Behavioral characterization of early nicotine withdrawal in the mouse: a potential model of acute dependence.

BACKGROUND: Clinical and preclinical research have demonstrated that short-term exposure to nicotine during the initial experimentation stage can lead to early manifestation of withdrawal-like signs, indicating the state of "acute dependence". As drug withdrawal is a major factor driving the progression toward regular drug intake, characterizing and understanding the features of early nicotine withdrawal may be important for the prevention and treatment of drug addiction. In this study, we corroborate the previous studies by showing that withdrawal-like signs can be precipitated after short-term nicotine exposure in mice, providing a potential animal model of acute dependence on nicotine. RESULTS: To model nicotine exposure from light tobacco use during the initial experimentation stage, mice were treated with 0.5 mg/kg (-)-nicotine ditartrate once daily for 3 days. On the following day, the behavioral tests were conducted after implementing spontaneous or mecamylamine-precipitated withdrawal. In the open field test, precipitated nicotine withdrawal reduced locomotor activity and time spent in the center zone. In the elevated plus maze test, the mecamylamine challenge increased the time spent in the closed arm and reduced the number of entries irrespective of nicotine experience. In the examination of the somatic aspect, precipitated nicotine withdrawal enhanced the number of somatic signs. Finally, nicotine withdrawal did not affect cognitive functioning or social behavior in the passive avoidance, spatial object recognition, or social interaction test. CONCLUSIONS: Collectively, our data demonstrate that early nicotine withdrawal-like signs could be precipitated by the nicotinic antagonist mecamylamine in mice, and that early withdrawal from nicotine primarily causes physical symptoms.

Nicotinic acetylcholine receptor subtype expression, function, and pharmacology: Therapeutic potential of α-conotoxins.

The pentameric nicotinic acetylcholine receptors (nAChRs) are typically classed as muscle- or neuronal-type, however, the latter has also been reported in non-neuronal cells. Given their broad distribution, nAChRs mediate numerous physiological and pathological processes including synaptic transmission, presynaptic modulation of transmitter release, neuropathic pain, inflammation, and cancer. There are 17 different nAChR subunits and combinations of these subunits produce subtypes with diverse pharmacological properties. The expression and role of some nAChR subtypes have been extensively deciphered with the aid of knock-out models. Many nAChR subtypes expressed in heterologous systems are selectively targeted by the disulfide-rich α-conotoxins. α-Conotoxins are small peptides isolated from the venom of cone snails, and a number of them have potential pharmaceutical value.

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.

Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation. SIGNIFICANCE STATEMENT: Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.

Cervical Cancer Correlates with the Differential Expression of Nicotinic Acetylcholine Receptors and Reveals Therapeutic Targets.

Nicotinic acetylcholine receptors (nAChRs) are associated with various cancers, but the relation between nAChRs and cervical cancer remains unclear. Therefore, this study investigated the differential expression of nAChR subunits in human cervical cancer cell lines (SiHa, HeLa, and CaSki) and in normal ectocervical cell lines (Ect1/E6E7) at mRNA and protein levels. Two specific nAChR subtype blockers, αO-conotoxin GeXIVA and α-conotoxin TxID, were then selected to treat different human cervical cancer cell lines with specific nAChR subtype overexpression. The results showed that α3, α9, α10, and ß4 nAChR subunits were overexpressed in SiHa cells compared with that in normal cells. α9 and α10 nAChR subunits were overexpressed in CaSki cells. α*-conotoxins that targeted either α9α10 or α3ß4 nAChR were able to significantly inhibit cervical cancer cell proliferation. These findings may provide a basis for new targets for cervical cancer targeted therapy.

α-Conotoxin TxIB: A Uniquely Selective Ligand for α6/α3ß2ß3 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Conditioned Place Preference in Mice.

Abstract: α-Conotoxin TxIB is a specific antagonist of α6/α3ß2ß3(α6ß2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6ß2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6ß2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.

Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor.

Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structure⁻activity relationship (SAR) between GI and mouse α1ß1δε nAChRs. The Pro5, Gly8, Arg8, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1ß1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1ß1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1ß1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1ß1δε nAChR in detail that will help to develop the novel analogues of GI.

Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: scheduled-controlled responding and hypothermia in C57BL/6J mice.

The tobacco-dependence pharmacotherapies varenicline and cytisine act as partial α4ß2 nAChR agonists. However, the extent to which α4ß2 nicotinic acetylcholine receptors (nAChRs) mediate their in-vivo effects remains unclear. Nicotine, varenicline, cytisine, and epibatidine were studied in male C57BL/6J mice for their effects on rates of fixed ratio responding and rectal temperature alone and in combination with the nonselective nAChR antagonist mecamylamine and the α4ß2 nAChR antagonist dihydro-ß-erythroidine. The effects of nicotine, varenicline, cytisine, epibatidine, and cocaine were assessed before and during chronic nicotine treatment. The rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine were antagonized by mecamylamine (1 mg/kg), but only the effects of nicotine and epibatidine were antagonized by dihydro-ß-erythroidine (3.2 mg/kg). Chronic nicotine produced 4.7 and 5.1-fold rightward shifts in the nicotine dose-effect functions to decrease response rate and rectal temperature, respectively. Nicotine treatment decreased the potency of epibatidine to decrease response rate and rectal temperature 2.2 and 2.9-fold, respectively, and shifted the varenicline dose-effect functions 2.0 and 1.7-fold rightward, respectively. Cross-tolerance did not develop from nicotine to cytisine. These results suggest that the in-vivo pharmacology of tobacco cessation aids cannot be attributed to a single nAChR subtype; instead, multiple receptor subtypes differentially mediate their effects.

The α7 nAChR selective agonists as drug candidates for Alzheimer's disease.

The nicotinic acetylcholine receptors (nAChRs) are ion channels distribute in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction. Current studies reveal relationship between the nAChRs and the learning and memory as well as cognation deficit in various neurological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and drug addiction. There are various subtypes in the nAChR family and the α7 nAChR is one of the most abundant subtypes in the brain. The α7 nAChR is significantly reduced in the patients of Alzheimer's disease and is believed to interact with the Aß amyloid. Aß amyloid is co-localized with α7 nAChR in the senile plaque and interaction between them induces neuron apoptosis and reduction of the α7 nAChR expression. Treatment with α7 agonist in vivo shows its neuron protective and procognation properties and significantly improves the learning and memory ability of the animal models. Therefore, the α7 nAChR agonists are excellent drug candidates for Alzheimer's disease and we summarized here the current agonists that have selectivity of the α7 nAChR over the other nAChR, introduced recent molecular modeling works trying to explain the molecular mechanism of their selectivity and described the design of novel allosteric modulators in our lab.

Artemin growth factor increases nicotinic cholinergic receptor subunit expression and activity in nociceptive sensory neurons.

BACKGROUND: Artemin (Artn), a member of the glial cell line-derived growth factor (GDNF) family, supports the development and function of a subpopulation of peptidergic, TRPV1-positive sensory neurons. Artn (enovin, neublastin) is elevated in inflamed tissue and its injection in skin causes transient thermal hyperalgesia. A genome wide expression analysis of trigeminal ganglia of mice that overexpress Artn in the skin (ART-OE mice) showed elevation in nicotinic acetylcholine receptor (nAChR) subunits, suggesting these ion channels contribute to Artn-induced sensitivity. Here we have used gene expression, immunolabeling, patch clamp electrophysiology and behavioral testing assays to investigate the link between Artn, nicotinic subunit expression and thermal hypersensitivity. RESULTS: Reverse transcriptase-PCR validation showed increased levels of mRNAs encoding the nAChR subunits α3 (13.3-fold), ß3 (4-fold) and ß4 (7.7-fold) in trigeminal ganglia and α3 (4-fold) and ß4 (2.8-fold) in dorsal root ganglia (DRG) of ART-OE mice. Sensory ganglia of ART-OE mice had increased immunoreactivity for nAChRα3 and exhibited increased overlap in labeling with GFRα3-positive neurons. Patch clamp analysis of back-labeled cutaneous afferents showed that while the majority of nicotine-evoked currents in DRG neurons had biophysical and pharmacological properties of α7-subunit containing nAChRs, the Artn-induced increase in α3 and ß4 subunits resulted in functional channels. Behavioral analysis of ART-OE and wildtype mice showed that Artn-induced thermal hyperalgesia can be blocked by mecamylamine or hexamethonium. Complete Freund's adjuvant (CFA) inflammation of paw skin, which causes an increase in Artn in the skin, also increased the level of nAChR mRNAs in DRG. Finally, the increase in nAChRs transcription was not dependent on the Artn-induced increase in TRPV1 or TRPA1 in ART-OE mice since nAChRs were elevated in ganglia of TRPV1/TRPA1 double knockout mice. CONCLUSIONS: These findings suggest that Artn regulates the expression and composition of nAChRs in GFRα3 nociceptors and that these changes contribute to the thermal hypersensitivity that develops in response to Artn injection and perhaps to inflammation.

Synthesis of α3ß4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3ß4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3ß4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

Anti-smoking drugs cytisine and varenicline reduce cardiac reperfusion injury in rat model of myocardial ischemia.

Evidence to date indicates that activation of nicotinic acetylcholine receptors (nAChRs) can reduce cardiac injury from ischemia and subsequent reperfusion. The use of nAChR agonists in various animal models leads to a reduction in reperfusion injury. Earlier this effect was shown for the agonists of α7 nAChR subtype. In this work, we demonstrated the expression of mRNA encoding α4, α6 and ß2 nAChR subunits in the left ventricle of rat heart. In a rat model of myocardial ischemia, we studied the effect of α4ß2 nAChR agonists cytisine and varenicline, medicines used for the treatment of nicotine addiction, and found them to significantly reduce myocardium ischemia-reperfusion injury, varenicline manifesting a higher protection. Dihydro-ß-erythroidine, antagonist of α4ß2 nAChR, as well as methyllycaconitine, antagonist of α7 and α6ß2-containing nAChR, prevented protective effect of varenicline. This together with the presence of α4, α6 and ß2 subunit mRNA in the left ventricule of rat heart raises the possibility that the varenicline effect is mediated by α4ß2 as well as by α7 and/or α6ß2-containing receptors. Our results point to a new way for the use of cytisine and varenicline as cardioprotective agents.

Varenicline to stop long-term nicotine replacement use: a double-blind, randomized, placebo-controlled trial.

INTRODUCTION: This study evaluated the effect of varenicline in combination with counseling to assist long-term nicotine replacement therapy (NRT) users to quit NRT. METHODS: This was a double-blind, placebo-controlled, randomized trial of varenicline or placebo for 12 weeks, with 52-week follow-up, performed in 1 hospital-based smoking cessation specialist clinic. At the first visit, 139 ex-smokers and long-term NRT users were allocated to treatment according to a computer-generated list with random numbers. Visits were scheduled at Weeks 0, 2, 4, 6, 9, 12, and 52. At each visit, nurse-led counseling was delivered, carbon monoxide in expired air, plasma cotinine, and body weight were assessed, and subjects were asked about craving, nausea, and dreams. The primary outcome was 12-week point prevalence quit rate (PPR) of nicotine replacement therapy use. RESULTS: At all time points, the PPR was superior for varenicline versus placebo, although the difference was only statistically significant at 12 and 36 weeks. The PPR was 64.3% (varenicline) versus 40.6% (placebo) at 12 weeks (p = .006), and 42.9% (varenicline) versus 36.2% (placebo) at 52 weeks (NS). The continuous abstinence rate from Week 9 to Week 12 was 48.6 % (varenicline) versus 30.4 % (placebo) (p = .03). Withdrawal symptoms were statistically significantly lower in the varenicline group than the placebo group. CONCLUSION: Varenicline for 12 weeks combined with supportive visits was superior to placebo to get long-term NRT users to quit NRT. A larger study is needed to evaluate long-term efficacy.

Ondansetron in patients with tinnitus: randomized double-blind placebo-controlled study.

The aim of this study was to assess the effect of ondansetron on symptoms of patients with subjective tinnitus accompanied by sensorineural hearing loss or normal hearing. Sixty patients with a chief complaint of tinnitus (with duration of more than 3 months) were equally randomized to ondansetron or placebo for 4 weeks. The dose of ondansetron was gradually increased from 4 mg/day (one tablet) to 16 mg/day (4 tablets) during 12 days and then continued up to 4 weeks. The exact number of tablets was prescribed in the placebo group. Patients underwent audiologic examinations and filled questionnaires at baseline and after 4 weeks of treatment. Our primary outcomes were changes in Tinnitus Handicap Inventory questionnaire (THI), Tinnitus Severity Index (TSI) and visual analog scale (VAS) scores. Our secondary outcomes were the changes in depression and anxiety based on Hospital Anxiety and Depression (HADS) questionnaire, side effects, tinnitus loudness matching, tinnitus pitch matching, pure tone audiometry and speech recognition threshold (SRT). In the ondansetron and placebo groups, 27 and 26 patients completed the study, respectively. The changes in VAS (P = 0.934), THI (P = 0.776), anxiety (P = 0.313) and depression (P = 0.163) scores were not different between the groups. TSI score decreased significantly in the ondansetron compared with the placebo group (P = 0.004). Changes in tinnitus loudness matching (P = 0.75) and pitch matching (P = 0.56) did not differ between the two groups. Ondansetron, but not placebo, decreased the SRT threshold (right, P < 0.001; left, P = 0.043) and mean PTA (right, P = 0.006; left, P < 0.001). In conclusion, ondansetron reduces the severity of tinnitus hypothetically through cochlear amplification.

Addressing Motor Dysfunction by a Selective α6-Containing Nicotinic Receptor Antagonist.

In the striatum, presynaptic α6-containig nicotinic receptors are crucially involved in the modulation of dopamine release. CVN417, a novel selective antagonist at this receptor subtype, attenuates motor dysfunction in a Parkinson's disease-relevant animal model, suggesting, for this pathology, a therapeutic strategy that could greatly profit from the restricted localization of α6* nicotinic receptors in the brain.

Novel small molecule α9α10 nicotinic receptor antagonist prevents and reverses chemotherapy-evoked neuropathic pain in rats.

BACKGROUND: Peripheral neuropathy is a common dose-limiting side effect of chemotherapy. There are no clinically proven analgesics for the treatment of this condition. Drugs from different classes have been tested with mixed results. Identification of novel molecular targets for analgesic(s) is important. Antagonism of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype (absent in brain) is thought to underlie analgesic efficacy of peptide α-conotoxins. We found novel nonpeptide small molecule analogs from a family of tetrakis-, tris-, and bis-azaaromatic quaternary ammonium salts (high potency with selectivity as antagonists at the α9α10 nAChRs) to produce dose-related analgesia in rat models of nerve injury-evoked neuropathy and persistent inflammatory pain. No tests were done in a model of neuropathy induced by drug administration (ie, chemotherapy). METHODS: In this study, a lead bis-analog, ZZ1-61c, was characterized in a rat model of vincristine-evoked neuropathy. Male Sprague-Dawley rats were repeatedly dosed with the vinca-alkaloid, vincristine (100 µg/kg/day IP, days 1 to 5 and 8 to 12). ZZ1-61c (100 µg/kg/day IP) was given either along with or after completion of vincristine (commencing by day 15 when neuropathy was maximum). Responsiveness was assessed with von Frey hairs and the paw-pressure test. The effects of ZZ1-61c on motor function (rotarod) and muscle strength (grip test) were characterized in naïve rats. RESULTS: The development of neuropathy was demonstrated with repeated dosing of vincristine (pain hypersensitivity in response to mechanical stimulation). ZZ1-61c showed both preventive and restorative effects on this condition: (1) vincristine-evoked sensitivity to pressure was reduced by coadministration of ZZ1-61c; (2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ1-61c did not cause motor dysfunction (rotarod) or muscular weakness (the grip test). CONCLUSIONS: This study suggests that ZZ1-61c, a novel compound with a unique mechanism of antagonistic action at the α9α10 nAChR, may be a potential drug candidate for prevention and attenuation of neuropathic pain resulting from chemotherapy. Such a strategy may provide effective treatment that circumvents toxicity of centrally acting agonists at nAChR.

Lobeline for smoking cessation.

BACKGROUND: Lobeline is a partial nicotine agonist, which has been used in a variety of commercially available preparations to help stop smoking. OBJECTIVES: The objective of this review was to assess the effects of lobeline on long term smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register (most recent search December 2011). SELECTION CRITERIA: Randomized trials comparing lobeline to placebo or an alternative therapeutic control, which reported smoking cessation with at least six months follow-up. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and form of lobeline, the outcome measures, method of randomisation, and completeness of follow-up. MAIN RESULTS: We identified no trials meeting the full inclusion criteria including long term follow-up. One large trial failed to detect any effect on short-term abstinence. AUTHORS' CONCLUSIONS: There is no evidence available from long term trials that lobeline can aid smoking cessation, and the short-term evidence suggests there is no benefit.

Motivational Interviewing for encouraging quit attempts among unmotivated smokers: study protocol of a randomized, controlled, efficacy trial.

BACKGROUND: Although the current Clinical Practice Guideline recommend Motivational Interviewing for use with smokers not ready to quit, the strength of evidence for its use is rated as not optimal. The purpose of the present study is to address key methodological limitations of previous studies by ensuring fidelity in the delivery of the Motivational Interviewing intervention, using an attention-matched control condition, and focusing on unmotivated smokers whom meta-analyses have indicated may benefit most from Motivational Interviewing. It is hypothesized that MI will be more effective at inducing quit attempts and smoking cessation at 6-month follow-up than brief advice to quit and an intensity-matched health education condition. METHODS/DESIGN: A sample of adult community resident smokers (N = 255) who report low motivation and readiness to quit are being randomized using a 2:2:1 treatment allocation to Motivational Interviewing, Health Education, or Brief Advice. Over 6 months, participants in Motivational Interviewing and Health Education receive 4 individual counseling sessions and participants in Brief Advice receive one brief in-person individual session at baseline. Rigorous monitoring and independent verification of fidelity will assure the counseling approaches are distinct and delivered as planned. Participants complete surveys at baseline, week 12 and 6-month follow-up to assess demographics, smoking characteristics, and smoking outcomes. Participants who decide to quit are provided with a self-help guide to quitting, help with a quit plan, and free pharmacotherapy. The primary outcome is self-report of one or more quit attempts lasting at least 24 hours between randomization and 6-month follow-up. The secondary outcome is biochemically confirmed 7-day point prevalence cessation at 6-month follow-up. Hypothesized mediators of the presumed treatment effect on quit attempts are greater perceived autonomy support and autonomous motivation. Use of pharmacotherapy is a hypothesized mediator of Motivational Interviewing's effect on cessation. DISCUSSION: This trial will provide the most rigorous evaluation to date of Motivational Interviewing's efficacy for encouraging unmotivated smokers to make a quit attempt. It will also provide effect-size estimates of MI's impact on smoking cessation to inform future clinical trials and inform the Clinical Practice Guideline. TRIAL REGISTRATION: ClinicalTrials.gov NCT01188018.

Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain.

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

[Pharmacotherapeutic treatment strategies for smoking cessation]. / Pharmakologische Strategien zur Unterstützung einer Raucherentwöhnung.

Regular tobacco smoking occurs in about 35% of the male and 25% of the female German population. Individual attempts to independently quit smoking and to remain abstinent for 1 year have been shown to be successful in less than 5% of cases. This rate can be doubled by means of individual consulting and cognitive-behavioral interventions and additional pharmacological treatment might increase abstinence rates up to 25%. Apart from nicotine substitution (e.g. transdermal, oral and inhalative applications) and bupropion, recent studies have shown beneficial effects of varenicline for smoking cessation and abstinence. Varenicline, a selective partial nicotinergic agonist, has been specifically developed for the purpose of smoking cessation. Currently available data suggest that varenicline is more effective compared to nicotine substitution therapy and bupropion, increasing the abstinence likelihood by a factor of 2.3 compared to a placebo. Recent data regarding anti-nicotine vaccines suggest that this approach might yield a comparable treatment outcome and probably even better relapse-preventing effects than conventional psychopharmacological strategies. The first anti-nicotine vaccines are expected to be approved by national authorities within the forthcoming 1-2 years.

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors.

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 α4ß2 nAChRs, MLA and DhßE, 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 α4ß2 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.