Nicotine Enhancement Research Articles

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

Behavioral and neuronal extracellular vesicle biomarkers associated with nicotine's enhancement of the reinforcing strength of cocaine in female and male monkeys

While the majority of people with cocaine use disorders (CUD) also co-use tobacco/nicotine, most preclinical cocaine research does not include nicotine. The present study examined nicotine and cocaine co-use under several conditions of intravenous drug self-administration in monkeys, as well as potential peripheral biomarkers associated with co-use. In Experiment 1, male rhesus monkeys (N = 3) self-administered cocaine (0.001–0.1 mg/kg/injection) alone and with nicotine (0.01–0.03 mg/kg/injection) under a progressive-ratio schedule of reinforcement. When nicotine was added to cocaine, there was a significant leftward/upward shift in the number of injections received. In Experiment 2, socially housed female and male cynomolgus monkeys (N = 14) self-administered cocaine under a concurrent drug-vs-food choice schedule of reinforcement. Adding nicotine to the cocaine solution shifted the cocaine dose-response curves to the left, with more robust shifts noted in the female animals. There was no evidence of social rank differences. To assess reinforcing strength, delays were added to the presentation of drug; the co-use of nicotine and cocaine required significantly longer delays to decrease drug choice, compared with cocaine alone. Blood samples obtained post-session were used to analyze concentrations of neuronally derived small extracellular vesicles (NDE); significant differences in NDE profile were observed for kappa-opioid receptors when nicotine and cocaine were co-used compared with each drug alone and controls. These results suggest that drug interactions involving the co-use of nicotine and cocaine are not simply changing potency, but rather resulting in changes in reinforcing strength that should be utilized to better understand the neuropharmacology of CUD and the evaluation of potential treatments.

Long-Term Impact of Daily E-cigarette Exposure on the Lungs of Asthmatic Mice.

Although the greater popularity of electronic cigarettes (EC) among asthmatics is alarming, there is limited knowledge of the long-term consequences of EC exposure in asthmatics. Mild asthmatic C57/BL6J adult male and female mice were established by intranasal insufflation with three combined allergens. The asthmatic and age and sex-matched' naïve mice were exposed to air, nicotine-free (propylene glycol [PG]/vegetable glycerin [VG]-only), or PG/VG+Nicotine, 4 hours daily for 3 months. The effects of EC exposure were accessed by measuring cytokines in bronchoalveolar lavage, periodic acid-schiff (PAS) staining, mitochondrial DNA copy numbers (mtCN), and the transcriptome in the lung. Significance was false discovery rate <0.2 for transcriptome and 0.05 for the others. In asthmatic mice, PG/VG+Nicotine increased PAS-positive cells and IL-13 compared to mice exposed to air and PG/VG-only. In naïve mice exposed to PG/VG+Nicotine and PG/VG-only, higher INF-γ was observed compared to mice exposed only to air. PG/VG-only and PG/VG+Nicotine had significantly higher mtCN compared to air exposure in asthmatic mice, while the opposite pattern was observed in non-asthmatic naïve mice. Different gene expression patterns were profoundly found for asthmatic mice exposed to PG/VG+Nicotine compared to PG/VG-only, including genes involved in mitochondrial dysfunction, oxidative phosphorylation, and p21-activated kinase (PAK) signaling. This study provides experimental evidence of the potential impact of nicotine enhancement on the long-term effects of EC in asthmatics compared to non-asthmatics. The findings from this study indicate the potential impact of EC in asthmatics by addressing multiple biological markers. The long-term health outcomes of EC in the susceptible group can be instrumental in supporting policymaking and educational campaigns and informing the public, healthcare providers, and EC users about the underlying risks of EC use.

Reinforcement enhancement by nicotine: A novel abuse-liability assessment of e-cigarettes in young adults.

Nicotine can act as a primary positive reinforcer, and as negative reinforcer to relieve withdrawal; we tested whether it can also enhance the reinforcing efficacy of non-drug reinforcers. Young-adult never-users were delivered nicotine via e-cigarette, and a videogame reinforcer was used to test nicotine enhancement. Three dose groups were tested (placebo-only, 6 or 12-mg nicotine), and participants returned to the lab for several sessions over the course of 1 month. Those in the two nicotine-dose groups received placebo on some occasions and nicotine on others; nicotine enhancement of the videogame reinforcer was assessed in a within-subjects fashion by comparing each of the two nicotine groups' dedicated nicotine dose to placebo. In the placebo-only group, progressive-ratio (PR) schedule breakpoints did not alter as a function of videogame exposure, suggesting that the videogame retained its basic-reinforcing properties throughout the study. For the two groups that received nicotine, both doses of nicotine increased PR-schedule breakpoints for the videogame reinforcer relative to the placebo condition. Although nicotine was associated with greater subjective evaluation of the enjoyment of the videogame, it was unrelated to the enjoyment of the e-cigarette device. No evidence was found that nicotine elevated either anhedonia or withdrawal symptoms in the timeframe of the study. The results provide initial evidence that nicotine enhancement, via electronic cigarettes, occurs in non-frequent users of nicotine products and may be a reason they can develop nicotine dependence in the absence of withdrawal and direct effects of nicotine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sex Differences in Nicotine Enhancement of Conditioned Place Avoidance Driven by Footshock in Male and Female Rats.

Tobacco use is driven by nicotine, which can enhance the ability of non-nicotine stimuli, including aversive stimuli, to alter behavior. Sex differences exist in the reinforcement enhancement properties of nicotine, but the degree to which this extends to nicotine's ability to enhance behavior driven by aversive stimuli is unclear. The current study used adult male and female Sprague-Dawley rats to explore sex differences in nicotine enhancement of footshock (FS)-conditioned place avoidance. FS-conditioned and control rats were tested for conditioned avoidance of FS- or control-paired chambers after injections of saline or nicotine (0.3 mg/kg, subcutaneously). FS supported place avoidance in both male and female rats, and nicotine enhanced avoidance. Females showed more avoidance after nicotine than males, even in nonconditioned control rats. These results support the idea that sex differences do exist in nicotine enhancement of aversive stimuli, and suggest the mechanisms through which nicotine supports tobacco dependence in males and females may differ. Nicotine enhancement of nondrug stimuli is thought to play a role in tobacco dependence. Yet previous research of enhancement has overwhelmingly used male subjects and appetitive stimuli. Our findings confirm that nicotine also enhances behavior driven by aversive stimuli, and suggests that females may be more susceptible to nicotine enhancement. Such sex differences suggest sex may be an important factor to consider in treating dependence.

Cortical nicotinic enhancement of tone-evoked heightened activities and subcortical nicotinic enlargement of activated areas in mouse auditory cortex

Systemic nicotine administration regulates neuronal activities in mouse auditory cortex. How nicotine regulates the spread of the activities across auditory cortical areas is not well known. We investigate this using flavoprotein fluorescence imaging. 20 kHz amplitude-modulated (AM) tones increased the peak intensity of flavoprotein fluorescence in presumptive primary auditory cortex (A1). 5 kHz AM tones activated at least three cortical areas, which are presumably A1, anterior auditory field, and secondary auditory cortex. Nicotine enlarged tone-activated cortical areas and enhanced both 20 kHz and 5 kHz tone-evoked fluorescence intensities at their respective, optimal frequency peak sites and at non-optimal frequency peak sites in A1. The extent of this enhancement was greater at non-optimal frequency sites than at optimal frequency sites. A cortical injection of dihydro-β-erythroidine, an inhibitor of nicotinic acetylcholine receptors composed of α4 and β2-subunits (α4β2*-nAChRs), blocked the enhancement of fluorescence intensity at the peak sites but did not appear to block the enlargement of activated areas. These results suggest that nicotine exposure activates cortical α4β2*-nAChRs to enhance tone-evoked local neuronal activities at an optimal frequency site. The nicotine-induced enlargement of a tone-activated area may depend on the nicotinic enhancement of cortical inputs or other activities.

Do perceptions and experiences of vaping among youth and young adults differ by device type?

Youth and young adult (YYA) vaping is an escalating public health concern. Due to their sleek designs, desirable flavors, and high nicotine concentrations, pod-based devices currently hold the largest e-cigarette market share. The major contribution of pod-based devices to the vaping epidemic substantiates studying differences in perceptions and experiences between YYAs for pod and non-pod devices. Such evidence is imperative in hopes of developing device-specific interventions to decelerate e-cigarette use, which to date is limited. To address aforementioned gaps, nicotine-based e-cigarette users residing in Canada [N = 403, 53.6% male, mean age = 18.3 years (SD = 1.9), pod users = 62.5%] were surveyed using open-ended questions. Responses to each question were coded by topic. Using these codes, differences between YYA (youth versus young adults) use of each device type (pods and non-pod devices) were quantitatively examined for each topic and underlying categories. Youth non-pod users frequently reported nicotine rush and enhancement more frequently and positive social aspects less frequently than young adult non-pod users. Youth pod users reported more exposure to buying and selling vaping content on social media than young adult pod users. The novel findings of this study highlight the need for considering differences among YYA users of each device-type in developing policies and interventions. Policies in the form of reducing nicotine concentration and alternative coping strategy interventions will likely work for youth non-pod users, yet de-normalizing vaping through social marketing distinctively benefits young adult counterparts. Additionally, regulating social media in both user- and industry-generated forms is key for youth pod users.

Receptor Mechanisms in Nicotinic Enhancement of Opioid Antinociception

The use of prescription opioids for pain management can be limited by their adverse behavioral effects, which usually are not measured in the initial preclinical assessment of established or novel candidate analgesics. Recently, we have developed a protocol for concurrently assessing the antinociceptive effects of drugs (an indicator of analgesic promise) and their ability to decrease rates of operant behavior (an indicator of unwanted behavioral effects). Under these procedures, nicotine has been shown to augment the antinociceptive, but not the rate‐decreasing, effects of opioid analgesics with an inverse relationship to efficacy at the m‐opioid receptor‐ e.g., nicotine‐induced enhancement of nalbuphine&gt;oxycodone&gt;fentanyl. The present study was designed to further elucidate nicotinic‐opioid interactions by exploring the role of nicotinic receptor efficacy in the nicotinic augmentation of opioid antinociception. Male squirrel monkeys (n=4) lever‐pressed under a fixed ratio (FR) 10 schedule of 20% (v/v) condensed milk reinforcement. A 30‐s timeout (TO) period followed either the completion of the FR 10 or the elapse of 20‐s (limited hold (LH) 20). During the 30‐s TO, the distal portion of the monkey’s tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose response functions for tail‐withdrawal latency and decreases in response rate were generated for the high efficacy m‐opioid agonist fentanyl and the low efficacy m‐agonist nalbuphine alone and in the presence of nicotinic agonists reported to have high or intermediate efficacy‐‐epibatidine (0.00056 mg/kg) or varenicline (0.032 mg/kg), respectively. Fentanyl dose‐dependently increased tail‐withdrawal latencies at all water temperatures and, concomitantly, decreased rates of responding. Nalbuphine did not significantly decrease response rate, and increased tail‐withdrawal latencies at 50 and 52°C, but not at 55°C. Neither epibatidine nor varenicline significantly modified the rate decreasing effects of any of the opioids or the antinociceptive effects of fentanyl. However, the antinociceptive potency of nalbuphine was markedly enhanced by epibatidine (up to ~70‐fold) and only slightly increased by varenicline. The present results add to previous findings with nicotine, showing that nicotinic enhancement of opioid antinociception is inversely related to m‐opioid efficacy. They also extend those findings to suggest that such adjuvant effects are more robustly produced by nicotinic full agonists (nicotine, epibatidine) than a partial agonist (varenicline). In conjunction with previous reports, these findings support the idea that nicotinic agonists may be clinically useful as adjuvants for opioid analgesia.Support or Funding InformationDA035857 and Harvard Medical School Livingston Fellowship

A review of the effects of nicotine on social functioning.

Many smokers are aware that smoking is a dangerous health behavior and eventually try to quit smoking. Unfortunately, most quit attempts end in failure. Traditionally, the addictive nature of smoking has been attributed to the pharmacologic effects of nicotine. In an effort to offer a more comprehensive, biobehavioral analysis of smoking behavior and motivation, some researchers have begun to consider the role of social factors in smoking. In line with recent recommendations to integrate social and pharmacological analyses of smoking, we reviewed the experimental literature examining the effects of nicotine and nicotine withdrawal on social functioning. The review identified 13 studies that experimentally manipulated nicotine and assessed social functioning, 12 of which found support for nicotine's enhancement of social functioning. Although few experiments have investigated social functioning, they nevertheless offer compelling evidence that nicotine enhances social functioning in smokers and suggest that nicotine deprivation may hamper social functioning in those dependent on nicotine. Future directions for investigating social outcomes and context in those who use nicotine products are discussed with a focus on leveraging advances in social and developmental psychology, animal research, sociology, and neuroimaging to more comprehensively understand smoking behavior. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Abstract 495: Nicotine Promotes Endothelial Dysfunction and Vascular Inflammation in Diet-induced Obese Rats: Role of Macrophage TNFa

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity . The rats were fed either a high fat (HFD) or normal rat chow (NFD) diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP 146 ± 3 vs. 130 ± 5 mmHg in NFD , p&lt;0.05), aortic superoxide (O 2 - 1357 ± 142 vs. 847 ± 102 counts/min/mg in NFD, p&lt;0.05) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR, Emax: 85 ± 5 vs. 99 ± 1% in NFD, p&lt;0.05). Nicotine further increased SBP (159 ± 5 mmHg, p&lt;0.05), O 2 - (1689 ± 87 counts/min/mg, p&lt;0.05) and impaired eNOS and EDR (Emax: 72 ± 4%, p&lt;0.05) in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2-4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet–induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.

Effects of nicotine self-administration on incentive salience in male Sprague Dawley rats.

Prolonged use of nicotine appears to enhance incentive salience, a motivational-cognitive process that transforms an otherwise neutral stimulus into a "wanted" stimulus. It has been suggested that nicotinic enhancement of incentive salience contributes to the potential of relapse in individuals with tobacco addiction. However, there are two main limitations of prior research that caution this claim: (a) the use of passive experimentally delivered nicotine and (b) the use of sign-tracking as an index of incentive salience, without acknowledging the competing nature of goal- and sign-tracking responses. To determine whether nicotinic enhancement of incentive salience attributed to non-nicotinic stimuli occurs when rats self-administer nicotine,and whether itis facilitated by a prior history of nicotine self-administration. Twenty-three male rats were trained daily, for 24days, on a nicotine self-administration (SA) paradigm in the morning, and on a four-conditioned-stimuli Pavlovian conditioned approach (4-CS PCA) task in the afternoon. Self-administration was followed by extinction and cue reinstatement. A subcutaneous nicotine challenge was performed during the last 7days of the study. Nicotine self-administration selectively enhanced sign-tracking in the 4-CS PCA. Upon extinction, sign-tracking quickly declined to control levels. Experimenter-administered nicotine enhanced sign-tracking similarly regardless of nicotine history. The results suggest that nicotinic enhancement of incentive salience is transient, and a previous history of nicotine use does not cause further sensitization. Taken together, these results suggest that nicotine enhances incentive salience, particularly-and perhaps exclusively-while onboard.

Oral nicotine aggravates endothelial dysfunction and vascular inflammation in diet-induced obese rats: Role of macrophage TNFα.

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet–induced obesity. The rats were fed either a high fat (HFD) or normal rat chow diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP), aortic superoxide (O2-) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR). Nicotine further increased SBP, O2- and impaired eNOS and EDR in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1β and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2–4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet–induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.

Nicotine Increases Activation to Anticipatory Valence Cues in Anterior Insula and Striatum.

Smoking is associated with significant morbidity and mortality. Understanding the neurobiology of the rewarding effects of nicotine promises to aid treatment development for nicotine dependence. Through its actions on mesolimbic dopaminergic systems, nicotine engenders enhanced responses to drug-related cues signaling rewards, a mechanism hypothesized to underlie the development and maintenance of nicotine addiction. We evaluated the effects of acute nicotine on neural responses to anticipatory cues signaling (nondrug) monetary reward or loss among 11 nonsmokers who had no prior history of tobacco smoking. In a double-blind, crossover design, participants completed study procedures while wearing nicotine or placebo patches at least 1 week apart. In each drug condition, participants underwent functional magnetic resonance imaging while performing the monetary incentive delay task and performed a probabilistic monetary reward task, probing reward responsiveness as measured by response bias toward a more frequently rewarded stimulus. Nicotine administration was associated with enhanced activation, compared with placebo, of right fronto-anterior insular cortex and striatal regions in response to cues predicting possible rewards or losses and to dorsal anterior cingulate for rewards. Response bias toward rewarded stimuli correlated positively with insular activation to anticipatory cues. Nicotinic enhancement of monetary reward-related brain activation in the insula and striatum in nonsmokers dissociated acute effects of nicotine from effects on reward processing due to chronic smoking. Reward responsiveness predicted a greater nicotinic effect on insular activation to salient stimuli. Previous research demonstrates that nicotine enhances anticipatory responses to rewards in regions targeted by midbrain dopaminergic systems. The current study provides evidence that nicotine also enhances responses to rewards and losses in the anterior insula. A previous study found enhanced insular activation to rewards and losses in smokers and ex-smokers, a finding that could be due to nicotine sensitization or factors related to current or past smoking. Our finding of enhanced anterior insula response after acute administration of nicotine in nonsmokers provides support for nicotine-induced sensitization of insular response to rewards and losses.

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions.

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.

540. Effects of N-methyl-D-aspartate Glutamate Receptor Disruption and Nicotinic Acetylcholine Enhancement on Mismatch Negativity

540. Effects of N-methyl-D-aspartate Glutamate Receptor Disruption and Nicotinic Acetylcholine Enhancement on Mismatch Negativity

Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area.

Neuronal synchronization at gamma band frequency (20–80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 μM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors

In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine.

Adolescent mice are less sensitive to the effects of acute nicotine on context pre-exposure than adults

Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine's effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36mg/kg) whereas both low (0.09mg/kg) and high (0.36mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they are less sensitive to the enhancing effects of nicotine on contextual processing.

Modulation of AMPA receptor mediated current by nicotinic acetylcholine receptor in layer I neurons of rat prefrontal cortex.

Layer I neurons in the prefrontal cortex (PFC) exhibit extensive synaptic connections with deep layer neurons, implying their important role in the neural circuit. Study demonstrates that activation of nicotinic acetylcholine receptors (nAChRs) increases excitatory neurotransmission in this layer. Here we found that nicotine selectively increased the amplitude of AMPA receptor (AMPAR)-mediated current and AMPA/NMDA ratio, while without effect on NMDA receptor-mediated current. The augmentation of AMPAR current by nicotine was inhibited by a selective α7-nAChR antagonist methyllycaconitine (MLA) and intracellular calcium chelator BAPTA. In addition, nicotinic effect on mEPSC or paired-pulse ratio was also prevented by MLA. Moreover, an enhanced inward rectification of AMPAR current by nicotine suggested a functional role of calcium permeable and GluA1 containing AMPAR. Consistently, nicotine enhancement of AMPAR current was inhibited by a selective calcium-permeable AMPAR inhibitor IEM-1460. Finally, the intracellular inclusion of synthetic peptide designed to block GluA1 subunit of AMPAR at CAMKII, PKC or PKA phosphorylation site, as well as corresponding kinase inhibitor, blocked nicotinic augmentation of AMPA/NMDA ratio. These results have revealed that nicotine increases AMPAR current by modulating the phosphorylation state of GluA1 which is dependent on α7-nAChR and intracellular calcium.

Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine.

Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10–1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine. PPI has been shown to be mediated, at least in part, by mesopontine cholinergic neurons that project to pontine startle neurons and activate muscarinic and potentially nicotine receptors (nAChRs). The subtypes and anatomical location of nAChRs involved in mediating and modulating PPI remain unresolved. We tested the hypothesis that nAChRs that are expressed by pontine startle neurons contribute to PPI. We also explored whether or not these pontine receptors are responsible for the nicotine enhancement of PPI. While systemic administration of nAChR antagonists had limited effects on PPI, PnC microinfusions of the non-α7nAChR preferring antagonist TMPH, but not of the α7nAChR antagonist MLA, into the PnC significantly reduced PPI. Electrophysiological recordings from startle-mediating PnC neurons confirmed that nicotine affects excitability of PnC neurons, which could be antagonized by TMPH, but not by MLA, indicating the expression of non-α7nAChR. In contrast, systemic nicotine enhancement of PPI was only reversed by systemic MLA and not by TMPH or local microinfusions of MLA into the PnC. In summary, our data indicate that non-α7nAChRs in the PnC contribute to PPI at stimulus intervals of 100 ms or less, whereas activation of α7nAChRs in other brain areas is responsible for the systemic nicotine enhancement of PPI. This is important knowledge for the correct interpretation of behavioral, preclinical, and clinical data as well as for developing drugs for the amelioration of PPI deficits and the enhancement of cognitive function.