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Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.

Introduction: It has been suggested that nicotinic acetylcholine receptors (nAchRs) expressed in the ventral tegmental area (VTA) and the nucleus accumbens (nAcc) modulate the effects of drug abuse. This research assessed the effects of intra-accumbal administration of the nAchR antagonist (mecamylamine) and agonist (cytisine) on the operant oral self-administration of ethanol (EtOH) in rats. Methods: Male Wistar rats were water-deprived for 24 h and then trained to lever-press for EtOH reinforcement on a fixed-ratio 1 (FR1) schedule for three sessions. After that, the number of responses in the FR schedule increased to 3 until the response rate remained stable at 80%. After this training, the rats received an intra-accumbal injection of the nAchR antagonist, mecamylamine (0.0, 1.25, 2.5, and 5.0 µg), then nAchR agonist, cytisine (0.0, 0.8, 1.6, and 3.2 µg) or the combination of mecamylamine (0.0, 1.25, 2.5, and 5.0 µg) and cytisine (3.2 µg) before being provided access to EtOH on a FR3 schedule. Results: The data showed that intra-accumbal administration of mecamylamine reduced operant oral self-administration of EtOH, whereas cytisine increased operant oral self-administration of EtOH. This effect was reversed by mecamylamine. Conclusion: These findings suggest that nAchRs in the nAcc may modulate the operant oral self-administration of EtOH in rats. [ABSTRACT FROM AUTHOR]

Background: Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. Aim: These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. Methods: The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. Results: The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets. Conclusion: These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is a major excitatory neurotransmitter in the insect central nervous system, and insect neurons express several types of ACh receptors (AChRs). AChRs are classified into two subgroups, muscarinic AChRs and nicotinic AChRs (nAChRs). nAChRs are also divided into two subgroups by sensitivity to α-bungarotoxin (α-BGT). The cricket Gryllus bimaculatus is one of the useful insects for studying the molecular mechanisms in olfactory learning and memory. However, the roles of nAChRs in olfactory learning and memory of the cricket are still unknown. In the present study, to investigate whether nAChRs are involved in cricket olfactory learning and memory, we tested the effects of two different AChR antagonists on long-term memory (LTM) formation and retrieval in a behavioral assay. The two AChR antagonists that we used are mecamylamine (MEC), an α-BGT-insensitive nAChR antagonist, and methyllycaconitine (MLA), an α-BGT-sensitive nAChR antagonist. In crickets, multiple-trial olfactory conditioning induced 1-day memory (LTM), whereas single-trial olfactory conditioning induced 1-h memory (mid-term memory, MTM) but not 1-day memory. Crickets injected with MEC 20 min before the retention test at 1 day after the multiple-trial conditioning exhibited no memory retrieval. This indicates that α-BGT-insensitive nAChRs participate in memory retrieval. In addition, crickets injected with MLA before the multiple-trial conditioning exhibited MTM but not LTM, indicating that α-BGT-sensitive nAChRs participate in the formation of LTM. Moreover, injection of nicotine (an nAChR agonist) before the single-trial conditioning induced LTM. Finally, the nitric oxide (NO)-cGMP signaling pathway is known to participate in the formation of LTM in crickets, and we conducted co-injection experiments with an agonist or inhibitor of the nAChR and an activator or inhibitor of the NO-cGMP signaling pathway. The results suggest that nAChR works upstream of the NO-cGMP signaling system in the LTM formation process. [ABSTRACT FROM AUTHOR]

IntroductionIngestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and unpleasant side effects such as nausea and dizziness.Aims and methodsHere we review the sensory effects of nicotine and the underlying neurobiological processes.Results and conclusionsNicotine elicits oral irritation and pain via the activation of neuronal nicotinic acetylcholine receptors (nAChRs) expressed by trigeminal nociceptors. These nociceptors excite neurons in the trigeminal subnucleus caudalis (Vc) and other brainstem regions in a manner that is significantly reduced by the nAChR antagonist mecamylamine. Vc neurons are excited by lingual application of nicotine and exhibit a progressive decline in firing to subsequent applications, consistent with desensitization of peripheral sensory neurons and progressively declining ratings of oral irritation in human psychophysical experiments. Nicotine also elicits a nAChR-mediated bitter taste via excitation of gustatory afferents. Nicotine solutions are avoided even when sweeteners are added. Studies employing oral self-administration have yielded mixed results: Some studies show avoidance of nicotine while others report increased nicotine intake over time, particularly in adolescents and females. Nicotine is consistently reported to increase human pain threshold and tolerance levels. In animal studies, nicotine is antinociceptive when delivered by inhalation of tobacco smoke or systemic infusion, intrathecally, and by intracranial microinjection in the pedunculopontine tegmentum, ventrolateral periaqueductal gray, and rostral ventromedial medulla. The antinociception is thought to be mediated by descending inhibition of spinal nociceptive transmission. Menthol cross-desensitizes nicotine-evoked oral irritation, reducing harshness that may account for its popularity as a flavor additive to tobacco products.ImplicationsNicotine activates brain systems underlying reward and antinociception, but at the same time elicits aversive sensory effects including oral irritation and pain, bitter taste, and other unpleasant side effects mediated largely by nicotinic acetylcholine receptors (nAChRs). This review discusses the competing aversive and antinociceptive effects of nicotine and exposure to tobacco smoke, and the underlying neurobiology. An improved understanding of the interacting effects of nicotine will hopefully inform novel approaches to mitigate nicotine and tobacco use.

Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by in vitro and ex vivo experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.

Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising during short active (SA) winter periods. Light-induced changes in behavior are also seen in healthy animals and are intensified in mice with reduced dopamine transporter expression. Specifically, decreasing the nocturnal active period (SA) of mice increases punishment perseveration and forced swim test (FST) immobility. Elevating acetylcholine with the acetylcholinesterase inhibitor physostigmine induces depression symptoms in people and increases FST immobility in mice. We used SA photoperiods and physostigmine to elevate acetylcholine prior to testing in a probabilistic learning task and the FST, including reversing subsequent deficits with nicotinic and scopolamine antagonists and targeted hippocampal adeno-associated viral administration. We confirmed that physostigmine also increases punishment sensitivity in a probabilistic learning paradigm. In addition, muscarinic and nicotinic receptor blockade attenuated both physostigmine-induced and SA-induced phenotypes. Finally, viral-mediated hippocampal expression of human AChE used to lower ACh levels blocked SA-induced elevation of FST immobility. These results indicate that increased hippocampal acetylcholine neurotransmission is necessary for the expression of SA exposure-induced behaviors. Furthermore, these studies support the potential for cholinergic treatments in depression. Taken together, these results provide evidence for hippocampal cholinergic mechanisms in contributing to seasonally depressed affective states induced by short day lengths.

Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.

Therapeutic intervention for spinal cord injury is limited, with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared with learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning remains an open question. In this study, mice were randomly assigned to receive intraperitoneal injection with the pan-nicotinic, non-competitive antagonist mecamylamine and the nicotinic α7 subunit selective antagonist methyllycaconitine citrate salt or vehicle (normal saline) prior to motor learning assays, then randomly reassigned after motor learning for rehabilitation study post-injury. Cervical spinal cord dorsal column lesion was used as a model of incomplete injury. Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury. Our findings indicate that critical differences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.

Abstract Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior.

Rationale: Acetylcholinergic antagonists have shown some promise in reducing addiction-related behaviors in both preclinical and clinical studies. However, the psychological mechanisms by which these drugs are able to affect addictive behavior remain unclear. A particular key process for the development of addiction is the attribution of incentive salience to reward-related cues, which can be specifically measured in animals using a Pavlovian conditioned approach procedure. When confronted with a lever that predicts food delivery, some rats engage with the lever directly (i.e., they sign track), indicating attribution of incentive-motivational properties to the lever itself. In contrast, others treat the lever as a predictive cue and approach the location of impending food delivery (i.e., they goal track), without treating the lever itself as a reward. Objectives: We tested whether systemic antagonism of the either nicotinic or muscarinic acetylcholine receptors would selectively affect sign- or goal-tracking behavior, indicating a selective effect on incentive salience attribution. Methods: A total of 98 male Sprague Dawley rats were either given the muscarinic antagonist scopolamine (100, 50, or 10 µg/kg i.p.) or the nicotinic antagonist mecamylamine (0.3, 1.0, or 3 mg/kg i.p.) before being trained on a Pavlovian conditioned approach procedure. Results: Scopolamine dose-dependently decreased sign tracking behavior and increased goal-tracking behavior. Mecamylamine reduced sign-tracking but did not affect goal-tracking behavior. Conclusions: Antagonism of either muscarinic or nicotinic acetylcholine receptors can reduce incentive sign-tracking behavior in male rats. This effect appears to be specifically due to a reduction in incentive salience attribution since goal-tracking either increased or was not affected by these manipulations. [ABSTRACT FROM AUTHOR]

BackgroundElectronic nicotine delivery systems (ENDS, e-cigarettes) are increasingly used for the self-administration of nicotine by various human populations, including previously nonsmoking adolescents. Studies in preclinical models are necessary to evaluate health impacts of ENDS including the development of nicotine addiction, effects of ENDS vehicles, flavorants and co-administered psychoactive substances such as Δ9-tetrahydrocannabinol (THC). This study was conducted to validate a rat model useful for the study of nicotine effects delivered by inhalation of vapor created by ENDS.MethodsMale Sprague-Dawley rats (N = 8) were prepared with radio telemetry devices for the reporting of temperature and activity. Experiments subjected rats to inhalation of vapor generated by an electronic nicotine delivery system (ENDS) adapted for rodents. Inhalation conditions included vapor generated by the propylene glycol (PG) vehicle, Nicotine (1, 10, 30 mg/mL in the PG) and THC (12.5, 25 mg/mL).ResultsNicotine inhalation increased spontaneous locomotion and decreased body temperature of rats. Pretreatment with the nicotinic cholinergic receptor antagonist mecamylamine (2 mg/kg, i.p.) prevented stimulant effects of nicotine vapor inhalation and attenuated the hypothermic response. Combined inhalation of nicotine and THC resulted in apparently independent effects which were either additive (hypothermia) or opposed (activity).ConclusionsThese studies provide evidence that ENDS delivery of nicotine via inhalation results in nicotine-typical effects on spontaneous locomotion and thermoregulation in male rats. Effects were blocked by a nicotinic antagonist, demonstrating mechanistic specificity. This system will therefore support additional studies of the contribution of atomizer/wick design, vehicle constituents and/or flavorants to the effects of nicotine administered by ENDS.

Maternal smoking with obligatory nicotine inhalation is associated with preterm delivery, low birth weight, fetal growth retardation and developmental defects. We tested the hypothesis that cigarette smoking-relevant nicotine inhalation during pregnancy impairs cardiovascular function and uterine hemodynamics with consequential fetal ischemia. Pregnant rats exposed to episodic inhaled nicotine via a novel lung alveolar region-targeted aerosol method produced nicotine pharmacokinetics resembling cigarette smoking in humans. This clinically relevant nicotine aerosol inhalation (NAI) induced transient reduction and irregular fluctuations in uterine artery blood flow associated with cardiac arrhythmia and high magnitude irregular fluctuations of systemic blood pressure. The arrhythmia included sinoatrial (SA) block, sinus arrest, 2° and 3° atrioventricular (A-V) block and supraventricular escape rhythm. These effects were blocked by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine. Resection of the ovarian nerve, which innervates uterine blood vessels, counteracted the NAI-induced reduction in uterine blood flow. We suggest that the rapid rise pattern of arterial blood nicotine concentration stimulates and then desensitizes autonomic nAChRs leading to disruptions of cardiac function as well as systemic and uterine hemodynamics that reduces uteroplacental blood flow, a mechanism underlying maternal smoking-associated pregnancy complications and developmental disorders. These findings challenge the safety of pure nicotine inhalation, i.e., E-cigarettes.

Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior. [ABSTRACT FROM AUTHOR]

Objective: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self‐reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β‐estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self‐reported (subjective) postmenopausal cognitive complaints. Methods: Forty postmenopausal women (aged 50–60 years) completed a 3‐month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). Results: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N‐back working memory task, regardless of whether they received estradiol treatment. Conclusions: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The strong reinforcing effects of nicotine and the negative symptoms such as anxiety experienced during a quit attempt often lead to relapse and low success rates for smoking cessation. Treatments that not only block the reinforcing effects of nicotine but also attenuate the motivation to relapse are needed to improve cessation rates. Recent genetic and preclinical studies have highlighted the involvement of the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits and the α3β4 nAChR subtype in nicotine dependence and withdrawal. However, the involvement of these nAChR in relapse is not fully understood. We previously reported that the α3β4 nAChR partial agonist AT-1001 selectively decreases nicotine self-administration in rats without affecting food responding. In the present experiments, we examined the efficacy of AT-1001 in attenuating reinstatement of nicotine-seeking behavior in a model of stress-induced relapse. Rats extinguished from nicotine self-administration were treated with the pharmacological stressor yohimbine prior to AT-1001 treatment and reinstatement testing. We also examined whether AT-1001 produced any withdrawal-related effects when administered to nicotine-dependent rats. We found that AT-1001 dose-dependently reduced yohimbine stress-induced reinstatement of nicotine seeking. When administered to nicotine-dependent rats at the dose that significantly blocked nicotine reinstatement, AT-1001 elicited minimal somatic withdrawal signs in comparison to the nicotinic antagonist mecamylamine, which is known to produce robust withdrawal. Our data suggest that α3β4 nAChR-targeted compounds may be a promising approach for nicotine addiction treatment because they can not only block nicotine's reinforcing effects, but also decrease motivation to relapse without producing significant withdrawal effects.

The dorsomedial striatum (DMS) has been strongly implicated in flexible, outcome-based decision making, including the outcome-specific Pavlovian-to-instrumental transfer effect (PIT), which measures the tendency for a reward-predictive cue to preferentially motivate actions that have been associated with the predicted reward over actions associated with different rewards. Although the neurochemical underpinnings of this effect are not well understood, there is growing evidence that striatal acetylcholine signaling may play an important role. This study investigated this hypothesis by assessing the effects of intra-DMS infusions of the nicotinic antagonist mecamylamine or the muscarinic antagonist scopolamine on expression of specific PIT in rats. These treatments produced dissociable behavioral effects. Mecamylamine infusions enhanced rats tendency to use specific cue-elicited outcome expectations to select whichever action was trained with the predicted outcome, relative to their performance when tested after vehicle infusions. In contrast, scopolamine infusions appeared to render instrumental performance insensitive to this motivational influence of reward-paired cues. These drug treatments had no detectable effect on conditioned food cup approach behavior, indicating that they selectively perturbed cue-guided action selection without producing more wide-ranging alterations in behavioral control. Our findings reveal an important role for DMS acetylcholine signaling in modulating the impact of cue-evoked reward expectations on instrumental action selection.

The dorsomedial striatum (DMS) has been strongly implicated in flexible, outcome-based decision making, including the outcome-specific Pavlovian-to-instrumental transfer effect (PIT), which measures the tendency for a reward-predictive cue to preferentially motivate actions that have been associated with the predicted reward over actions associated with different rewards. Although the neurochemical underpinnings of this effect are not well understood, there is growing evidence that striatal acetylcholine signaling may play an important role. This study investigated this hypothesis by assessing the effects of intra-DMS infusions of the nicotinic antagonist mecamylamine or the muscarinic antagonist scopolamine on expression of specific PIT in rats. These treatments produced dissociable behavioral effects. Mecamylamine infusions enhanced rats' tendency to use specific cue-elicited outcome expectations to select whichever action was trained with the predicted outcome, relative to their performance when tested after vehicle infusions. In contrast, scopolamine infusions appeared to render instrumental performance insensitive to this motivational influence of reward-paired cues. These drug treatments had no detectable effect on conditioned food cup approach behavior, indicating that they selectively perturbed cue-guided action selection without producing more wide-ranging alterations in behavioral control. Our findings reveal an important role for DMS acetylcholine signaling in modulating the impact of cue-evoked reward expectations on instrumental action selection.

Levamisole is a veterinary anthelmintic drug and a common adulterant of misused drugs. This study analyses the lethal, antinociceptive and haematological effects produced by acute or repeated levamisole administration by itself or combined with morphine. Independent groups of male Swiss Webster mice were i.p. injected with 100 mg/kg morphine, 31.6 mg/kg levamisole (lethal doses at 10%, LD10 ) or the same doses combined. Naloxone pretreatment (10 mg/kg, i.p.) prevented morphine-induced death, as did 2.5 mg/kg, i.p. mecamylamine with levamisole. Co-administration of levamisole and morphine (Lvm + Mor) increased lethality from 10% to 80%. This augmented effect was prevented by 30 mg/kg, i.p. naloxone and reduced with 10 mg/kg naloxone plus 2.5 mg/kg, i.p. mecamylamine. In independent groups of mice, 17.7 mg/kg, i.p. levamisole antagonized the acute morphine's antinociceptive effect evaluated in the tail-flick test. Repeated 17.7 mg/kg levamisole administration (2×/day/3 weeks) did not affect tolerance development to morphine (10 mg/kg, 3×/day/1 week). Blood samples obtained from mice repeatedly treated with levamisole showed leukopenia and neutropenia. Morphine also produced neutropenia, increased erythrocyte count and other related parameters (e.g. haemoglobin). Lvm + Mor had similar effects on leukocyte and neutrophil counts to those seen with levamisole only, but no erythrocyte-related alterations were evident. Blood chemistry analysis did not indicate liver damage but suggested some degree of electrolyte balance impairment. In conclusion, Lvm + Mor increased death risk, altered morphine-induced antinociceptive effects and produced haematologic abnormalities. The importance of studying combinations of drugs of abuse lies in the fact that drug users frequently combine drugs, which are commonly adulterated. [ABSTRACT FROM AUTHOR]

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by ‘priming’ feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

Background: Animal models are critical to improve our understanding of the neuronal mechanisms underlying nicotine withdrawal. Nicotine dependence in rodents can be established by repeated nicotine injections, chronic nicotine infusion via osmotic minipumps, oral nicotine intake, tobacco smoke exposure, nicotine vapor exposure, and e-cigarette aerosol exposure. The time course of nicotine withdrawal symptoms associated with these methods has not been reviewed in the literature. Aim: The goal of this review is to discuss nicotine withdrawal symptoms associated with the cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure in rats and mice. Furthermore, age and sex differences in nicotine withdrawal symptoms are reviewed. Results: Cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure leads to nicotine withdrawal symptoms such as somatic withdrawal signs, changes in locomotor activity, anxiety- and depressive-like behavior, learning and memory deficits, attention deficits, hyperalgesia, and dysphoria. These withdrawal symptoms are most pronounced within the first week after cessation of nicotine exposure. Anxiety- and depressive-like behavior, and deficits in learning and memory may persist for several months. Adolescent (4–6 weeks old) rats and mice display fewer nicotine withdrawal symptoms than adults (>8 weeks old). In adult rats and mice, females show fewer nicotine withdrawal symptoms than males. The smoking cessation drugs bupropion and varenicline reduce nicotine withdrawal symptoms in rodents. Conclusion: The nicotine withdrawal symptoms that are observed in rodents are similar to those observed in humans. Tobacco smoke and e-cigarette aerosol contain chemicals and added flavors that enhance the reinforcing properties of nicotine. Therefore, more valid animal models of tobacco and e-cigarette use need to be developed by using tobacco smoke and e-cigarette aerosol exposure methods to induce dependence. [ABSTRACT FROM AUTHOR]

AimsStudying the normal role of nicotinic cholinergic systems in hippocampal synaptic plasticity is critical for understanding how cholinergic loss in Alzheimer's disease (AD) and tobacco use affect cognitive function. However, it is largely unknown how nicotinic cholinergic systems regulate the induction of long-term depression (LTD).Main methodsExtracellular field potential recordings were performed in hippocampal slices prepared from wild-type, α2, α7, and β2 knockout (KO) mice. Effects of nicotine and nicotinic antagonists on LTD induction in wild-type, α2, α7, and β2 KO mice were compared.Key findingsActivation of α7 nicotinic acetylcholine receptors (nAChRs) occurs during LTD-inducing stimulation to suppress LTD induction at CA3-CA1 synapses. Nicotine relieves this suppression, causing larger LTD. This nicotine effect was mediated by the activation of non-α7 nAChR subtypes, which were not activated by ACh released during LTD-inducing stimulation, and requires the presence of endogenous ACh-induced α7 nAChR activation. Furthermore, the effect of nicotine was prevented in the presence of mecamylamine, but not dihydro-β-erythroidine, and was still observed in both α2 KO and β2 KO mice.SignificanceThis is the first report to evaluate the involvement of different nAChR subtypes in LTD induction. Findings indicate the involvement of unique non-α7 nAChR subtypes, which have not been considered in the nicotinic modulation of hippocampal long-term potentiation, in the control of LTD induction. The implication of our results is that the loss of cholinergic projections to the hippocampus, which reduces ACh release as seen in AD patients, and nicotine from tobacco smoking can differentially affect LTD induction.

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value--we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

Context affects the salience and visibility of image elements in visual scenes. Collinear flankers can enhance or decrease the perceptual and neuronal sensitivity to flanked stimuli. These effects are mediated through lateral interactions between neurons in the primary visual cortex (area V1), in conjunction with feedback from higher visual areas. The strength of lateral interactions is affected by cholinergic neuromodulation. Blockade of muscarinic receptors should increase the strength of lateral intracortical interactions, while nicotinic blockade should reduce thalamocortical feed-forward drive. Here we test this proposal through local iontophoretic application of the muscarinic receptor antagonist scopolamine and the nicotinic receptor antagonist mecamylamine, while recording single cells in parafoveal representations in awake fixating macaque V1. Collinear flankers generally reduced neuronal contrast sensitivity. Muscarinic and nicotinic receptor blockade equally reduced neuronal contrast sensitivity. Contrary to our hypothesis, flanker interactions were not systematically affected by either receptor blockade. [ABSTRACT FROM AUTHOR]

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety. [ABSTRACT FROM AUTHOR]

Rationale: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects Objectives: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. Methods: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest—central hubs of the DMN in which consistent nAChR agonist–induced changes had previously been identified. Results: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. Conclusions: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Rationale and objectives: The reinforcement-enhancing effect (REE) of nicotine refers to the drug's ability to enhance the strength of other primary and conditioned reinforcers. The main aim was to investigate neuropharmacological mechanisms underlying nicotine's strengthening of a primary visual reinforcer (i.e., a light cue), using a subcutaneous (SC) dose previously shown to provide plasma nicotine levels associated with habitual smoking. Methods: Adult male rats pressed an "active" lever to illuminate a brief cue light during daily 60-min sessions. Rats that showed a clear REE were tested with systemically administered pretreatment drugs followed by nicotine (0.1 mg/kg SC) or saline challenge, in within-subject counterbalanced designs. Pretreatments were mecamylamine (nicotinic, 0.1-1 mg/kg SC), SCH 39166 (D1-like dopaminergic, 0.003-0.2 mg/kg SC), naloxone (opioid, 1 and 5 mg/kg SC), prazosin (alpha1-adrenergic antagonist, 1 and 2 mg/kg IP), rimonabant (CB1 cannabinoid inverse agonist, 3 mg/kg IP), sulpiride (D2-like dopaminergic antagonist, 40 mg/kg SC), or propranolol (beta-adrenergic antagonist, 10 mg/kg IP). Results: The nicotine REE was abolished by three antagonists at doses that did not impact motor output, i.e., mecamylamine (1 mg/kg), SCH 39166 (0.01 and 0.03 mg/kg), and naloxone (5 mg/kg). Prazosin and rimonabant both attenuated the nicotine REE, but rimonabant also suppressed responding more generally. The nicotine REE was not significantly altered by sulpiride or propranolol. Conclusions: In adult male rats, the reinforcement-enhancing effect of low-dose nicotine depends on nicotinic receptor stimulation and on neurotransmission via D1/D5 dopaminergic, opioid, alpha1-adrenergic, and CB1 cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Mecamylamine is a nonselective antagonist of nicotinic acetylcholine receptors that was developed as an antihypertensive medication and is now being studied for its beneficial effects in several pathological conditions, such as substance abuse, depression, anxiety and epilepsy. In this work, we investigate the effect of mecamylamine on the manifestations of seizure-like activity evoked by perfusion of hippocampal slices with low-Mg2+ solution of artificial cerebrospinal fluid. Reducing Mg2+ concentration in extracellular solution induced two distinct types of epileptiform activity: recurring seizure-like activity and continuous discharges. Application of mecamylamine significantly increased internal frequency of recurring seizurelike activity and significantly decreased inter-event intervals between continuous discharges. We also show that mecamylamine significantly decreased internal frequency of continuous epileptiform discharges. The results of our work show that mecamylamine exerts modulatory effect on the low-Mg2+ epileptiform activity induced in hippocampal acute rat brain slices. Additionally, obtained results indicate the role of nicotinic acetylcholine receptors in the modulation of hippocampal network activity, which might explain some of the therapeutic effects of mecamylamine in CNS. [ABSTRACT FROM AUTHOR]

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity.

Abstract Objectives There is a long‐standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross‐tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. Methods Schedule‐controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate‐decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro‐β‐erythroidine (DHβE) were studied in combination with nicotine. Results The ED50 values of nicotine to produce rate‐decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate‐decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine. Conclusions The differential antagonism of rate‐decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.

• Mecamylamine increases the firing rate of dorsal raphe neurons. • Mecamylamine increases glutamatergic input to dorsal raphe neurons. • Mecamylamine decreases GABAergic inputs to dorsal raphe neurons. Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5−9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT 1A receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release. [ABSTRACT FROM AUTHOR]

Objectives: Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of concurrent use of cocaine and nicotine. Mirtazapine, an antagonist of the α2-adrenoceptor and the 5-HT2A/C and the 5-HT3 receptors has proven effective in reducing the cocaine, nicotine and methamphetamine behavioural effects in humans and animals. Our study evaluated the effect of mirtazapine on enhancing locomotor activity during the induction and expression of locomotor sensitisation induced by a cocaine + nicotine mixture. Methods: Wistar rats were dosed with cocaine, nicotine or cocaine + nicotine combination. Mirtazapine (30 mg/kg, i.p.) was administered during the extinction phase. Results: Mirtazapine decreased cocaine + nicotine-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, we found that co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine on cocaine + nicotine-induced locomotor activity during induction and expression of behavioural sensitisation. Conclusions: Our results suggest that mirtazapine demonstrated efficacy in decreasing the psycho-stimulant effects of concurrent use of cocaine and nicotine. [ABSTRACT FROM AUTHOR]

• Nicotine and mecamylamine impaired memory acquisition, enhanced locomotion, and did not alter pain perception. • TSD and RSD for 24 h impaired memory acquisition with no effect on locomotion, and only TSD induced analgesic effect. • Subthreshold doses of nicotine and mecamylamine reversed the effects of TSD/RSD on memory acquisition and pain perception. • Nicotine and mecamylamine increased locomotion in TSD rats, while only mecamylamine increased locomotion in RSD rats. • Dorsal hippocampal nicotinic receptors play a significant role in TSD/RSD-induced behavioral changes. Sleep deprivation (SD) is a common issue in today's society. Sleep is essential for proper cognitive functions, including learning and memory. Furthermore, sleep disorders can alter pain information processing. Meanwhile, hippocampal nicotinic receptors have a role in modulating pain and memory. The goal of this study is to investigate the effect of dorsal hippocampal (CA1) nicotinic receptors on behavioral changes induced by Total (TSD) and REM Sleep Deprivation (RSD). A modified water box and multi-platform apparatus were used to induce TSD and RSD, respectively. To investigate the interaction between nicotinic receptors and hippocampus-dependent memory, nicotinic receptor agonist (nicotine) or antagonist (mecamylamine) was injected into the CA1 region. The results showed, nicotine at the doses of 0.001 and 0.1 µg/rat and mecamylamine at the doses of 0.01 and 0.1 µg/rat decreased memory acquisition, while both at the doses of 0.01 and 0.1 µg/rat enhanced locomotor activity. Additionally, all doses used for both drugs did not alter pain perception. Also, 24 h TSD or RSD attenuated memory acquisition with no effect on locomotor activity and only TSD induced an analgesic effect. Intra-CA1 administration of subthreshold dose of nicotine (0.0001 µg/rat) and mecamylamine (0.001 µg/rat) did not alter memory acquisition, pain perception and locomotor activity in sham of TSD/RSD rats. Both drugs reversed all behavioral changes induced by TSD. Furthermore, both drugs reversed the effect of RSD on memory acquisition, while only mecamylamine reversed the effect of RSD on locomotor activity. In conclusion, CA1 nicotinic receptors play a significant role in TSD/RSD-induced behavioral changes. [ABSTRACT FROM AUTHOR]

Objectives: There is a long‐standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross‐tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. Methods: Schedule‐controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate‐decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro‐β‐erythroidine (DHβE) were studied in combination with nicotine. Results: The ED50 values of nicotine to produce rate‐decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate‐decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine. Conclusions: The differential antagonism of rate‐decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence. [ABSTRACT FROM AUTHOR]

The nucleus basalis of the basal forebrain is an essential component of the neuromodulatory system controlling the behavioral state of an animal and it is thought to be important in regulating arousal and attention. However, the effect of nucleus basalis activation on sensory processing remains poorly understood. Using polytrode recording in rat visual cortex, we found that nucleus basalis stimulation caused prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes. The decorrelation depended on local activation of cortical muscarinic acetylcholine receptors, whereas the increased reliability involved distributed neural circuits, as evidenced by nucleus basalis-induced changes in thalamic responses. Further analysis showed that the decorrelation and increased reliability improved cortical representation of natural stimuli in a complementary manner. Thus, the basal forebrain neuromodulatory circuit, which is known to be activated during aroused and attentive states, acts through both local and distributed mechanisms to improve sensory coding.