Nicotine Drugs Research Articles

S34 - Optimizing the Training Conditions of Rats in Nicotine Drug Discrimination Studies

S34 - Optimizing the Training Conditions of Rats in Nicotine Drug Discrimination Studies

Evaluation of novel epibatidine analogs in the rat nicotine drug discrimination assay and in the rat chronic constriction injury neuropathic pain model.

Nicotine is the primary psychoactive component responsible for maintaining tobacco dependence in humans. Chronic pain is often a consequence of tobacco-related pathologies, and the development of a dual therapeutic that could treat chronic pain and tobacco dependence would be advantageous. Epibatidine reliably substitutes for nicotine in the drug discrimination assay, and is a potent analgesic, but has a side-effect profile that limits its therapeutic potential. Thus, considerable efforts to produce epibatidine derivatives are underway. Here we tested three epibatidine derivatives, 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102; i.e., RTI-102), 2'-fluorodeschloroepibatidine (RTI-7527-36; i.e., RTI-36), and 3'-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76; i.e., RTI-76) in both the rat nicotine drug discrimination assay as well as in the rat chronic constriction injury (CCI) of the sciatic nerve neuropathic pain model. Male and female Sprague-Dawley rats were trained on a fixed-ratio 10 schedule to discriminate nicotine (0.32mg/kg base) from vehicle. All compounds dose-dependently substituted for nicotine, without significant decreases in response rates. In the discrimination assay the rank order potency was RTI-36 > nicotine > RTI-102 > RTI-76. Evidence suggests the α4β2* subtype is particularly important to nicotine-related abuse potential. Thus, here we utilized the antagonist dihydro-β-erythroidine (DHβE) to examine relative β2 subunit contribution. DHβE (3.2mg/kg, s.c.) antagonized the discriminative stimulus effects of nicotine. However, relative to antagonism of nicotine, DHβE produced less antagonism of RTI-102 and RTI-76 and greater antagonism of RTI-36. It is likely that at nicotinic receptor subunits RTI-102, RTI-76 and RTI-36 possess differing activity. To confirm that the full discriminative stimulus of these compounds was due to nAChR activity beyond the β2 subunit, we examined these compounds in the presence of the non-selective nicotinic receptor antagonist mecamylamine. Mecamylamine (0.56mg/kg, s.c.) pretreatment abolished nicotine-paired lever responding for all compounds. In a separate cohort, male and female Sprague-Dawley rats underwent CCI surgery and tested for CCI-induced mechanical allodynia via the von Frey assay. Each compound produced CCI-induced mechanical allodynia reversal. RTI-36 displayed higher potency than either RTI-102 or RTI-76. These novel epibatidine analogs may prove to be useful tools in the fight against nicotine dependence as well as novel neuropathic pain analgesics.

You Don't Know Nicotine: Novel Applications of Nicotinic Therapeutics in Aging

Overall AbstractNicotine binds to nicotinic cholinergic receptors in the brain and the periphery. These receptors are ligand-gated ion channels that modulate other neurotransmitter systems and have important roles in cognitive and emotional functioning. Recent advances have expanded the understanding of how stimulation or blockade of nicotinic receptors affects brain activity, cortical networks, and behavior. While nicotine has been mostly thought of as a substance of abuse connected to tobacco smoking, the potential exists for utilizing nicotine and/or nicotinic stimulation as a therapeutic agent for the treatment of a variety of brain disorders. This symposium will present recent advances in the understanding of how nicotine and nicotinic drugs affect the brain and explore the possible utilization of nicotine for age-related brain disorders. While nicotinic therapeutics has a history dating back to the 1920s, work began in earnest in the 1980s with examining nicotine in Alzheimer's disease. This continued with the development of receptor-selective nicotinic agonists targeted towards Alzheimer’ disease, ADHD, and schizophrenia. These efforts failed, in part because of limited understanding of the appropriate brain system neural targets as well as lack of clarity as to whether the drugs engaged these targets in a meaningful way.Recent research has significantly expanded our understanding of the neural circuitry affected by nicotine and nicotinic stimulation and better human and animal models have offered new insights into the potential for nicotine therapeutics in areas as disparate as hearing loss and stress response mechanisms. Nicotine is now being investigated for its potential in age-related disorders including memory impairment, late life depression, cognitive impairment following cancer treatment and COVID, and age-related hearing loss. The symposium will examine how the effects of nicotine on cognitive functioning differ between older versus younger individuals to explore how nicotinic stimulation benefits may be age specific. We will also present the background and progress of the MIND study, a multi-center nicotine treatment study for mild cognitive impairment, the largest and longest nicotine study of non-smokers ever conducted. New clinical and neural evidence for nicotine as an augmentation treatment for late life depression and the cognitive deficits that accompany this condition will be discussed. Finally, the use of translational animal-human models for discerning the potential beneficial effects of nicotine and the potential for combination therapies to enhance the beneficial effects of nicotine will be presented. These studies of nicotine have broad clinical and scientific significance. If the hypotheses are validated, this will support a novel, broadly available, and inexpensive repurposed intervention for age-related brain disorders and would encourage early treatment to improve symptoms, retard progression of cognitive impairment or improve mood, and lead to combined trials with other agents for brain disorders of aging.

Memantine has a nicotinic neuroprotective pathway in acute hippocampal slices after an NMDA insult

Memantine is a non-competitive antagonist with a moderate affinity to the N-methyl-d-Aspartate (NMDA) receptor. The present study assessed memantine's neuroprotective activity using electrophysiology of ex-vivo hippocampal slices. Interestingly, a nicotinic component was necessary for memantine's neuroprotection (NP). Memantine demonstrated a bell-shaped dose-response curve of NP against NMDA. Memantine was neuroprotective at concentrations below 3 μM, but the NP declined at higher concentrations (>3 μM) when memantine inhibits the NMDA receptor. Additional evidence that memantine NP is mediated by an alternate mechanism independent of the inhibition of the NMDA receptor is supported by its ability to protect neurons when applied before or after the NMDA insult and in the presence of D(−)-2-Amino-5-phosphonopentanoic acid (APV), the standard NMDA receptor inhibitor. We found several similarities between the memantine NP mechanism and the neuroprotective nicotinic drug, the 4R cembranoid. Memantine's NP requires the release of acetylcholine, the activation of α4β2, and is independent of MEK/MAPK signaling. Both 4R and memantine require the activation of PI3K/AKT for NP against NMDA-mediated excitotoxicity, although at different concentrations. In conclusion, our studies show memantine is neuroprotective through a nicotinic pathway, similar to the nicotinic drug 4R. This information leads to a better understanding of memantine's mechanisms of action and explains its dose-dependent effectiveness in Alzheimer's and other neurological disorders.

DESIGN OF EXPERIMENTS FOR PREPARATION OF POLYVINYL ALCOHOL–BASED OPTIMIZED FILMS FOR NICOTINE TRANSDERMAL DELIVERY

Optimized polyvinyl alcohol (PVA)-based films were prepared by blending with other excipients: deproteinized natural rubber, glycerin, and poloxamer 407. The properties of the developed optimized PVA-based film: thickness, weight variable, folding endurance, swelling ratio, and moisture content, were predicted by the Design-Expert® program. The thickness and weight variables were not found to be significantly different, but folding endurance, swelling ratio, and moisture content had significant differences. The predicted mathematical models for dependent variables were quadratic, linear, and special cubic. The linear relationships of the model conditions for optimized PVA-based films were 0.5099–0.8521 within a 95% confidence interval. The selected optimized PVA-based film was evaluated for all parameters again. The thickness, weight variable, folding endurance, swelling ratio, and moisture content were 0.209 ± 0.025 mm, 27.660 ± 3.446 mg/cm2, 1646.667 ± 45.092 times, 100.575 ± 17.121%, and 5.337 ± 0.319%, respectively. The obtained optimal formulation was then mixed with nicotine drug, and subsequently applied for transdermal delivery systems. The nicotine could be released as 1.60 ± 0.30 mg/cm2 from the film, in accordance with Higuchi’s model (R2 = 0.9701). The constant rate for nicotine release was 0.373 ± 0.049 mg/ Thus, it was concluded that the film was an effective polymer for controlling the nicotine release behavior.

The Role of Impulsivity and Reward Deficiency in "Liking" and "Wanting" of Potentially Problematic Behaviors and Substance Uses.

A few studies have examined the changes in substance- and behavior-related “wanting” and “liking” of human subjects, the key properties of Incentive Sensitization Theory (IST). The aim of this study was to examine the dissociation between “wanting” and “liking” as a function of usage frequency, intensity, and subjective severity in individuals across four substances (alcohol, nicotine, cannabis, and other drugs) and ten behaviors (gambling, overeating, gaming, pornography use, sex, social media use, Internet use, TV-series watching, shopping, and work). Also, the potential roles of impulsivity and reward deficiency were investigated in “wanting,” “liking,” and wellbeing. The sex differences between “wanting” and “liking” were also examined. Based on our findings using structural equation modeling with 749 participants (503 women, Mage = 35.7 years, SD = 11.84), who completed self-report questionnaires, “wanting” increased with the severity, frequency, and intensity of potentially problematic use, while “liking” did not change. Impulsivity positively predicted “wanting,” and “wanting” positively predicted problem uses/behaviors. Reward deficiency positively predicted problem uses/behaviors, and both impulsivity and problem uses/behaviors negatively predicted wellbeing. Finally, women showed higher levels of “wanting,” compared to men. These findings demonstrate the potential roles of incentive sensitization in both potentially problematic substance uses and behaviors.

Together we can begin fixing public health globally

It is irrefutable that most convenience and favored foods and beverages are the leading cause of morbidity and mortality worldwide. Government and private health agencies and organizations and cardiologists specifically, and clinicians in general, have failed and should be held liable for malpractice for pushing procedures and pills above longevity-lifestyle redirection for Maillard, alcohol, nicotine, and other drug abuse disorders. Particular lifestyle transitioning training for specific Maillard, alcohol, nicotine, fentanyl, and other drug misuse lifestyle transitioning programs have proven the most successful. And medical publishers and medical school deans to front-line medical clinicians and technicians are either unwilling or unable to conceptualize the basics of how lifestyle transitioning for substance misuse works. A must when trying to sell a joyous longevity lifestyle to themselves, their students, and their overweight residential and ambulatory guests. A detailed understanding of recovery lifestyle training programs is privy to a small number of experts globally, RL DuPont, NS Miller, and JA Cocores, for example. Specifics surrounding why Maillard foods are powerful opiate and dopaminergic agonists are clear to the author. Falsely arrested and silenced by the Florida Board of Medicine in February 2013 for putting lifestyle changes above the pharmaceutical industry and prescription cardiology and other pill-pushing by Hillary Clinton's Florida-based Drug Czar Dave Aronberg. The purpose of this article is to supply clinicians and healers with information surrounding why and how Maillard-coated favorite foods and beverages within each country behave like fentanyl and methamphetamine. And how to sell the unwanted proposition of helping unhappy browned-food compelled people slowly begin moving towards a joyous longevity lifestyle. These steps and much more should have been worldwide headlines over the past few decades. Instead, the world was distracted away from vital, joyous longevity lifestyle information by corporatocracies and autocratic governments posing as democracies that feed off their wealth and power. The world is perpetually distracted from what the average person is most concerned about by the so-called elite with a self-serving agenda. The elite-funded news of February 23, 2022, is no exception. Healers and everyday people need to begin fending for their joyous longevity lifestyle. These are the first baby steps and formulas to outlive the elites to once again form governments by and for the people.

Appetitive Pavlovian conditioning of the stimulus effects of nicotine enhances later nicotine self-administration.

Nicotine produces robust stimulus effects that can be conditioned to exert stimulus control over behavior through associative learning. Additionally, nicotine has weak reinforcing effects that are inconsistent with its prevalence of use and the tenacity of nicotine dependence. The present study investigated whether conditioned associations to the nicotine drug stimulus may confer additional reinforcing strength to nicotine that thereby increase its use liability, and presents a new methodological approach to investigating the interaction between the stimulus effects and reinforcing effects of drugs. Male and female Sprague-Dawley rats were divided into groups receiving intravenous infusions of either 0.03 mg/kg nicotine or 0.9% saline that were either Paired (30 s delayed) or explicitly Unpaired (4 to 6 min delayed) with sucrose deliveries over 24 daily conditioning sessions. Thereafter, recessed nosepoke response devices were installed in the chambers and infusions of their assigned drug solutions were contingently available according to a progressive ratio schedule. Rats in the Paired Nicotine condition acquired the nosepoke response, expressed active nosepoke discrimination, and self-administered significantly more infusions than rats in any of the other groups. These results demonstrate that the interoceptive stimulus effects of nicotine can form Pavlovian associations with reinforcing events that alter its reinforcement efficacy.

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands.

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

Role of Genetic Interactions in Lung Diseases Detection Using Computational Approaches: A Review

: Genome-wide Association Studies (GWAS) give special insight into genetic differences and environmental influences that are part of different human disorders and provide prognostic help to increase the survival of patients. Lung diseases such as lung cancer, asthma, and tuberculosis are detected by analyzing Single Nucleotide Polymorphism (SNP) genetic variations. The key causes of lung-related diseases are genetic factors, environmental and social behaviors. : The epistasis effects act as a blueprint for the researchers to observe the genetic variation associated with lung diseases. The manual examination of the enormous genetic interactions is complicated to detect the lung syndromes for diagnosis of acute respiratory diseases. Due to its importance, several computational approaches have been modeled to infer epistasis effects. This article includes a comprehensive and multifaceted review of all the relevant genetic studies published between 2006 and 2020. In this critical review, various computational approaches are extensively discussed in detecting respondent epistasis effects for various lung diseases such as asthma, tuberculosis, lung cancer, and nicotine drug dependence. : The analysis shows that different computational models identified candidate genes such as CHRNA4, CHRNB2, BDNF, TAS2R16, TAS2R38, BRCA1, BRCA2, RAD21, IL4Ra, IL-13 and IL-1β, have important causes for genetic variants linked to pulmonary disease. These computational approaches' strengths and limitations are described. The issues behind the computational methods while identifying the lung diseases through epistasis effects and the parameters used by various researchers for their evaluation are also presented.

Pharmacotherapy of substance use disorders in the neuroscience-based nomenclature (NbN)

In the field of substance use disorders (SUDs), medications are frequently labeled according to their main symptomatic effect (e.g., "anticraving drugs") or according to imprecise and sometimes old concepts related to treatment strategies (e.g., "replacement therapies", "antabuse drugs", or "substitution treatments"). By contrast, the neuroscience-based nomenclature (NbN) offers a clearer and more consistent rationale, according to which the main element of classification is based on the pharmacological mode of action of the medication. This review aims to display the different approved treatments used in SUDs, and to discuss the pros and cons of using this new conceptual framework in the field of addiction. According to the NbN classification, medications approved in the different SUDs can be classified in the different following categories: 1) nicotinic drugs; 2) GABAergic drugs; 3) opioid drugs; and 4) others. More specifically, medications can be distinguished between whether they mimic the same pharmacological action of the "substance" whose use should be stopped or reduced, or whether they target other more general pharmacological systems, that are supposed to be common to all SUDs, as they reflect the "universal" addiction process. The NbN offers obvious advantages, compared with previous classifications. In particular, it allows to no longer mix drugs with very different pharmacological targets under the same label. The main limitation of the NbN, when applied to psychopharmacology in general, and to SUDs medications in particular, is that drugs frequently have a "dirty" action, with multiple pharmacological targets. In this respect, it may be hard to classify drugs according to the NbN classification, without making the individual profile of each medicine more complex.

A description of drug use among adolescents in Slovakia in different age and gender groups

The paper describes the drug-using behaviour among young people (12-19 y.) within two age groups in Slovakia. The study aims to describe the prevalence of two different forms of drug-use (experimentation and use within the last 30 days) of legal and illegal substances: alcohol, nicotine (cigarettes), marijuana, and other illegal drugs. A descriptive analysis was applied to two age and gender groups. The research sample was made up of 2489 pupils in primary and secondary schools (various types) from different regions within Slovakia. One set was made up of 39.1% (N = 974) boys and 61.3% (N = 1515) girls aged 12-19 years which was divided into two age groups: group “14” (14 to 15 years, N = 923) and group “16” (16 and older, N = 1566). The SAHA method was used for data collection (Social and Health Assessment, Weissberg et al., 1991; a Slovak version by Rojková, 2017). Gender differences were tested statistically, and some differences were identified. The results are discussed in the context of European and national surveys that are available and a decrease in experimentation with marijuana and smoking was found.

MARIJUANA USE AMONG OLDER ADULTS: HARMS MAY OUTWEIGH BENEFITS

The US Epidemiologic data show that past-year marijuana use rates among the 50+ age group rose more than 300% between 2002 and 2017. In 2017, 10.2% of those aged 50-64 years and 3.7% of those aged 65+ years were past-year users, and 15% of these users reported all or part of their use to have been for medical purposes. In this symposium, using findings from previous research and recent epidemiologic data, we will present both positive and adverse effects of late-life marijuana use. Marijuana may be useful for the treatment of pain (particularly neuropathic pain) and chemotherapy-induced nausea and vomiting. However, older marijuana users are often long-term users and significant proportions suffer from marijuana use disorder along with other substance (nicotine, alcohol, prescription and illicit drugs) use and/or mental disorders. Adverse effects also include dizziness, confusion, impairments in memory and attention, somnolence, and hallucinations, which may outweigh purported positive effects.

Nicotine Bound to Its Receptors: New Structures for a Vexing Pathopharmacological Problem

In this issue of Neuron, Gharpure etal. (2019) nearly complete atomic-level descriptions for binding, permeation, and subunit interactions at the two major heteropentameric nicotinic receptors-those governing nicotine's rewarding and aversive effects. Can we finally design highly selective and useful nicotinic drugs?

Yield and Efficiency of Mental Disorder Screening at Intake to Prison: A Comparison of DIA-X Short- and Long-Screening-Protocols in Compensation Prisoners.

Background: Inmates are several times more likely to suffer from mental disorders than the general population.In order to take appropriate curative or preventive measures, a precise psychiatric diagnosis at detention start would therefore be imperative, but is frequently not carried out for reasons of time. The computer-aided expert system DIA-X enables a rapid and reliable diagnosis of psychiatric disorders. DIA-X is available as a short screening questionnaire with a processing time of a few minutes and as a standardized interview, which takes ~1 h to complete.Objective: The aim of this study was to assess the efficiency and accuracy of the DIA-X short screening questionnaire.Methods: One hundred detainees were recruited randomly from compensation prisoners, who were imprisoned because they were unwilling or unable to pay a fine for committing a criminal offence, from the penal institution Berlin-Plötzensee in 2017. Both the short screening questionnaire and the standardized interview from the DIA-X expert system were used for diagnosing mental disorders. Based on the results of the standardized interview from four study populations of compensation prisoners from 1999, 2004, 2010, and 2017, the sensitivity, specificity and the predictive values of the screening form were inferred.Results: More than half of the compensation prisoners suffered from mental and behavioral disorders caused by the abuse of alcohol or psychoactive substances. Phobic anxiety disorders were detected in one out of ten compensation prisoners and two out of ten compensation prisoners suffered from major depressive disorders. The DIA-X screening questionnaire was able to detect all mental illnesses with a sensitivity of 100%. However, specificities were low for nicotine dependency, drug and alcohol abuse. High specificities and high predictive values were obtained for psychoses and anxiety disorders.Conclusions: As the main test quality criteria of the DIA-X screening forms were so low, we cannot recommend the application of the DIA-X screening form for obtaining a valid diagnosis. Therefore, we explicitly recommend using the long form DIA-X for the detection of the most serious cases of mental illness. Then, these prisoners could receive either therapy or special social training.

Optical probing of acetylcholine receptors on neurons in the medial habenula with a novel caged nicotine drug analogue.

A new caged nicotinic acetylcholine receptor (nAChR) agonist was developed, ABT594, which is photolysed by one- and two-photon excitation. The caged compound is photolysed with a quantum yield of 0.20. One-photon uncaging of ABT594 elicited large currents and Ca2+ transients at the soma and dendrites of medial habenula (MHb) neurons of mouse brain slices. Unexpectedly, uncaging of ABT594 also revealed highly Ca2+ -permeable nAChRs on axons of MHb neurons. Photochemical release of neurotransmitters has been instrumental in the study of their underlying receptors, with acetylcholine being the exception due to its inaccessibility to photochemical protection. We caged a nicotinic acetylcholine receptor (nAChR) agonist, ABT594, via its secondary amine functionality. Effective photolysis could be carried out using either one- or two-photon excitation. Brief flashes (0.5-3.0ms) of 410nm light evoked large currents and Ca2+ transients on cell bodies and dendrites of medial habenula (MHb) neurons. Unexpectedly, photorelease of ABT594 also revealed nAChR-mediated Ca2+ signals along the axons of MHb neurons.

Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys.

Evidence suggests that the α4β2, but not the α7, subtype of the nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine and related drugs. However, the importance of other nAChR subtypes remains unclear. The present studies were conducted to examine the involvement of nAChR subtypes by determining the effects of selected nicotinic agonists and antagonists in squirrel monkeys either 1) responding for food reinforcement or 2) discriminating the nicotinic agonist (+)-epibatidine (0.001 mg/kg) from vehicle. In food-reinforcement studies, nicotine, (+)-epibatidine, varenicline and cytisine all produced dose-dependent decreases in rates of food-maintained responding. The rate-decreasing effects of nicotine were antagonized by mecamylamine (nonselective), not appreciably altered by dihydro-β-erythroidine (α4β2 selective), and exacerbated by the nicotinic partial agonists, varenicline and cytisine. Results from discrimination studies show that non-nicotinic drugs did not substitute for (+)-epibatidine, and that except for lobeline, the nicotinic agonists produced either full [(+)-epibatidine, (-)-epibatidine, and nicotine] or partial (varenicline, cytisine, anabaseine, and isoarecolone) substitution for (+)-epibatidine. In interaction studies with antagonists differing in selectivity, (+)-epibatidine discrimination was substantively antagonized by mecamylamine, slightly attenuated by hexamethonium (peripherally restricted) or dihydro-β-erythroidine, and not altered by methyllycaconitine (α7 selective). Varenicline and cytisine enhanced (+)-epibatidine's discriminative-stimulus effects. Correlational analysis revealed a close correspondence between relative behavioral potencies of nicotinic agonists in both studies and their published relative binding affinities at α4β2 and α3β4, but not α7 nAChR, subtypes. Collectively, these results are consistent with the idea that the α4β2 and α3β4, but not α7 nAChR subtypes play a role in the behavioral effects of nicotinic agonists.

Nicotine drug discrimination and nicotinic acetylcholine receptors in differentially reared rats.

Individuals vary in sensitivity to the behavioral effects of nicotine, resulting in differences in vulnerability to nicotine addiction. The role of rearing environment in determining individual sensitivity to nicotine is unclear. The neuropharmacological mechanisms mediating the effect of rearing environment on the behavioral actions of nicotine are also poorly understood. The contribution of rearing environment in determining the sensitivity to the interoceptive effects of nicotine was determined in rats reared in isolated conditions (IC) or enriched conditions (EC). The role of dopamine receptors and α4β2*-nicotinic acetylcholine (nACh) receptors in mediating the differential effect of IC and EC on the interoceptive action of nicotine was determined. The interoceptive action of nicotine was measured as the discriminative stimulus effect of nicotine. Mecamylamine- and eticlopride-inhibition of the nicotine stimulus were used to examine nACh and dopamine receptors, respectively. α4β2*-nACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125I]-epibatidine binding. EC-reared rats are less sensitive than IC-reared rats to the discriminative stimulus effects of nicotine at all but maximally effective doses. Mecamylamine inhibited the nicotine stimulus threefold more potently in EC-reared rats (IC50 = 0.25mg/kg) compared to IC-reared rats (IC50 = 0.75mg/kg); eticlopride inhibition was not different. [125I]-epibatidine binding in the ventral tegmental area of EC-reared rats was reduced (2.8 ± 0.3fmol) compared to that of IC-reared rats (4.0 ± 0.4fmol); there was no difference in the nucleus accumbens. Rearing environment regulates the sensitivity to the interoceptive effects of nicotine and α4β2*-nACh receptor expression in the mesolimbic dopamine pathway.

Mutually augmenting interactions of dextromethorphan and sazetidine-A for reducing nicotine self-administration in rats

A variety of nicotinic drug treatments have been found to decrease nicotine self-administration. However, interactions of drugs affecting different nicotinic receptor subtypes have not been much investigated. This study investigated the interactions between dextromethorphan, which blocks nicotinic α3β2 receptors as well as a variety of other receptors with sazetidine-A which is a potent and selective α4β2 nicotinic receptor partial agonist with desensitizing properties. This interaction was compared with dextromethorphan combination treatment with mecamylamine, which is a nonspecific nicotinic channel blocker. Co-administration of dextromethorphan (either 0.5 or 5 mg/kg) and lower dose of sazetidine-A (0.3 mg/kg) caused a significant reduction in nicotine SA. With regard to food-motivated responding, 3 mg/kg of sazetidine-A given alone caused a significant decrease in food intake. However, the lower 0.3 mg/kg sazetidine-A dose did not significantly affect food-motivated responding even when given in combination with the higher 5 mg/kg dextromethorphan dose which itself caused a significant decrease in food motivated responding. Interestingly, this higher dextromethorphan dose significantly attenuated the decrease in food motivated responding caused by 3 mg/kg of sazetidine-A. Locomotor activity was increased by the lower 0.3 mg/kg sazetidine-A dose and decreased by the 5 mg/kg dextromethorphan dose. Mecamylamine at the doses (0.1 and 1 mg/kg) did not affect nicotine SA, but at 1 mg/kg significantly decreased food-motivated responding. None of the mecamylamine doses augmented the effect of dextromethorphan in reducing nicotine self-administration. These studies showed that the combination of dextromethorphan and sazetidine-A had mutually potentiating effects, which could provide a better efficacy for promoting smoking cessation, however the strength of the interactions was fairly modest.

Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging.

Patients with schizophrenia self-administer nicotine at rates higher than is self-administered for any other psychiatric illness. Although the reasons are unclear, one hypothesis suggests that nicotine is a form of 'self-medication' in order to restore normal levels of nicotinic signaling and target abnormalities in neuronal function associated with cognitive processes. This brief review discusses evidence from neurophysiological and neuroimaging studies in schizophrenia patients that nicotinic agonists may effectively target dysfunctional neuronal circuits in the illness. Evidence suggests that nicotine significantly modulates a number of these circuits, although relatively few studies have used modern neuroimaging techniques (e.g. functional magnetic resonance imaging (fMRI)) to examine the effects of nicotinic drugs on disease-related neurobiology. The neuronal effects of nicotine and other nicotinic agonists in schizophrenia remain a priority for psychiatry research.