Nicotine-induced Behaviors Research Articles

Activation of mediodorsal thalamic dopamine receptors inhibited nicotine-induced anxiety in rats: A possible role of corticolimbic NMDA neurotransmission and BDNF expression

The present study aimed to evaluate the functional interaction between the dopaminergic and glutamatergic systems of the mediodorsal thalamus (MD), the ventral hippocampus (VH), and the prefrontal cortex (PFC) in nicotine-induced anxiogenic-like behaviors. Brain-derived neurotrophic factor (BDNF) level changes were measured in the targeted brain areas following the drug treatments. The percentage of time spent in the open arm (% OAT) and open arm entry (% OAE) were calculated in the elevated plus maze (EPM) to measure anxiety-related behaviors in adult male Wistar rats. Systemic administration of nicotine at a dose of 0.5 mg/kg induced an anxiogenic-like response associated with decreased BDNF levels in the hippocampus and the PFC. Intra-MD microinjection of apomorphine (0.1–0.3 μg/rat) induced an anxiogenic-like response, while apomorphine inhibited nicotine-induced anxiogenic-like behaviors associated with increased hippocampal and PFC BDNF expression levels. Interestingly, the blockade of the VH or the PFC NMDA receptors via the microinjection of D-AP5 (0.3–0.5 μg/rat) into the targeted sites reversed the inhibitory effect of apomorphine (0.5 μg/rat, intra-MD) on the nicotine response and led to the decrease of BDNF levels in the hippocampus and the PFC. Also, the microinjection of a higher dose of D-AP5 (0.5 μg/rat, intra-PFC) alone produced an anxiogenic effect. These findings suggest that the functional interaction between the MD dopaminergic D1/D2-like and the VH/PFC glutamatergic NMDA receptors may be partially involved in the anxiogenic-like effects of nicotine, likely via the alteration of BDNF levels in the hippocampus and the PFC.

The Attenuation of Alcohol and Nicotine Induced Behaviors in Drosophila melanogaster by Sinomenine

The purpose of this experiment is to determine the efficacy of Sinomenine, an opioid receptor antagonist, in attenuating ethanol and nicotine induced behaviors in Drosophila melanogaster. While ethanol and nicotine are quite different in their direct mechanism of action, current research suggests that opiate reward, CREB-mediated transcription, and long-term potentiation are common pathways implicated in the development of various addictions. Due to its ability to antagonize the mu-opioid receptor, Sinomenine prevents endorphin binding, drug-induced CREB transcription, and consequent increase in dopamine production by tyrosine hydroxylase that leads to euphoria and addiction. Sinomenine may be particularly promising over other opioid receptor antagonists for sedative addictions due to its opioid-receptor independent anxiolytic effects. In a CAFE assay performed to measure preference through consumption of ethanol or nicotine, Sinomenine reverses both naive and conditioned preference for ethanol, as well as conditioned nicotine aversion. Measuring locomotion, Sinomenine attenuated both the ethanol and nicotine induced decreases in negative geotaxis exhibition in Drosophila melanogaster. Quantifying olfactory preference, Sinomenine reversed conditioned odor preference in a Y-maze, but not naive preference. Reflecting its effects on the CREB pathway, Sinomenine inhibited a nicotine-induced increase in cAMP, but did not significantly affect cAMP levels in ethanol treated Drosophila. According to these results, Sinomenine is particularly effective in attenuating conditioned ethanol or nicotine-induced behavior, and produces mixed results in terms of naive exposure. The natural chemosensory preferences or aversion of ethanol and nicotine may be independent of the CREB pathway, while developed preference may be directly dependent on it.

Nicotine Rather Than Non-Nicotine Substances in 3R4F WCSC Increases Behavioral Sensitization and Drug-Taking Behavior in Rats.

Nicotine increases reinforcing effects of cigarette smoking by upregulating glutamate and dopamine releases via stimulation of nicotinic acetylcholine receptors (nAChRs) in the dorsal striatum (CPu). The present study was conducted to evaluate whether non-nicotine substances in cigarette smoke potentiate nicotine-induced behaviors by increasing glutamate and dopamine concentrations in the CPu. Changes in the levels of glutamate and dopamine in the CPu were analyzed using a glutamate colorimetric assay and dopamine enzyme-linked immunosorbent assay, respectively, after repeated administration of nicotine or whole cigarette smoke condensate (WCSC) in male Sprague-Dawley rats. Changes in locomotion and drug-taking behavior were analyzed using the measurements of locomotor activity and self-administration under a fixed ratio 1 schedule in response to repeated administration of nicotine or WCSC. Repeated subcutaneous (s.c.) injections of nicotine (0.25mg/kg/day) for 7 consecutive days significantly increased the levels of glutamate and dopamine in the CPu. Similar results were obtained from repeated injections of WCSC (0.25mg/kg nicotine/day, s.c.) extracted from 3R4F Kentucky reference cigarettes. Parallel with the increases in the neurotransmitter levels in the CPu, both nicotine and WCSC increased locomotor activity and self-administration (0.03mg/kg nicotine/infusion). However, repeated injections of WCSC did not change the nicotine-induced increases in neurotransmitter levels, locomotor activity, and self-administration. Nicotine rather than non-nicotine substances in WCSC play a major role in potentiating behavioral sensitization and drug-taking behavior via elevation of glutamate and dopamine concentrations in the CPu of rats. WCSC does not augment the nicotine-induced increases in behavioral sensitization, drug-taking behavior, and glutamate and dopamine concentrations, suggesting that non-nicotine substances do not potentiate the nicotine-induced behaviors by increasing the concentrations of the neurotransmitters in the CPu. These findings imply that nicotine, but not non-nicotine substances in WCSC, may be a major contributor that induces tobacco dependence in rats.

Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adolescent Rats with a Human Polymorphism (rs2304297) in the 3′-UTR of the CHRNA6 Gene

In human adolescents, a single nucleotide polymorphism (SNP), rs2304297, in the 3′-UTR of the nicotinic receptor subunit gene, CHRNA6, has been associated with increased smoking. To study the effects of the human CHRNA6 3′-UTR SNP, our lab generated knock-in rodent lines with either C or G SNP alleles. The objective of this study was to determine if the CHRNA6 3′-UTR SNP is functional in the knock-in rat lines. We hypothesized that the human CHRNA6 3′-UTR SNP knock-in does not impact baseline but enhances nicotine-induced behaviors. For baseline behaviors, rats underwent food self-administration at escalating schedules of reinforcement followed by a locomotor assay and a series of anxiety tests (postnatal day (PN) 25-39). In separate cohorts, adolescent rats underwent 1- or 4-day nicotine pretreatment (2×, 30 μg/kg/0.1 mL, i.v.). After the last nicotine injection (PN 31), animals were assessed behaviorally in an open-field chamber, and brain tissue was collected. We show the human CHRNA6 3′-UTR SNP knock-in does not affect food reinforcement, locomotor activity, or anxiety. Further, 4-day, but not 1-day, nicotine exposure enhances locomotion and anxiolytic behavior in a genotype- and sex-specific manner. These findings demonstrate that the human CHRNA6 3′-UTR SNP is functional in our in vivo model.

Epigenetic Mechanisms Mediate Nicotine-Induced Reward and Behaviour in Zebrafish.

Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in the installation of persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific effects on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate epigenetic regulation of gene expression should be considered as a potential therapeutic method to treat nicotine addiction.

YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy.

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial–mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.

Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice.

Nicotine causes psychological dependence through its interactions with nicotinic acetylcholine receptors in the brain. We previously demonstrated that fatty acid-binding protein 3 (FABP3) colocalizes with dopamine D2 receptors (D2Rs) in the dorsal striatum, and FABP3 deficiency leads to impaired D2R function. Moreover, D2R null mice do not exhibit increased nicotine-induced conditioned place preference (CPP) following chronic nicotine administration. To investigate the role of FABP3 in nicotine-induced CPP, FABP3 knockout (FABP3-/-) mice were evaluated using a CPP apparatus following consecutive nicotine administration (0.5mg/kg) for 14days. Importantly, nicotine-induced CPP was suppressed in the conditioning, withdrawal, and relapse phases in FABP3-/- mice. To resolve the mechanisms underlying impaired nicotine-induced CPP in these mice, we assessed c-Fos expression and Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) signaling in both dopamine D1 receptor (D1R)- and D2R-positive neurons in the nucleus accumbens (NAc). Notably, 64% of dopamine receptor-positive neurons in the mouse NAc expressed both D1R and D2R. Impaired nicotine-induced CPP was correlated with lack of responsiveness of both CaMKII and ERK phosphorylation. The number of D2R-positive neurons was increased in FABP3-/- mice, while the number of D1R-positive neurons and the responsiveness of c-Fos expression to nicotine were decreased. The aberrant c-Fos expression was closely correlated with CaMKII but not ERK phosphorylation levels in the NAc of FABP3-/- mice. Taken together, these results indicate that impaired D2R signaling due to lack of FABP3 may affect D1R and c-Fos signaling and underlie nicotine-induced CPP behaviors.

Evaluating a school-based science program that teaches the physiological effects of nicotine

School-based drug prevention programs represent a widely endorsed public health goal, with an important aspect of knowledge-based curricula being education about the physiological effects of drugs. Nicotine is one of the world’s most addictive substances and in this program we have used nicotine-induced mammalian-like behaviors in flatworms called planarians to successfully teach students (4th-12th grade; n = 1,616 students) about the physiological and addictive effects of nicotine. An initial study tested the change in knowledge about addictive substances in 6th-12th grade students after they completed a lab examining the effects of two concentrations of nicotine on the number of stereotypies (C-shaped spasms) planarians demonstrate in a 5-minute period of time. Lab discussion focused on developing and testing hypotheses, measurement reliability, and mechanisms of nicotine action. Surveys given pre- and post-lab experience showed that 6th grade students have significantly lower knowledge about nicotine than 7th-12th grade students (6th grade: 40.65 ± 0.78% correct, 7th-12th grade: 59.29 ± 1.71%, p < 0.001) pre-lab, but that students in all grades showed a significant increase in knowledge post-lab (p < 0.001). In 6th grade the lab was effective in improving knowledge about nicotine in urban, suburban and rural schools, p < 0.001, with students in suburban schools showing significantly greater knowledge both pre-test (urban: 37.62 ± 1.45%; suburban: 48.78 ± 1.62%; rural: 37.33 ± 0.99%; p < 0.001) and post-test (urban:60.60 ± 1.85%; suburban: 67.54 ± 1.82%; urban: 61.66 ± 1.18%; p < 0.001).A second study, modifying the lab so that the time spent observing the planarians is reduced to a 1-minute period, showed that students in both 4th and 5th grades had a significant increase in knowledge about the physiological and addictive effects of nicotine post-lab (p < 0.001).

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

BackgroundThe mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined.MethodsShort hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotine-treated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model.ResultsNicotine increased SNCG expression in a time- and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression.ConclusionNicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.

Nicotine-induced Brain Stimulation Reward is Modulated by Melanocortin-4 Receptors in Ovariectomized Rats

Apart from reproduction, estrogen influences a multitude of processes. Increase in estrogen levels in women is known to promote reward probably mediated via the melanocortin and dopamine systems. Reduced estrogen in post-menopausal women attenuates reward, evoking the need for stimulation with greater rewarding salience. This is reflected in the well-recognized phenomena of difficulty in quitting and increased craving for nicotine in women following the onset of menopause. The present study aims at understanding the role of melanocortin receptors (MC-R) in nicotine-induced reward behavior following ovariectomy in rats. The MC4-R mRNA level was increased in ipsilateral nucleus accumbens (Acb) of the intact rats implanted with electrode in medial forebrain bundle and trained in intracranial self-stimulation (ICSS) paradigm. Additional groups of ICSS trained rats were ovariectomized (OVX) and subjected to reward evaluation. Trained OVX rats revealed a significant increase in threshold frequency and rightward shift in rate frequency curve, suggesting reward deficit behavior. However, pre-administration with nicotine, alpha-melanocyte stimulating hormone (α-MSH) or NDP-MSH (MC4-R agonist) to OVX animals restored the rewarding activity in ICSS protocol; HS014 (MC4-R antagonist) suppressed the lever press activity. Prior treatment with sub-effective doses of α-MSH or NDP-MSH potentiated the reward effect of nicotine, but was attenuated by HS014. Alpha-MSH-immunoreactivity was decreased in the Acb shell, arcuate and paraventricular nucleus of hypothalamus, and ventral bed nucleus of stria terminalis in the OVX rats, while nicotine treatment restored the same. We suggest a role for the endogenous MC system, perhaps acting via MC4-R, in the nicotine-induced reward in OVX rats.

Influence of neuropathic pain on nicotinic acetylcholine receptor plasticity and behavioral responses to nicotine in rats.

Tobacco smoking is particularly evident in individuals experiencing chronic pain. This complex relationship is poorly understood at both molecular and behavioral levels. Here, we describe experiments aimed at understanding whether a chronic pain state induces neuroadaptations into the brain or peripheral nerves that involve nicotinic acetylcholine receptors (nAChRs) and whether these neuroadaptations directly lead to increased vulnerability to nicotine addiction or to the development of coping strategies to relieve pain symptoms. We found that ligation of the rat L5 spinal nerve led to a dramatic downregulation in the mRNA expression levels of all nAChR subunits examined in dorsal root ganglia and a time-dependent downregulation of discrete subunits, particularly in the cingulate cortex and the amygdala. Spinal nerve ligation and sham-operated rats showed minor or no changes in patterns of acquisition and motivation for nicotine taking. Spinal nerve ligation rats also showed similar vulnerability to nicotine seeking as sham animals when reinstatement was induced by nicotine-associated cues, but failed to reinstate lever pressing when relapse was induced by nicotine priming. Spinal nerve ligation and sham rats were equally sensitive to nicotine-induced anxiety-like behavior and antinociception; however, nicotine produced a potent and long-lasting antiallodynic effect in spinal nerve ligation rats. These results demonstrate that chronic pain leads to plasticity of nAChRs that do not directly facilitate nicotine addictive behaviors. Instead, nicotine potently decreases allodynia, an effect that could lead to increased nicotine consumption in chronic pain subjects.

Baclofen Reversed the Nicotine-Induced Anxiety-Like Behavior: A Beneficial Therapeutic Strategy for Smoking Cessation Aid

Background: Nicotine dependence is the most widespread form of substance abuse. Anxiety is one of the prominent symptoms in withdrawal syndromes of nicotine. Nucleus Accumbens (NAc) is a principle area which participates in several behavioral responses (e.g., anxiety), and several studies reported that receptors are involved in the modulation of anxiety. This study was aimed to examine the interaction of baclofen and nicotine on anxiety behavior in NAc shell. Materials and Methods: Rats weighing between 220 and 250g were used. The guide cannulas were implanted bilaterally into the shell of the NAc. Nicotine (0.025, 0.05 and 0.5 μg/rat) and baclofen (0.25, 0.5 and 2 μg/rat) and the co-administration of nicotine (0.025, 0.05 and 0.5μg/rat) with baclofen (0.25 μg/rat) were microinjected through the infusion cannula. The elevated plus-maze (EPM) was used to evaluate the anxiety-like parameters, and all data were recorded and analyzed. Results: Intra-NAc administration of nicotine (0.5μg/rat) decreased anxiety (P&lt;0.001). Microinjections of baclofen (0.5 and 2 μg/rat) decreased anxiety (P&lt; 0.001). However, there were no significant changes in anxiety-like parameters at the lowest dose of baclofen (0.25μg/rat). Co-administration of an ineffective dose of baclofen (0.25 μg/rat) with 3 doses of nicotine (0.025, 0.05 and 0.5 μg/rat) reversed the effects of nicotine in an effective dose (0.5μg/rat). Conclusion: Our result indicated that GABAergic agonist baclofen in ineffective doses could reverse the effects of nicotine on anxiety symptoms. Furthermore, our result suggested that enhancement of GABA transmission through activation of GABA-B receptors on NAc shell could reverse nicotine anxiety-related effects. It may be a strategy of treatment for smoking cessation aid.[GMJ.2017;6(2):118-27]

Individual differences in the behavioral effects of nicotine: A review of the preclinical animal literature

Not everyone who tries tobacco or other nicotine-containing products becomes a long-term user. Certain traits or factors that are differentially present in these individuals must be able to help health care providers and researchers determine who is more likely to become chronic users of nicotine-containing products. Some of these factors, particularly sensation-seeking/novelty, impulsivity, and anxiety, lend themselves to the creation of animal models of reactivity to nicotine. These models of reactivity to nicotine can improve the translational aspects of preclinical animal research on nicotine-induced behaviors and treatments in order to help reduce negative outcomes in human populations. The goal of this review is to evaluate the current status of animal models of individual differences that serve to predict the later behavioral effects of nicotine. The limited utility and inconsistency of existing novelty models is considered, as well as the promise of impulsivity and anxiety models in preclinical animal populations. Finally, other models that could be employed to extend the benefit of the current research are examined.

Drug-dependent behaviors and nicotinic acetylcholine receptor expressions in Caenorhabditis elegans following chronic nicotine exposure

Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans’ (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine-induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine-induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software. Our results indicate that the combined system is an advantageous alternative to define drug-dependent locomotion behavior in C. elegans. Chronic (24-h dosing) nicotine exposure at 6.17 and 61.7μM induced nicotine-dependent behaviors, including drug stimulation, tolerance/adaption, and withdrawal responses. Specifically, the movement speed of naïve worms on nicotine-containing environments was significantly higher than on nicotine-free environments, suggesting locomotion stimulation by nicotine. In contrast, the 24-h 6.17μM nicotine-treated worms exhibited significantly higher speeds on nicotine-free plates than on nicotine-containing plates. Furthermore significantly increased locomotion behavior during nicotine cessation was observed in worms treated with a higher nicotine concentration of 61.7μM. The relatively low locomotion speed of nicotine-treated worms on nicotine-containing environments also indicates adaption/tolerance of worms to nicotine following chronic nicotine exposure. In addition, this study provides useful information regarding the comprehensive in vivo expression profile of the 28 “core” nAChRs following different dosages of chronic nicotine treatments. Eleven genes (lev-1, acr-6, acr-7, acr-11, lev-8, acr-14, acr-16, acr-20, acr-21, ric-3, and unc-29) were significantly up-regulated following 61.7μM nicotine treatment, in which worms showed significantly increased locomotion behavior. This study provides insights into the linkage between nicotine-induced locomotion behavior and the regulation of nicotinic acetylcholine receptors.

Developmental alterations in locomotor and anxiety-like behavior as a function of D1 and D2 mRNA expression

The majority of smokers start smoking in adolescence, beginning a potentially lifelong struggle with nicotine use and abuse. In rodent models of the effects of nicotine, the drug has been shown to elicit both locomotor and anxiety-like behavioral effects. Research suggests that these behavioral effects may be due in part to dopamine (DA) receptors D1 and D2 in the mesolimbic system, specifically the nucleus accumbens (NAc). We examined early adolescent (P28), late adolescent (P45), and adult (P80) male Long–Evans rats in the elevated plus maze (EPM) under normal conditions and the open field (OF) post-nicotine in order to test locomotor and anxiety-like behavior. These behavioral findings were then correlated with expression of DA D1 and D2 mRNA levels as determined via in situ hybridization. Nicotine-induced locomotor behavior was found to be significantly different between age groups. After a single injection of nicotine, early adolescents exhibited increases in locomotor behavior, whereas both late adolescents and adults responded with decreases in locomotor behavior. In addition, it was found that among, early adolescents, open arm and center time in the EPM were negatively correlated with D2 mRNA expression. In contrast, among adults, distance traveled in the center and center time in the OF were negatively correlated with D2 mRNA expression. This study suggests that DA D2 receptors play a role in anxiety-like behavior and that the relationship between observed anxiety-like behaviors and D2 receptor expression changes through the lifespan.

Role of the medial septum cholinoceptors in anxiogenic-like effects of nicotine

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

Suppression of Nicotine-Induced Pathophysiology by an Adenovirus Hexon-Based Antinicotine Vaccine

Despite antismoking campaigns, cigarette smoking remains a pervasive addiction with significant societal impact, accounting for one of every five deaths. Smoking cessation therapies to help smokers quit are ineffective with a high recidivism rate. With the knowledge that nicotine is the principal addictive compound of cigarettes, we have developed an antismoking vaccine based on the highly immunogenic properties of the hexon protein purified from the serotype 5 adenovirus (Ad) capsid. We hypothesized that an effective antinicotine vaccine could be based on coupling the nicotine hapten AM1 to purified Ad hexon protein. To assess this, AM1 was conjugated to hexon purified from serotype 5 Ad to produce the HexonAM1 vaccine. C57Bl/6 mice were sensitized by 10 daily nicotine administrations (0.5 mg/kg, subcutaneous) to render the mice addicted to nicotine. Control groups were sensitized to phosphate-buffered saline (PBS). The mice were then immunized with HexonAM1 (4 μg, intramuscular) at 0, 3, and 6 weeks. By 6 weeks, the HexonAM1-vaccinated mice had serum antinicotine antibody titers of 1.1×10(6)±7.6×10(4). To demonstrate that these high antinicotine titers were sufficient to suppress the effects of nicotine, HexonAM1-vaccinated mice were evaluated for nicotine-induced hypoactive behavior with nicotine challenges (0.5 mg/kg wt) over 5 weeks. In all challenges, the HexonAM1-vaccinated mice behaved similar to PBS-challenged naive mice. These data demonstrate that a vaccine comprised of a nicotine analog coupled to Ad hexon can evoke a high level of antinicotine antibodies sufficient to inhibit nicotine-induced behavior. The HexonAM1 vaccine represents a platform paradigm for vaccines against small molecules.

Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose

Perfluoroalkyl acids, including perfluorohexane sulfonate (PFHxS), are fluorinated organic compounds used as surfactants and water and stain repellents in carpets, paper, and textiles, with characteristics to bioaccumulate and biomagnify in the food chain. PFHxS is found in umbilical cord blood, human milk and child serum from all over the world. We have recently reported that neonatal exposure to certain perfluoroalkyl acids, PFOS and PFOA, can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. The present study indicates that a single exposure to PFHxS on postnatal day 10, during a vulnerable period of brain development can alter adult spontaneous behavior and cognitive function in both male and female mice, effects that are both dose–response related and long-lasting/irreversible. PFHxS affected the cholinergic system, manifested as altered nicotine-induced behavior in adult animals. This is also in agreement with earlier studies on neonatal exposure to PFOS and PFOA. The present findings show that PFHxS, a member of the perfluoroalkyl acid group, can act as a developmental neurotoxicant and affect the cholinergic system and cognitive function and the effects show similarities with effects earlier reported after neonatal exposure to other POPs, such as bisphenol A, PBDEs and PCBs.

Modulation of ventral tegmental area dopamine receptors inhibit nicotine-induced anxiogenic-like behavior in the central amygdala

Nicotine, the major addictive substance in tobacco, increases the activity of the central amygdala (CeA). Amygdala is directly implicated in anxiety modulation and sends projections to the vicinity of the midbrain dopamine neurons, including the ventral tegmental area (VTA) which is a key area that controls nicotine dependence processes. In this study, the role of dopamine D(1) and D(2)/(3) receptors of the VTA on anxiogenic-like behavior induced with intra-CeA injection of nicotine has been investigated. Male Wistar rats with cannula aimed to the left CeA and the left VTA were submitted to the elevated plus-maze (EPM). The nicotine injection (1 μg/rat) into the CeA decreased the percentage of open arm time and open arm entries, but not locomotor activity, indicating an anxiogenic-like response. Intra-VTA injection of a dopamine D1 receptor antagonist, SCH23390 (0.25 μg/rat), and a dopamine D2/3 receptor antagonist, sulpiride (0.7 μg/rat), inhibited the anxiogenic-like response caused by intra-CeA injection of nicotine. These results suggest that the relationship between the VTA and the CeA may be involved in nicotine-induced anxiogenic-like behavior via dopamine D(1) and D(2)/(3) receptors. An understanding of these cellular processes will be crucial for the development of new intervention to combat nicotine effect.

Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: Effects of the cannabinoid receptor 1 antagonist AM251

A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.