Cognitive improvements in a rat model with polyunsaturated fatty acids EPA and DHA through α7-nicotinic acetylcholine receptors.

The α7-nicotinic acetylcholine receptor (α7-nAChR) is a recognized target for the treatment of dementia associated with aging and certain developmental disorders. This study evaluates memory improvement in a rat model by the effects of polyunsaturated fatty acids EPA and DHA mediated by α7-nAChR, as well as identifying the minimum dose of EPA/DHA required to generate an effect in the improvement of cognition through α7-nAChR in rats. The modified Y-maze and object recognition behavioral tests were performed in scopolamine-induced amnesic rats, in order to study the effects of long-term supplementation (10, 15, 30, and 60 mg/kg) of the two polyunsaturated fatty acids in improving cognitive impairment. Cognitive enhancement by EPA and DHA is mediated through α7-nAChRs, as evidenced by memory recovery after treatment with a selective α7-nAChR antagonist, methyllycaconitine (MLA). Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU282987, an α7-nAChR agonist, are employed as reference standards. Our data demonstrate that 15 mg/kg EPA and DHA can affect cholinergic neurotransmission positively through memory and cognition and, thus, can exert a beneficial action on learning and memory deficits.

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction.

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or α4ß2 nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.

Prepulse inhibition based grouping of rats and assessing differences in response to pharmacological agents.

Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350 g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5 mg/kg and 1 mg/kg), amphetamine (4 mg/kg), MK-801 (0.05 mg/kg and 0.15 mg/kg), scopolamine (0.4 mg/kg), nicotine (1 mg/kg) and caffeine (10 mg/kg and 30 mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10 mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary.

APOE genotype influences P3b amplitude and response to smoking abstinence in young adults.

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

Chronic exposure to cigarette smoke extract upregulates nicotinic receptor binding in adult and adolescent rats.

Heavy smokers display increased radioligand binding of nicotinic acetylcholine receptors (nAChRs). This "upregulation" is thought to be a contributing factor to tobacco dependence. Although cigarette smoke contains thousands of constituents that can contribute to nicotine dependence, it is not well understood whether non-nicotine constituents contribute to nAChR upregulation. In this study, we used an aqueous cigarette smoke extract (CSE), which contains nicotine and soluble constituents of cigarette smoke, to induce nAChR upregulation in adult and adolescent rats. To do this, male rats were exposed to nicotine or CSE (1.5 mg/kg/day nicotine equivalent, intravenously) daily for ten days. This experimental procedure produces equivalent levels of brain and plasma nicotine in nicotine- and CSE-treated animals. We then assessed nAChR upregulation using quantitative autoradiography to measure changes in three nAChR types. Adolescents were found to have consistently greater α4ß2 nAChR binding than adults in many brain regions. Chronic nicotine exposure did not significantly increase nAChR binding in any brain region at either age. Chronic CSE exposure selectively increased α4ß2 nAChR binding in adolescent medial amygdala and α7 binding in adolescent central amygdala and lateral hypothalamus. CSE also increased α3ß4 nAChR binding in the medial habenula and interpeduncular nucleus, and α7 binding in the medial amygdala, independent of age. Overall, this work provides evidence that cigarette smoke constituents influence nAChR upregulation in an age-, nAChR type- and region-dependent manner.

Effects of nicotine on regional blood flow in the olfactory bulb in response to olfactory nerve stimulation.

This study examined the effect of olfactory nerve stimulation on regional cerebral blood flow and assessed the effect of intravenous nicotine administration on this response in anesthetized rats. Regional cerebral blood flow was measured with laser Doppler flowmetry or laser speckle contrast imaging. Unilateral olfactory nerve stimulation for 5 s produced current (≥ 100 µA) and frequency-dependent (≥ 5 Hz) increases in blood flow in the olfactory bulb ipsilateral to the stimulus. The increased olfactory bulb blood flow peaked at 30 ± 7% using stimulus parameters of 300 µA and 20 Hz. Nerve stimulation did not change frontal cortical blood flow or mean arterial pressure. The intravenous injection of nicotine (30 µg/kg) augmented the olfactory bulb blood flow response to nerve stimulation (20 Hz, 300 µA) by approximately 1.5-fold (60-s area after the stimulation). These results indicate that olfactory nerve stimulation increases olfactory bulb blood flow, and the response is potentiated by the activation of nicotinic cholinergic transmission.

Differential Effects of Nicotine and Nicotine Withdrawal on Fear Conditioning in Male Rats.

BACKGROUND: Tobacco use is prevalent in individuals who are routinely exposed to stress. However, little is known about how nicotine affects responses to trauma. We examined in rats how nicotine exposure affects fear conditioning, a procedure often used to study stress-related psychiatric illness. METHODS: We examined 2 methods of nicotine exposure: self-administration, modeling voluntary use, and experimenter-programmed subcutaneous administration, modeling medicinal administration (nicotine patch). For self-administered nicotine, rats trained to self-administer nicotine i.v. were fear conditioned (via light cue preceding foot-shock) either immediately after a 12-hour self-administration session or 12 hours later during a period with somatic signs of nicotine withdrawal. For experimenter-delivered nicotine, rats were conditioned after 1-21 days of nicotine delivered by programmable (12 hours on) subcutaneous mini-pumps. Tests to evaluate acoustic startle responses to the conditioning environment (context-potentiated startle) and in the presence or absence of the light cue (fear-potentiated startle) occurred after a 10-day period. RESULTS: Rats fear conditioned immediately after nicotine self-administration showed reduced responses to the shock-associated context, whereas those trained during nicotine withdrawal showed exaggerated responses. Experimenter-programmed nicotine produced effects qualitatively similar to those seen with self-administered nicotine. CONCLUSIONS: Self-administration or experimenter-programmed delivery of nicotine immediately before exposure to aversive events can reduce conditioned fear responses. In contrast, exposure to aversive events during nicotine withdrawal exacerbates fear responses. These studies raise the possibility of developing safe and effective methods to deliver nicotine or related drugs to mitigate the effects of stress while also highlighting the importance of preventing withdrawal in nicotine-dependent individuals.

Preclinical and clinical research on the discriminative stimulus effects of nicotine.

Across species, nicotine can produce robust discriminative stimulus (DS) effects, as with other drugs of abuse, a feature that has been harnessed to advance our understanding on the neuropharmacological mechanisms of nicotine's actions. With the crucial role played by nicotine in supporting tobacco dependence, nicotine DS effects have presented an ideal platform to develop novel generation of smoking cessation compounds. Findings from preclinical strands of research have invigorated the field of human discrimination research to objectively assess nicotine's interoceptive stimulus effects. As such, translation studies provide proof of concept for nicotine DS research as a method to assess the subjective effects of nicotine per se, separate from non-nicotine stimuli involved in smoking. Recent clinical studies with low doses have demonstrated that perceiving nicotine's DS effects is necessary, yet not sufficient, for that dose to be reinforcing. These measures have been instrumental in developing novel strategies with regards to establishing threshold doses of nicotine contained in tobacco products, to then determine subthreshold doses that cannot be discriminated and, therefore, fail to maintain reinforcement. Findings from preclinical and clinical nicotine DS research could substantially inform public health policies aimed at regulating nicotine content of consumer products so that they minimize risks of dependency. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Suppressive effect of ghrelin on nicotine-induced clock gene expression in the mouse pancreas.

Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.

Characterization of AN317, a novel selective agonist of α6ß2-containing nicotinic acetylcholine receptors.

Neuronal nicotinic acetylcholine receptors (nAChRs) are crucial mediators of central presynaptic, postsynaptic, and extrasynaptic signaling, and they are implicated in a range of CNS disorders. The numerous nAChR subtypes are differentially expressed and mediate distinct functions throughout the CNS, and thus there is considerable interest in developing subtype-selective nAChR modulators, both for use as pharmacological tools and as putative therapeutics. α6ß2-containing (α6ß2*) nAChRs are highly expressed in and regulate the activity of midbrain dopaminergic neurons, which makes them attractive drug targets in several psychiatric and neurological diseases, including nicotine addiction and Parkinson's disease. This paper presents the preclinical characterization of AN317, a novel α6ß2* agonist exhibiting functional selectivity toward other nAChRs, including α4ß2, α3ß4 and α7 receptors. AN317 induced [3H]dopamine release from rat striatal synaptosomes and augmented dopaminergic neuron activity in substantia nigra pars compacta brain slices in Ca2+ imaging and electrophysiological assays. In line with this, AN317 alleviated the high-frequency tremors arising from reserpine-mediated dopamine depletion in rats. Finally, AN317 mediated significant protective effects on cultured rat mesencephalic neurons treated with the dopaminergic neurotoxin MPP+. AN317 displays good bioavailability and readily crosses the blood-brain barrier, which makes it a unique tool for both in vitro and in vivo studies of native α6ß2* receptors in the nigrostriatal system and other dopaminergic pathways. Altogether, these findings highlight the potential of selective α6ß2* nAChR activation as a treatment strategy for symptoms and possibly even deceleration of disease progression in neurodegenerative diseases such as Parkinson's disease.

Synthesis, Pharmacological Characterization, and Structure-Activity Relationships of Noncanonical Selective Agonists for α7 nAChRs.

A lack of selectivity of classical agonists for the nicotinic acetylcholine receptors (nAChR) has prompted us to identify and develop a distinct scaffold of α7 nAChR-selective ligands. Noncanonical 2,4,6-substituted pyrimidine analogues were framed around compound 40 for a structure-activity relationship study. The new lead compounds activate selectively the α7 nAChRs with EC50's between 30 and 140 nM in a PNU-120596-dependent, cell-based calcium influx assay. After characterizing the expanded lead landscape, we ranked the compounds for rapid activation using Xenopus oocytes expressing human α7 nAChR with a two-electrode voltage clamp. This approach enabled us to define the molecular determinants governing rapid activation, agonist potency, and desensitization of α7 nAChRs after exposure to pyrimidine analogues, thereby distinguishing this subclass of noncanonical agonists from previously defined types of agonists (agonists, partial agonists, silent agonists, and ago-PAMs). By NMR, we analyzed pKa values for ionization of lead candidates, demonstrating distinctive modes of interaction for this landscape of ligands.

Qualitative Assay to Detect Dopamine Release by Ligand Action on Nicotinic Acetylcholine Receptors.

A pheochromocytoma of the rat adrenal medulla derived (a.k.a. PC12) cell-based assay for dopamine measurement by luminescence detection was customized for the qualitative evaluation of agonists and antagonists of nicotinic acetylcholine receptors (nAChRs). The assay mechanism begins with ligand binding to transmembrane nAChRs, altering ion flow into the cell and inducing dopamine release from the cell. Following release, dopamine is oxidized by monoamine oxidase generating hydrogen peroxide that catalyzes a chemiluminescence reaction involving luminol and horseradish peroxidase, thus producing a detectable response. Results are presented for the action of nAChR agonists (acetylcholine, nicotine, and cytisine), and antagonists (α-conotoxins (α-CTxs) MII, ImI, LvIA, and PeIA) that demonstrate a luminescence response correlating to the increase or decrease of dopamine release. A survey of cell growth and treatment conditions, including nerve growth factor, nicotine, ethanol, and temperature, led to optimal assay requirements to achieve maximal signal intensity and consistent response to ligand treatment. It was determined that PC12 cells treated with a combination of nerve growth factor and nicotine, and incubated at 37 °C, provided favorable results for a reduction in luminescence signal upon treatment of cells with α-CTxs. The PC12 assay is intended for use as a fast, efficient, and economic qualitative method to assess the bioactivity of molecules that act on nAChRs, in which testing of ligand-nAChR binding hypotheses and computational predictions can be validated. As a screening method for nAChR bioactivity, lead compounds can be assessed for their likelihood of exhibiting desired bioactivity prior to being subjected to more complex quantitative methods, such as electrophysiology or live animal studies.

Natural and Drug Rewards Engage Distinct Pathways that Converge on Coordinated Hypothalamic and Reward Circuits.

Motivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheral→central pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards.

Acute separate and combined effects of cannabinoid and nicotinic receptor agonists on MMN-indexed auditory deviance detection in healthy humans.

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.

Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward.

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARα signalling and show potential in the treatment of nicotine dependence.

Nicotine modulates human brain plasticity via calcium-dependent mechanisms.

KEY POINTS: Nicotine (NIC) modulates cognition and memory function by targeting the nicotinic ACh receptor and releasing different transmitter systems postsynaptically. With both NIC-generated mechanisms, calcium influx and calcium permeability can be regulated, which is a key requirement for the induction of long-term potentiation, comprising the physiological basis of learning and memory function. We attempt to unmask the underlying mechanism of nicotinic effects on anodal transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity based on the hypothesis of calcium-dependency. Abolished tDCS-induced neuroplasticity as a result of NIC administration is reversed by calcium channel blockade with flunarizine in a dose-dependent manner. The results of the present study suggest that there is a dose determination of NIC/NIC agonists in therapeutical settings when treating cognitive dysfunction, which partially explains the heterogeneous results on cognition observed in subjects in different experimental settings. ABSTRACT: Nicotine (NIC) modulates neuroplasticity and improves cognitive performance in animals and humans mainly by increased calcium permeability and modulation of diverse transmitter systems. NIC administration impairs calcium-dependent plasticity induced by non-invasive brain stimulation with transcranial direct current stimulation (tDCS) in non-smoking participants probably as a result of intracellular calcium overflow. To test this hypothesis, we analysed the effect of calcium channel blockade with flunarizine (FLU) on anodal tDCS-induced cortical excitability changes in healthy non-smokers under NIC. We applied anodal tDCS combined with NIC patch and FLU at three different doses (2.5, 5 and 10 mg) or with placebo medication. NIC abolished anodal tDCS-induced neuroplasticity. Under medium dosage (but not under low and high dosage) of FLU combined with NIC, plasticity was re-established. For FLU alone, the lowest dosage weakened long-term potentiation (LTP)-like plasticity, whereas the highest dosage again abolished tDCS-induced plasticity. The medium dosage turned LTP-like plasticity in long-term depression-like plasticity. The results of the present study suggest a key role of calcium influx and calcium levels in nicotinic effects on LTP-like plasticity in humans. This knowledge might be relevant for the development of new therapeutic strategies in cognitive dysfunction.

Identification by virtual screening and functional characterisation of novel positive and negative allosteric modulators of the α7 nicotinic acetylcholine receptor.

Several previous studies have demonstrated that the activity of neurotransmitters acting on ligand-gated ion channels such as the nicotinic acetylcholine receptor (nAChR) can be altered by compounds binding to allosteric modulatory sites. In the case of α7 nAChRs, both positive and negative allosteric modulators (PAMs and NAMs) have been identified and have attracted considerable interest. A recent study, employing revised structural models of the transmembrane domain of the α7 nAChR in closed and open conformations, has provided support for an inter-subunit transmembrane allosteric binding site (Newcombe et al 2017). In the present study, we have performed virtual screening of the DrugBank database using pharmacophore queries that were based on the predicted binding mode of PAMs to α7 nAChR structural models. A total of 81 compounds were identified in the DrugBank database, of which the 25 highest-ranked hits corresponded to one of four previously-identified therapeutic compound groups (carbonic anhydrase inhibitors, cyclin-dependent kinase inhibitors, diuretics targeting the Na+-K+-Cl- cotransporter, and fluoroquinolone antibiotics targeting DNA gyrase). The top-ranked compound from each of these four groups (DB04763, DB08122, furosemide and pefloxacin, respectively) was tested for its effects on human α7 nAChR expressed in Xenopus oocytes using two-electrode voltage-clamp electrophysiology. These studies, conducted with wild-type, mutant and chimeric receptors, resulted in all four compounds exerting allosteric modulatory effects. While DB04763, DB08122 and pefloxacin were antagonists, furosemide potentiated ACh responses. Our findings, supported by docking studies, are consistent with these compounds acting as PAMs and NAMs of the α7 nAChR via interaction with a transmembrane site.

Evaluation of the Influence of Three Newly Developed Bispyridinium Anti-nicotinic Compounds (MB408, MB442, MB444) on the Efficacy of Antidotal Treatment of Nerve Agent Poisoning in Mice.

The influence of three newly developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-oximes was dose-dependent. To conclude, the addition of bispyridinium non-oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning.

Age-dependent sensitivity of the mouse kidney to chronic nicotine exposure.

BackgroundMany adolescents are exposed to nicotine via smoking, e-cigarette use, or second-hand smoke. Nicotine-induced renal oxidative stress and its long-term consequences may be higher in adolescents than in adults because of intrinsic factors in the adolescent kidney.MethodsAdolescent and adult male C57Bl/6J mice were subjected to 2 or 200 µg/ml nicotine, which closely emulates passive or active smoking, respectively, for 4 weeks. Extent of nicotine exposure (cotinine content), oxidative stress (HNE), renal function (creatinine), tubular injury (KIM-1), and pretreatment renal levels of select pro-oxidant (p66shc) and antioxidant (Nrf2/MnSOD) genes were determined. Impact of p66shc overexpression or Nrf2/MnSOD knockdown on low-/high-dose nicotine-induced oxidative stress was determined in cultured renal proximal tubule cells.ResultsDespite similar plasma/renal cotinine levels, renal HNE and KIM-1 contents were higher in adolescents compared with those in adults, whereas renal function was unaltered after passive or active smoking-equivalent nicotine exposure. Pretreatment levels of p66shc were higher, whereas Nrf2/MnSOD levels were lower in the adolescent kidney. In agreement with this, overexpression of p66shc or knockdown of Nrf2/MnSOD augmented nicotine-induced ROS production in renal proximal tubule cells.ConclusionChronic nicotine exposure incites higher oxidative stress in the adolescent than in adult kidney because of a pre-existent pro-oxidant milieu.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.