CS+ and CS- flavors mixed in 0.2% saccharin occurred following vehicle, SCOP (0.1-10mg/kg) and MEC (1-8mg/kg). For fructose-CFP acquisition, six groups of rats received vehicle, SCOP (1 or 2.5mg/kg), MEC (4 or 6mg/kg) or a limited intake vehicle control 0.5h prior to 10 CS+ and CS- training sessions followed by six 2-bottle CS+ and CS- choice tests in 0.2% saccharin. For quinine-CFA acquisition, five groups of rats received vehicle, SCOP (1 or 2.5mg/kg) or MEC (4 or 6mg/kg) 0.5h prior to 8 one-bottle CS- (8% fructose+0.2% saccharin: FS) and CS+ (fructose+saccharin+quinine (0.030%: FSQ) training sessions followed by six 2-bottle CS- and CS+ choice tests in fructose-saccharin solutions. Fructose-CFP expression was significantly reduced by SCOP (2.5-10mg/kg: 65-68%) and MEC (4-8mg/kg: 67-73%) relative to vehicle (89-90%), that occurred only when antagonist doses reduced total saccharin intake but in which CS+ intake was still significantly higher than CS- intake. Fructose-CFP acquisition was eliminated by SCOP at doses of 1 (40-54%) and 2.5 (45-58%)mg/kg, and was accompanied by a failure to observe CS+ and CS- intake differences during testing relative to vehicle (85-92%) and limited control (74-88%) conditions. In contrast, MEC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was significantly enhanced and prolonged by MEC at 4 (18-24%) and 6 (11-13%) mg/kg relative to vehicle (34-48%). In contrast, SCOP failed to alter quinine-CFA acquisition. These data implicate the cholinergic receptor system in mediating acquisition (learning) of sugar-induced preferences and quinine-induced aversions with muscarinic receptor signaling controlling the former and nicotinic receptor signaling controlling the latter., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Nicotinic acetylcholine and opioid receptors are involved in modulation of pain. In the present study, we investigated the effects of microinjection of nicotinic acetylcholine and opioid compounds into the ventral orbital cortex (VOC) on the formalin-induced orofacial pain in rats. For this purpose, two guide cannulas were placed into the left and right sides of the VOC of the brain. Orofacial pain was induced by subcutaneous injection of a diluted formalin solution (50μl, 1.5%) into the right vibrissa pad and face rubbing durations were recorded at 3-min blocks for 45min. Formalin produced a marked biphasic pain response (first phase: 0-3min and second phase: 15-33min). Epibatidine (a nicotinic receptor agonist) at doses of 0.05, 0.1 and 0.2μg/site, morphine (an opioid receptor agonist) at doses of 0.5, 1 and 2μg/site and their sub-analgesic doses (0.025μg/site epibatidine with 0.25μg/site morphine) combination treatment suppressed the second phase of pain. The antinociceptive effect induced by 0.2μg/site of epibatidine, but not morphine (2μg/site), was prevented by 2μg/site of mecamylamine (a nicotinic receptor antagonist). Naloxone (an opioid receptor antagonist) at a dose of 2μg/site prevented the antinociceptive effects induced by 2μg/site of morphine and 0.2μg/site of epibatidine. No above-mentioned chemical compounds affected locomotor activity. These results showed that at the VOC level, epibatidine and morphine produced antinociception. In addition, opioid receptor might be involved in epibatidine-induced antinociception, but the antinociception induced by morphine was not mediated through nicotinic acetylcholine receptor., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.

Background and Objective: Dexmecamylamine (TC-5214) is a nicotinic channel modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis., Methods: A single-dose, open-label, parallel-group study was conducted at two study centers in the USA. There were four treatment groups with eight subjects in each, receiving a single dose of dexmecamylamine 8 mg (subjects with normal renal function and mild renal impairment) or TC-5412 2 mg [subjects with moderate renal impairment and end-stage renal disease (ESRD)]. The pharmacokinetics of dexmecamylamine in plasma, urine, and dialysate were evaluated using non-compartmental analysis., Results: The plasma pharmacokinetics of dexmecamylamine were influenced by renal function. The increase in dose-normalized area under the plasma concentration-time curve (AUC) was statistically significant with an approximately doubled exposure in subjects with moderate renal impairment compared with subjects with normal renal function. The maximum plasma concentration was not impacted by renal function. Plasma clearance of dexmecamylamine in ESRD subjects appeared negligible, with flat plasma concentration-time profiles. Hemodialysis had a relatively modest effect on reduction of dexmecamylamine plasma concentrations. There was no discernable relationship between renal clearance and urinary pH., Conclusion: Renal impairment increased the AUC, prolonged the elimination half-life, and decreased the clearance of dexmecamylamine following administration as a single oral dose. It is likely that renal function would need to be taken into account when setting the dose. Dexmecamylamine administration should be avoided or the dose significantly reduced in patients with severe renal impairment and ESRD.

This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1-4 mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥ 10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

Alcohol use disorders and post-traumatic stress disorder (PTSD) are highly prevalent and commonly co-occur, notably in veterans. We explored differences in the pre-treatment characteristics of veterans with alcohol dependence (AD) alone compared to those with co-occurring AD and PTSD. Veterans were recruited to participate in two different treatment studies and baseline characteristics were compared. Those with co-occurring illnesses demonstrated significantly higher pre-treatment pathology across all psychopathological domains. While those with AD alone averaged more days of drinking and had more heavy drinking days, those with co-occurring illnesses reported more drinking-related symptoms. The presence of a major depressive episode had no effect on drinking. Within the PTSD group, combat exposure was associated with increased drinking independent of the severity of PTSD symptoms. This study underscores the importance of screening for comorbidity in clinical treatment settings, and for collecting detailed drinking histories and assessing psychiatric symptoms across all domains of psychopathology., (© 2013.)

The naked mole-rat (Heterocephalus glaber) is a promising animal model for the study of pain mechanisms, therefore a thorough characterization of this species is essential. The aim of the present study was to establish the naked mole-rat as a model for studying the cholinergic receptor system in antinociception by investigating the involvement of muscarinic, nicotinic and opioid receptors in nociceptive tests in this species. The effects of systemic administration of the muscarinic receptor agonist oxotremorine and the nicotinic receptor agonist epibatidine were investigated in the tail-flick, the hot-plate, and the formalin tests. The effects of co-administration of the muscarinic receptor antagonist atropine, the nicotinic receptor antagonist mecamylamine, and the opioid receptor antagonist naloxone were also investigated. Oxotremorine and epibatidine induced a significant, dose-dependent antinociceptive effect in the tail-flick, hot-plate, and formalin tests, respectively. The effects of oxotremorine and epibatidine were blocked by atropine and mecamylamine, respectively. In all three nociceptive tests, naloxone in combination with oxotremorine or epibatidine enhanced the antinociceptive effects of the drugs. The present study demonstrated that stimulation of muscarinic and nicotinic receptors produces antinociceptive effects in the naked-mole rat. The reversal effect of atropine and mecamylamine suggests that this effect is mediated by cholinergic receptors. As naloxone increases the antinociceptive effects of cholinergic agonists, it is suggested that the cholinergic antinociception acts via a gateway facilitated by opioid receptor blockage; however, the precise interaction between these receptor systems needs further investigation.

Rationale: In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive-compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse., Objectives: The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food., Methods: The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10)., Results: Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model., Conclusions: Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.

The medial septum which is extensively connected to the hippocampus is involved in cholinergic theta oscillation control as well as the anxiety related disorders. In the present study, we aimed to investigate the possible involvement of the medial septum cholinoceptors in the nicotine-induced anxiogenic-like behaviors in rats, using the elevated plus-maze (EPM) test. Intraperitoneal administration of nicotine at 0.6 and 0.8 mg/kg, decreased the open-arms time percentage (%OAT) and open-arms entries percentage (%OAE); indicating an anxiogenic-like response. Intra-medial septum microinjection of mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist at the doses of 1-4 μg/rat, increased %OAT (4 μg/rat), suggesting an anxiolytic-like effect. This however, did not alter the anxiogenic-like response induced by the effective dose of nicotine (0.6 mg/kg). Moreover, co-administration of the subthreshold dose of mecamylamine (2 μg/rat) plus nicotine at the dose of 0.5 or 0.6 mg/kg, increased or decreased the anxiolytic-like behaviors, respectively. On the other hand, sole intra-medial septum infusion of atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, induced an anxiolytic (0.05 μg/rat) and anxiogenic (0.25 μg/rat)-like effects, respectively. The dose of 0.05 μg/rat however, blocked the nicotine response. Furthermore, intra-medial septum microinjection of the highest dose of mecamylamine (4 μg/rat) plus nicotine (0.6 mg/kg) decreased the locomotor activity, while other treatments had no effect on this parameter. Our results suggested that, nicotine-induced anxiogenic-like behaviors may be mediated via the activation of cholinoceptors and possibly other receptor mechanism(s) in the medial septum., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Although a body of evidence shows the crucial role of hippocampal nitrergic and cholinergic systems in the modulation of anxiety, little is known about their functional relationship with regard to anxiety. The present study investigated the relationship between intra-CA1 administration of a nicotinic acetylcholine receptor antagonist (mecamylamine) and a nitric oxide synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] or its precursor (L-arginine) in anxiety-related behaviors. Mice received bilateral intra-CA1 injections of either L-NAME or L-arginine in the presence of mecamylamine and were subsequently tested in the elevated plus maze. A dose of 0.5 μg/0.5 μl mecamylamine bilaterally administered into CA1 did not change the percentage of open arm time (%OAT) or the percentage of open arm entries (%OAE) in the elevated plus maze task and thus was considered as a subeffective dose. Intra-CA1 administration of either L-arginine (1 and 1.5 μg/0.5 μl, bilaterally) or L-NAME (at 60 ng/0.5 μl, bilaterally) decreased %OAT, which represents an anxiogenic-like effect. Coadministration of the subeffective dose of mecamylamine together with the lower doses of L-NAME (10 and 30 ng/0.5 μl, bilaterally) or L-arginine (0.5 μg/0.5 μl, bilaterally) led to a decrease in %OAT and %OAE. Thus, both L-NAME and L-arginine showed anxiogenic-like effects, but the effects of mecamylamine were too small to support a functional relationship between the hippocampal cholinergic and nitrergic systems., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

The aim of this work was to study the influence of co-administration of agonist and antagonist of Nalpha7-cholinoreceptors with low dose of 17beta-estradiol on dynamics of acquisition and retention in active avoidance test, on the behavior in the "open field" test, as well as tropic and gonadal hormones levels in ovariectomiczed female rats. Antagonist of Nalpha7-cholinoreceptors - RJR-2403 (1.0 mg/kg, i. p.) and antagonist of Nalpha7-cholinoreceptors - mecamylamine (1.0 mg/kg, i. p.) were administered chronically (14 days) isolated or in combination with low dose of 17beta-estradiol (0.5 m/rat, s. c.) to ovariectomized rats. It was revealed that RJR-2403 in combination with low dose of 17beta -estradiol completely restored impairments in mechanisms of dynamics of active avoidance performance and increased exploratory and grooming behavior in the "open field" test in ovariectomized rats. Moreover, RJR-2403 treatment decreased follitropine and lutropine levels and increased estradiol level in the blood serum in ovariectomized rats. Administration ofmecamylamine alone or in combination with low dose of 17beta-estradiol in ovariectomiczed rats failed to influence on dynamics of passive avoidance learning and failed to modify behavior in the "open field" test. The results of the present study suggest positive effect of Nalpha7-cholinoreceptors stimulation on background of low dose for 17beta-estradiol on active avoidance learning and tropic and gonadal hormones levels at estrogen deficiency.

Background: AGI004 is a controlled-release transdermal patch preparation of mecamylamine. We conducted a randomised placebo-controlled phase II study of two dose levels of AGI004 in chemotherapy-induced diarrhoea (CID)., Methods: Adult patients receiving chemotherapy who had experienced diarrhoea (NCI grade 1-2) during previous cycles of chemotherapy were eligible. In all, 64 patients were randomised to receive AGI004 4 mg then 8 mg per 24 h transdermal patch or placebo for two sequential cycles of chemotherapy. Patients' severity of diarrhoea was physician-assessed using NCI grade of diarrhoea and patient-assessed using information recorded in daily diaries of bowel movements., Results: Overall AGI004 doubled the odds of a response to treatment on the first day of chemotherapy based on physician assessment of NCI grade of diarrhoea compared with placebo (odds ratio=2.0, 90% confidence interval: 0.9-4.5) and there was a trend to improved response rates for AGI004 for the full treatment cycle although these results were not statistically significant. There was also evidence of significantly improved response rates based on patient assessment of diarrhoea both overall (P=0.05) and at the 8-mg dose level (P=0.02) compared with placebo., Conclusion: AGI004 demonstrated effectiveness in reducing chemotherapy-associated diarrhoea, with results suggesting response across multiple measurements of diarrhoea. Treatment was well tolerated with no drug-related adverse events. Further evaluation of this agent in the management of CID is warranted.

In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rationale: The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established., Objective: The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure., Methods and Results: Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect., Conclusions: Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.

β-carboline alkaloids such as harmane (HA) are naturally present in the human food chain. They are derived from the plant Peganum harmala and have many cognitive effects. In the present study, effects of the nicotinic system of the dorsal hippocampus (CA1) on HA-induced amnesia and exploratory behaviors were examined. One-trial step-down and hole-board paradigms were used to assess memory retention and exploratory behaviors in adult male mice. Pre-training (15 mg/kg) but not pre-testing intraperitoneal (i.p.) administration of HA decreased memory formation but did not alter exploratory behaviors. Moreover, pre-testing administration of nicotine (0.5 µg/mouse, intra-CA1) decreased memory retrieval, but induced anxiogenic-like behaviors. On the other hand, pre-test intra-CA1 injection of ineffective doses of nicotine (0.1 and 0.25 µg/mouse) fully reversed HA-induced impairment of memory after pre-training injection of HA (15 mg/kg, i.p.) which did not alter exploratory behaviors. Furthermore, pre-testing administration of mecamylamine (0.5, 1 and 2 µg/mouse, intra-CA1) did not alter memory retrieval but fully reversed HA-induced impairment of memory after pre-training injection of HA (15 mg/kg, i.p.) which had no effect on exploratory behaviors. In conclusion, the present findings suggest the involvement of the nicotinic cholinergic system in the HA-induced impairment of memory formation.

Objective: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism., Method: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive., Results: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense., Conclusion: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.

The zona incerta (ZI) is a subthalamic nucleus connected to several structures, some of them known to be involved with antinociception. The ZI itself may be involved with both antinociception and nociception. The antinociceptive effects of stimulating the ZI with glutamate using the rat tail-flick test and a rat model of incision pain were examined. The effects of intraperitoneal antagonists of acetylcholine, noradrenaline, serotonin, dopamine, or opioids on glutamate-induced antinociception from the ZI in the tail-flick test were also evaluated. The injection of glutamate (7 μg/0.25 μl) into the ZI increased tail-flick latency and inhibited post-incision pain, but did not change the animal performance in a Rota-rod test. The injection of glutamate into sites near the ZI was non effective. The glutamate-induced antinociception from the ZI did not occur in animals with bilateral lesion of the dorsolateral funiculus, or in rats treated intraperitoneally with naloxone (1 and 2 m/kg), methysergide (1 and 2 m/kg) or phenoxybenzamine (2 m/kg), but remained unchanged in rats treated with atropine, mecamylamine, or haloperidol (all given at doses of 1 and 2 m/kg). We conclude that the antinociceptive effect evoked from the ZI is not due to a reduced motor performance, is likely to result from the activation of a pain-inhibitory mechanism that descends to the spinal cord via the dorsolateral funiculus, and involves at least opioid, serotonergic and α-adrenergic mechanisms. This profile resembles the reported effects of these antagonists on the antinociception caused by stimulating the periaqueductal gray or the pedunculopontine tegmental nucleus., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase is documented to mediate the pathogenesis of substance dependence. Therefore, the present study has been designed to investigate the effect of SU-6656, selective src kinase inhibitor, on the development of nicotine dependence in a mouse model of mecamylamine-induced nicotine withdrawal syndrome., Methods: Our experimental protocol consisted of administration of nicotine (2.5 mg/kg, subcutaneously), 4 times daily for 7 days. In order to precipitate nicotine withdrawal, mice were given 1 injection of mecamylamine (3 mg/kg, intraperitoneally), 1 hr after the last nicotine injection on the test day (Day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. Withdrawal syndrome was quantitated in terms of a composite withdrawal severity score (WSS), and withdrawal syndrome-related anxiety was assessed by elevated plus maze test results., Results: SU-6656 markedly and dose dependently (p < .01) attenuated mecamylamine-induced experimental nicotine withdrawal syndrome in mice measured in terms of WSS and anxiety score., Conclusions: Thus, it is suggested that src kinase is involved in the development of nicotine dependence-induced precipitation of its withdrawal syndrome and thus may serve as a viable pharmacological target to tackle the problem of nicotine addiction.

Bile duct ligation (BDL) induces primary biliary cirrhosis characterized by cholestasis, impaired liver function and cognition including impairment of memory formation and anxiety-like behaviors. Endogenous opioid and acetylcholine levels are elevated in animal model of cholestasis. In addition, there is no data about the effects of interaction opioidergic and cholinergic systems of dorsal hippocampus (CA1) on amnesia-induced by cholestasis. Male mice weighing 25-35 g were used in this study. Cholestasis was induced by the ligation of the common bile duct. One-trial step-down and hole-board paradigms were used for the assessment of memory retrieval and anxiety-like behaviors respectively. All drugs injected intra-CA1. The data showed that cholestasis (24 days after BDL) decreased memory retrieval. Sole intra-CA1 injection of higher dose of mecamylamine (0.125, 0.25, 0.5 and 1 μg/mice) and scopolamine (0.125, 0.25, 0.5 1 and 2 μg/mice) but not all doses of naloxone (0.0125, 0.025 and 0.05 μg/mice) decreased memory retrieval in the sham operated BDL. The ineffective doses of naloxone (0.025 and 0.05 μg/mice), mecamylamine (0.5 μg/mice) and scopolamine (0.5 μg/mice) restored cholestasis-induced amnesia 24 days after BDL. Further, all cross co-administration ineffective doses of naloxone (0.0125 μg/mice), mecamylamine (0.125 μg/mice) and scopolamine (0.125 μg/mice) reversed cholestasis-induced amnesia. All doses of the drugs have no effect on exploratory behaviors. The data strongly revealed that synergistic effect between opioidergic and cholinergic systems of CA1 on the modulation of cholestasis-induced amnesia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nicotine, varenicline, and cytisine are pharmacotherapies for tobacco dependence; the extent to which their in vivo effects vary as a function of differences in nicotinic acetylcholine receptor agonism is not clear. Male C57BL/6J mice responding under a fixed ratio 30 schedule of food delivery were used to establish the potency and time course of nicotine, varenicline, and cytisine; antagonism was examined with the non-competitive, non-selective antagonist mecamylamine and the competitive, α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE). Intraperitoneal nicotine, varenicline, and cytisine dose-dependently decreased responding; nicotine was more potent (ED(50) value=0.83 mg/kg) than varenicline (ED(50) value=2.51 mg/kg) and cytisine (ED(50) value=2.97 mg/kg). The agonists had a similar time course including a rapid onset (5 min or less) and relatively short duration of action (30 min). Mecamylamine dose-dependently attenuated the rate-decreasing effects of a fixed dose of nicotine (1.78 mg/kg), varenicline (5.6 mg/kg), and cytisine (5.6 mg/kg). Mecamylamine (1mg/kg) produced parallel rightward shifts in the dose-response curves for nicotine (3.3-fold), varenicline (3.1-fold), and cytisine (2.3-fold). In contrast, DHβE (3.2mg/kg) produced 2-fold antagonism of nicotine and did not antagonize varenicline or cytisine. The data strongly suggest that nicotinic acetylcholine receptors mediate the effects of the agonists to decrease operant responding in mice. However, α4β2 receptor agonism appears to contribute partially to the rate-decreasing effects of nicotine but not to the rate-decreasing effects of varenicline and cytisine. Differential activation of α4β2 receptors in vivo might contribute to differences in the effectiveness of these smoking cessation aids., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

Purpose: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema., Design: A multicenter phase I/II clinical trial., Methods: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks., Results: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine., Conclusions: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects., (Copyright 2010 Elsevier Inc. All rights reserved.)

Nicotine addiction is a chronic disorder characterized by a relatively high rate of relapse even after long period of abstinence. In the present study, we used the conditioned place preference (CPP) paradigm to investigate the establishment, extinction, reinstatement, and cross-reinstatement of nicotine-induced place conditioning in rats. First, we revealed that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, base, intraperitoneally (i.p.)). Once established, nicotine CPP was extinguished by repeated testing. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Furthermore, given the important role of alpha4beta2 (a4b2) nicotinic receptor subtype in the acquisition and maintenance of nicotine dependence, we evaluated and compared the efficacy of varenicline, a partial a4b2 nicotinic receptor agonist (0.5, 1, and 2 mg/kg, subcutaneously (s.c.)), and mecamylamine (0.5, 1, and 2 mg/kg, s.c.), a non-selective nicotinic receptor antagonist, in blocking nicotine-induced CPP as well as reinstatement of nicotine CPP provoked by nicotine and morphine. It was shown that both nicotinic receptor ligands attenuated the acquisition and expression of nicotine CPP as well as the expression of reinstatement of nicotine CPP provoked by both drugs. Our results indicate similar cholinergic mechanisms, probably through the a4b2 receptors involved in the rewarding effects of nicotine and morphine in rats and may suggest that nicotinic receptors could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction and relapse.

Rationale: Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents., Objectives: The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats., Methods: The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central alpha7 nicotinic acetylcholine receptor (nAChR) and non-alpha7 nAChR levels (primarily alpha4beta2 nAChRs)., Results: The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the alpha7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-alpha7 nAChR density in the dentate gyrus., Conclusion: Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.

The introduction of transgenic and knockout mice has shaped new interest in developing novel and modified behavioral methods for mice that evaluate the various manifestations of nicotine withdrawal syndromes. This study assessed the disruption of operant baselines during drug withdrawal, an established rat model of nicotine dependence, in mice. Subjects were trained to lever press for food reinforcement during daily operant sessions. After stable operant baselines were established, mice were implanted with osmotic minipumps containing 0 (saline), 6, 12, 24, or 48 mg/kg/day nicotine base. Operant responding was assessed for disruptions in daily sessions throughout the experiment. Somatic signs of withdrawal were assessed after the operant session on day 7, following administration of mecamylamine (1 mg/kg), and on days 12, 13, and 14, following spontaneous removal of nicotine. Spontaneous removal of nicotine increased somatic signs of withdrawal but did not disrupt operant responding. Mecamylamine failed to produce signs of precipitated withdrawal in either procedure. This study demonstrated nicotine dependence in mice during spontaneous removal of nicotine. Moreover, since signs of behavioral withdrawal (i.e. disruptions in operant response rates) were not observed, these findings suggest the importance of considering differences in the apparent manifestations of withdrawal syndromes while evaluating nicotine dependence.

The ascending nociceptive control (ANC), a novel spinostriatal pain modulation pathway, mediates a form of pain-induced analgesia referred to as noxious stimulus-induced antinociception (NSIA). ANC includes specific spinal cord mechanisms as well as circuitry in nucleus accumbens, a major component of the ventral striatum. Here, using the trigeminal jaw-opening reflex (JOR) in the rat as a nociceptive assay, we show that microinjection of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine into the rostral ventral medulla (RVM) blocks NSIA, implicating RVM as a potentially important link between ANC and the PAG-RVM-spinal descending pain modulation system. A circuit connecting nucleus accumbens to the RVM is proposed as a novel striato-RVM pathway.

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.

Objective: Nicotinic cholinergic stimulation has known beneficial effects in attention-deficit/hyperactivity disorder (ADHD). Mecamylamine is a non-competitive nicotinic antagonist which is reported in several animal studies to have paradoxical positive effects on cognition at ultra-low doses. Comparable studies in humans have not been conducted. The aim of this study was to determine the effects of acute ultra-low doses of mecamylamine on cognition in adult ADHD., Methods: Fifteen (6 female) non-smokers with ADHD completed this acute, within subjects, double blind study of 0.2, 0.5, 1.0 mg of oral mecamylamine and placebo. Behavioral inhibition, recognition memory, and delay aversion were assessed at each dose., Results: The 0.5 mg dose of mecamylamine significantly improved recognition memory and reduced tolerance for delay. Mecamylamine increased participant rated irritability and investigator rated restlessness. There were no effects on vital signs or physical side effects., Conclusion: This is the first study to find measurable effects of ultra-low doses of mecamylamine in humans. Mecamylamine did not improve core ADHD cognitive symptoms, but significantly improved recognition memory. These effects may represent mixed receptor activity (activation and blockade) at the doses tested. The finding of beneficial effects on memory processes has important clinical implications and further exploration of this effect is warranted.

The orosensory responses elicited by nicotine are relevant for the development and maintenance of addiction to tobacco products. However, although nicotine is described as bitter tasting, the molecular and neural substrates encoding the taste of nicotine are unclear. Here, rats and mice were used to determine whether nicotine activates peripheral and central taste pathways via TRPM5-dependent mechanisms, which are essential for responses to other bitter tastants such as quinine, and/or via nicotinic acetylcholine receptors (nAChRs). When compared with wild-type mice, Trpm5(-/-) mice had reduced, but not abolished, chorda tympani (CT) responses to nicotine. In both genotypes, lingual application of mecamylamine, a nAChR-antagonist, inhibited CT nerve responses to nicotine and reduced behavioral responses of aversion to this stimulus. In accordance with these findings, rats were shown to discriminate between nicotine and quinine presented at intensity-paired concentrations. Moreover, rat gustatory cortex (GC) neural ensemble activity could also discriminate between these two bitter tastants. Mecamylamine reduced both behavioral and GC neural discrimination between nicotine and quinine. In summary, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and nAChR-dependent and TRPM5-independent pathways, thus creating a unique sensory representation that contributes to the sensory experience of tobacco products.