Anthocyanins in Lycium ruthenicum Murray reduce nicotine withdrawal-induced anxiety and craving in mice.

Lycium ruthenicum Murray is widely used in traditional Chinese medicine and is believed to have antimicrobial, antioxidant, and anti-fatigue effects. Anthocyanins are considered to be one of the main active components. The previous work by our research team found that the anthocyanins in Lycium ruthenicum extract (ALRM) produce a stable anti-anxiety effect. The mechanisms of action include reducing the level of corticotropin-releasing factor (CRF) as well as regulating extracellular signal-regulated kinase/mitogen activation, protein kinase (ERK/MAPK) pathways, and others, all of which are related to the mechanisms of nicotine addiction. To investigate the effects of ALRM on anxiety and craving behavior after nicotine withdrawal, the components of ALRM were analyzed using the UPLC-Orbitrap MS method. The effects of ALRM on anxiety behavior induced by nicotine withdrawal were investigated in mice using the elevated plus maze (EPM) and light-dark box (LDB) tests. The effects of ALRM on craving behavior after nicotine withdrawal were further investigated using the conditional place preference (CPP) test. The EPM and LDB tests demonstrated that ALRM could alleviate the anxiety behavior induced by nicotine withdrawal and reduce nicotine craving in mice. Based on the identified ALRM components, the network pharmacology method was used to predict the mechanism of ALRM alleviating anxiety after nicotine withdrawal in mice. It was speculated that ALRM was involved in the production and transmission of dopamine, choline, and other nervous system functions and exhibited a potential role in treating nicotine addiction.

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

Independent and Combined Effects of Nicotine or Chronic Tobacco Smoking and HIV on the Brain: A Review of Preclinical and Clinical Studies.

Tobacco smoking is highly prevalent among HIV-infected individuals. Chronic smokers with HIV showed greater cognitive deficits and impulsivity, and had more psychopathological symptoms and greater neuroinflammation than HIV non-smokers or smokers without HIV infection. However, preclinical studies that evaluated the combined effects of HIV-infection and tobacco smoking are scare. The preclinical models typically used cell cultures or animal models that involved specific HIV viral proteins or the administration of nicotine to rodents. These preclinical models consistently demonstrated that nicotine had neuroprotective and anti-inflammatory effects, leading to cognitive enhancement. Although the major addictive ingredient in tobacco smoking is nicotine, chronic smoking does not lead to improved cognitive function in humans. Therefore, preclinical studies designed to unravel the interactive effects of chronic tobacco smoking and HIV infection are needed. In this review, we summarized the preclinical studies that demonstrated the neuroprotective effects of nicotine, the neurotoxic effects of the HIV viral proteins, and the scant literature on nicotine or tobacco smoke in HIV transgenic rat models. We also reviewed the clinical studies that evaluated the neurotoxic effects of tobacco smoking, HIV infection and their combined effects on the brain, including studies that evaluated the cognitive and behavioral assessments, as well as neuroimaging measures. Lastly, we compared the different approaches between preclinical and clinical studies, identified some gaps and proposed some future directions. Graphical abstract Independent and combined effects of HIV and tobacco/nicotine. Left top and bottom panels: Both clinical studies of HIV infected persons and preclinical studies using viral proteins in vitro or in vivo in animal models showed that HIV infection could lead to neurotoxicity and neuroinflammation. Right top and bottom panels: While clinical studies of tobacco smoking consistently showed deleterious effects of smoking, clinical and preclinical studies that used nicotine show mild cognitive enhancement, neuroprotective and possibly anti-inflammatory effects. In the developing brain, however, nicotine is neurotoxic. Middle overlapping panels: Clinical studies of persons with HIV who were smokers typically showed additive deleterious effects of HIV and tobacco smoking. However, in the preclinical studies, when nicotine was administered to the HIV-1 Tg rats, the neurotoxic effects of HIV were attenuated, but tobacco smoke worsened the inflammatory cascade.

Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis.

A combined experimental and computational model approach was developed to assess heat effects on drug delivery from transdermal delivery systems (TDSs) in vitro and nicotine was the model drug. A Franz diffusion cell system was modified to allow close control of skin temperature when heat was applied from an infrared lamp in vitro. The effects of different heat application regimens on nicotine fluxes from two commercial TDSs across human cadaver skin were determined. Results were interpreted in terms of transport parameters estimated using a computational heat and mass transport model. Steady-state skin surface temperature was obtained rapidly after heat application. Increasing skin surface temperature from 32 to 42°C resulted in an approximately 2-fold increase in average nicotine flux for both TDSs, with maximum flux observed during early heat application. ANOVA statistical analyses of the in vitro permeation data identified TDS differences, further evidenced by the need for a two-layer model to describe one of the TDSs. Activation energies associated with these data suggest similar temperature effects on nicotine transport across the skin despite TDS design differences. Model simulations based on data obtained from continuous heat application were able to predict system response to intermittent heat application, as shown by the agreement between the simulation results and experimental data of nicotine fluxes under four different heat application regimens. The combination of in vitro permeation testing and a computational model provided a parameter-based heat and mass transport approach to evaluate heat effects on nicotine TDS delivery.

Inhibition of monoacylglycerol lipase reduces nicotine reward in the conditioned place preference test in male mice.

Nicotine, the primary psychoactive component in tobacco, plays a major role in the initiation and maintenance of tobacco dependence and addiction, a leading cause of preventable death worldwide. An essential need thus exists for more effective pharmacotherapies for nicotine-use cessation. Previous reports suggest that pharmacological and genetic blockade of CB1 receptors attenuate nicotine reinforcement and reward; while exogenous agonists enhanced these abuse-related behaviors. In this study, we utilized complementary genetic and pharmacologic approaches to test the hypothesis that increasing the levels of the endocannabinoid 2-arachindonoylglycerol (2-AG), will enhance nicotine reward by stimulating neuronal CB1 receptors. Contrary to our hypothesis, we found that inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme of 2-AG, attenuates nicotine conditioned place preference (CPP) in mice, through a non-CB1 receptor-mediated mechanism. MAGL inhibition did not alter palatable food reward or Lithium Chloride (LiCl) aversion. In support of our findings, repeated MAGL inhibition did not induce a reduction in CB1 brain receptor levels or hinder function. To explore the potential mechanism of action, we investigated if MAGL inhibition affected other fatty acid levels in our CPP paradigm. Indeed, MAGL inhibition caused a concomitant decrease in arachidonic acid (AA) levels in various brain regions of interest, suggesting an AA cascade-dependent mechanism. This idea is supported by dose-dependent attenuation of nicotine preference by the selective COX-2 inhibitors valdecoxib and LM-4131. Collectively, these findings, along with our reported studies on nicotine withdrawal, suggest that inhibition of MAGL represents a promising new target for the development of pharmacotherapies to treat nicotine dependence.

Recent findings in the pharmacology of inhaled nicotine: Preclinical and clinical in vivo studies.

INTRODUCTION: The rise of vaping in adolescents, the recent entrance of new inhaled nicotine products such as iQOS on the market and e-cigarette or vaping product use-associated lung injury cases has created concern for the use of inhaled non-combustible nicotine products. This narrative review discusses recent experimental in vivo studies that utilize human, rat and mouse models to understand the pharmacological impact of nicotine from non-combustible products. METHODS: The search engine PubMed was utilized with the following search terms: inhaled nicotine, nicotine e-cigarette, heated tobacco products, iQOS, electronic cigarette, nicotine inhaler, nicotine vaping. This review highlights recent primary in vivo studies of inhaled nicotine administration experimental paradigms that occurred in laboratory settings using human and rodent (rats and mice) models that have been published from January 2017-December 2019. RESULTS: The pharmacokinetics of nicotine via e-cigarettes is influenced by the PG/VG and flavor constituents in e-liquids, the presence of nicotine salts in e-liquids, puff topography of nicotine and tobacco product users and the power of the e-cigarette device. The pharmacodynamic impact of inhaled nicotine has cardiovascular, pulmonary and central nervous system implications. CONCLUSION: The articles reviewed here highlight the importance of both animal and human models to fully understand the impact of inhaled nicotine pharmacology There is a need for more rodent pharmacokinetic inhaled nicotine studies to understand the influences of factors such as flavor and nicotine salts. Additionally, consensus on nicotine measurement in both human and rodent studies is greatly needed.

Comparison of Protective Effects of Electroacupuncture at ST 36 and LU 5 on Pulmonary and Hypothalamic Pituitary Adrenal Axis Changes in Perinatal Nicotine-Exposed Rats.

BACKGROUND: Maternal smoking and/or exposure to environmental tobacco smoke continue to be significant factors in fetal and childhood morbidity and are a serious public health issue worldwide. Nicotine passes through the placenta easily with minimal biotransformation, entering fetal circulation, where it results in many harmful effects on the developing offspring, especially on the developing respiratory system. OBJECTIVES: Recently, in a rat model, electroacupuncture (EA) at maternal acupoints ST 36 has been shown to block perinatal nicotine-induced pulmonary damage; however, the underlying mechanism and the specificity of ST 36 acupoints for this effect are unknown. Here, we tested the hypothesis that compared with EA at ST 36, EA at LU 5 acupoints, which are on lung-specific meridian, will be equally or more effective in preventing perinatal nicotine-induced pulmonary changes. METHODS: Twenty-four pregnant rat dams were randomly divided into 4 groups: saline ("S"), nicotine ("N"), nicotine + ST 36 (N + ST 36), and nicotine + LU 5 (N + LU 5) groups. Nicotine (1 mg/kg, subcutaneously) and EA (at ST 36 or LU 5 acupoints, bilaterally) were administered from embryonic day 6 to postnatal day 21 once daily. The "S" group was injected saline. As needed, using ELISA, western analysis, q-RT-PCR, lung histopathology, maternal and offspring hypothalamic pituitary adrenal axes, offspring key lung developmental markers, and lung morphometry were determined. RESULTS: With nicotine exposure, alveolar count decreased, but mean linear intercept and septal thickness increased. It also led to a decrease in pulmonary function and PPARγ and an increase of ß-catenin and glucocorticoid receptor expression in lung tissue and corticosterone in the serum of offspring rats. Electroacupuncture at ST 36 normalized all of these changes, whereas EA at LU 5 had no obvious effect. CONCLUSION: Electroacupuncture applied to ST 36 acupoints provided effective protection against perinatal nicotine-induced lung changes, whereas EA applied at LU 5 acupoints was ineffective, suggesting mechanistic specificity and HPA axis' involvement in mediating EA at ST 36 acupoints' effects in mitigating perinatal nicotine-induced pulmonary phenotype. This opens the possibility that other acupoints, besides ST 36, can have similar or even more robust beneficial effects on the developing lung against the harmful effect of perinatal nicotine exposure. The approach proposed by us is simple, cheap, quick, easy to administer, and is devoid of any significant side effects.

Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis.

Background: Characterizing the determinants of the abuse liability of electronic cigarettes (ECs) in adolescents is needed to inform product regulation by the United States Food and Drug Administration (FDA). We recently reported that Vuse Menthol EC aerosol extract containing nicotine and a range of non-nicotine constituents (e.g., menthol, propylene glycol) had reduced aversive effects compared to nicotine alone in adolescent rats, whereas Aroma E-Juice EC aerosol extract did not. The current study used a behavioral economic approach to compare the relative abuse liability of these EC extracts and nicotine alone in an i.v. self-administration (SA) model in adolescents. Methods: Adolescents were tested for the SA of EC extracts prepared using an ethanol (ETOH) solvent or nicotine and saline, with and without 4% ETOH (i.e., the same concentration in the EC extracts) in 23 h/day sessions. Results. Although acquisition of SA was faster for nicotine + ETOH compared to all other formulations, the elasticity of demand for all nicotine-containing formulations was similar. Conclusions: EC aerosol extracts did not have greater abuse liability than nicotine alone in adolescents. These data suggest that nicotine may be the primary determinant of the abuse liability of these ECs in youth, at least in terms of the primary reinforcing effects of ECs mediated within the central nervous system.

Nicotinic Acetylcholine Receptor Signaling in the Hypothalamus: Mechanisms Related to Nicotine's Effects on Food Intake.

Despite health risks associated with smoking, up to 20% of the US population persist in this behavior; many smoke to control body weight or appetite, and fear of post-cessation weight gain can motivate continued smoking. Nicotine and tobacco use is associated with lower body weight, and cessation yields an average weight gain of about 4 kg, which is thought to reflect a return to the body weight of a typical nonsmoker. Nicotine replacement therapies can delay this weight gain but do not prevent it altogether, and the underlying mechanism for how nicotine is able to reduce weight is not fully understood. In rodent models, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Nicotine, acting through nicotinic acetylcholine receptors (nAChRs), increases the firing rate of both orexigenic agouti-related peptide and anorexigenic proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Manipulation of nAChR subunit expression within the ARC can block the ability of nicotine and the nicotinic agonist cytisine from decreasing food intake; however, it is unknown exactly how this reduces food intake. This review summarizes the clinical and preclinical work on nicotine, food intake, and weight gain, then explores the feeding circuitry of the ARC and how it is regulated by nicotine. Finally, we propose a novel hypothesis for how nicotine acts on this hypothalamic circuit to reduce food intake. Implications: This review provides a comprehensive and updated summary of the clinical and preclinical work examining nicotine and food intake, as well as a summary of recent work examining feeding circuits of the hypothalamus. Synthesis of these two topics has led to new understanding of how nAChR signaling regulates food intake circuits in the hypothalamus.

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

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

Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal.

Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

Nicotine enhances auditory processing in healthy and normal-hearing young adult nonsmokers.

RATIONALE: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual's baseline performance. METHODS: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

A Multicenter, Randomized, Double-blind, Parallel, Placebo-controlled Clinical Study to Evaluate the Efficacy and Safety of a Nicotine Mint Lozenge (2 and 4 mg) in Smoking Cessation.

OBJECTIVE: To evaluate the efficacy in smoking cessation and safety of 2 and 4 mg nicotine mint lozenges in Chinese adult smokers. METHODS: This was a multicenter, randomized, stratified, double-blind, placebo-controlled, parallel-group study. The low-dependence stratum included 483 smokers (241 randomized to active 2 mg nicotine lozenge and 242 to placebo lozenge). The high-dependence stratum included 240 smokers (120 randomized to active 4 mg nicotine lozenge and 120 to placebo lozenge). The primary endpoint was successful smoking cessation at 6 weeks postquit, defined as continuous abstinence from smoking for the 28-day period up to and including the 6-week visit (verified by CO measurement). Cochran-Mantel-Haenszel tests were performed to compare quit rates between active nicotine and placebo separately for the high-dependence and low-dependence strata. RESULTS: The primary analysis showed that in the low-dependence (2 mg) stratum, 59 subjects (24.5%) of 241 in the active nicotine group and 52 subjects (21.5%) of 242 in the placebo group were successful quitters (P = .3851). In the high-dependence (4 mg) stratum, 37 subjects (30.8%) of 120 in the active nicotine group and 24 subjects (20.2%) of 119 in the placebo group were successful quitters (P = .0565). CONCLUSIONS: The 4 mg nicotine lozenge provided a directionally significant improvement in smoking cessation rates compared with placebo in Chinese adult smokers with high nicotine dependence for the primary endpoint. The 2 mg nicotine lozenge provided higher, but nonsignificant, smoking cessation rates than placebo. Both nicotine lozenges were generally well tolerated in Chinese adult smokers.

Clinical presentation, treatment, and short-term outcomes of lung injury associated with e-cigarettes or vaping: a prospective observational cohort study.

BACKGROUND: An ongoing outbreak of lung injury associated with e-cigarettes or vaping (also known as E-VALI or VALI) started in March, 2019, in the USA. The cause, diagnosis, treatment, and course of this disease remains unknown. METHODS: In this multicentre, prospective, observational, cohort study, we collected data on all patients with lung injury associated with e-cigarettes or vaping seen in Intermountain Healthcare, an integrated health system based in Utah, USA, between June 27 and Oct 4, 2019. Telecritical care, based in Salt Lake City, UT, USA, was used as the central repository for case validation, public reporting, and system-wide dissemination of expertise, which included a proposed diagnosis and treatment guideline for lung injury associated with e-cigarettes or vaping. We extracted data on patient presentation, treatment, and short-term follow-up (2 weeks after discharge) from chart review and interviews with patients undertaken by the Utah Department of Health (Salt Lake City, UT, USA). FINDINGS: 60 patients presented with lung injury associated with e-cigarettes or vaping at 13 hospitals or outpatient clinics in the integrated health system. 33 (55%) of 60 were admitted to an intensive care unit (ICU). 53 (88%) of 60 patients presented with constitutional symptoms, 59 (98%) with respiratory symptoms, and 54 (90%) with gastrointestinal symptoms. 54 (90%) of 60 were given antibiotics and 57 (95%) were given steroids. Six (10%) of 60 patients were readmitted to an ICU or hospital within 2 weeks, three (50%) of whom had relapsed with vaping or e-cigarette use. Of 26 patients who were followed up within 2 weeks, despite clinical and radiographic improvement in all, many had residual abnormalities on chest radiographs (ten [67%] of 15) and pulmonary function tests (six [67%] of nine). Two patients died and lung injury associated with e-cigarettes or vaping was thought to be a contributing factor, but not the cause of death, for both. INTERPRETATION: Lung injury associated with e-cigarettes or vaping is an emerging illness associated with severe lung injury and constitutional and gastrointestinal symptoms. Increased awareness has led to identification of a broad spectrum of severity of illness in patients who were treated with antibiotics and steroids. Despite improvement, at short-term follow-up many patients had residual abnormalities. Lung injury associated with e-cigarettes or vaping remains a clinical diagnosis with symptoms that overlap infectious and other lung diseases. Maintaining a high index of suspicion for this disease is important as work continues in understanding the cause or causes, optimal therapy, and long-term outcomes of these patients. FUNDING: Intermountain Healthcare.

Central nicotine induces browning through hypothalamic κ opioid receptor.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.

Ameliorative Effects of Hydromethanolic Extract of Citrullus lanatus (Watermelon) Rind on Semen Parameters, Reproductive Hormones and Testicular Oxidative Status Following Nicotine Administration in Male Wistar Rats.

The present study examines the possible ameliorative effects of the hydromethanolic extract of Citrullus lanatus rind (HECL) on some reproductive function and oxidative indices of the testes in male Wistar rats following administration of nicotine. Twenty male rats were assigned into four groups: Group A to D of five rats each. Group A served as control and received 2ml/kg body weight of 10% extract vehicle; Group B received 1mg/kg body weight of nicotine; Group C were co-administered 1mg/kg body weight nicotine and 500 mg/kg body weight of HECL and Group D received only 500mg/kg body weight of HECL. The drugs and extracts were administered orally to the rats for 42days; blood samples were collected by direct cardiac puncture for determination of serum concentrations of testosterone, Follicle Stimulating Hormone and Luteinizing Hormone. The testes were also harvested for determination of semen parameters: motility, morphology, viability and count and testicular tissue processed for superoxide dismutase and malondialdehyde concentration. Compared to Group A control rats, administration of HECL significantly increased sperm count and reproductive hormone concentrations amongst Group B rats (p<0.05). Treatment with nicotine caused a significant reduction in the levels of all reproductive hormones with significant diminution of some sperm parameters: motility, morphology and viability; and decrease in superoxide dismutase and increase in malondialdehyde concentration amongst Group B rats compared to Group A control rats (p<0.05). Co-administration of HECL with nicotine to Group C rats apparently reversed the effects of nicotine resulting in significant increases in sperm count and the reproductive hormones concentration as compared to Group A control rats (p<0.05). Amongst Group D rats, the extract also caused a significant increase in superoxide dismutase concentration and a significant decrease in malondialdehyde concentration compared with the Group A control rats (p<0.05). The findings suggest that the hydromethanolic extract of Citrullus lanatus rind possibly ameliorates the deleterious effects of nicotine on some reproductive indices in male Wistar rats.

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

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

Vapor inhalation of cannabidiol (CBD) in rats.

RATIONALE: Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE: To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS: Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS: Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.

Acupuncture reduces nicotine-induced norepinephrine release in the hypothalamus via the solitary NMDA receptor/NOS pathway.

Noradrenergic projections from the nucleus tractus solitarius (NTS) to the hypothalamic paraventricular nucleus (PVN) are involved in nicotine (Nic) dependence. Nic induces hypothalamic norepinephrine (NE) release through N-methyl-d-aspartate receptors (NMDARs) and nitric oxide in the NTS. However, acupuncture attenuates Nic withdrawal-induced anxiety. Therefore, this study investigated the effects of acupuncture on Nic-induced hypothalamic NE release. Rats received an intravenous infusion of Nic (90 µg/kg, over 60 s) and extracellular NE levels in the PVN were determined by in vivo microdialysis. Immediately after Nic administration, the rats were bilaterally treated with acupuncture at acupoint HT7 (Shen-Men) or PC6 (Nei-Guan), or a non-acupoint (tail) for 60 s. Acupuncture at HT7, but not at PC6 or the tail, significantly reduced Nic-induced NE release. However, this was abolished by a post-acupuncture infusion of either NMDA or sodium nitroprusside into the NTS. Additionally, acupuncture at HT7, but not the control points, prevented Nic-induced plasma corticosterone secretion and inhibited Nic-induced increases in the phosphorylation of neuronal nitric oxide synthase (nNOS) and endothelial NOS in the NTS. These findings suggest that acupuncture at HT7 reduces Nic-induced NE release in the PVN via inhibition of the solitary NMDAR/NOS pathway.

Randomized within-subject trial to evaluate smokers' initial perceptions, subjective effects and nicotine delivery across six vaporized nicotine products.

BACKGROUND AND AIMS: Vaporized nicotine products (VNPs) can vary in important characteristics including size, shape, flavor and nicotine yield. We examined whether complex interactions among these characteristics could affect smokers' VNP perceptions and usage patterns. DESIGN: A within-subject randomized cross-over trial. SETTING: Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. PARTICIPANTS: Eighteen daily cigarette smokers. MEASUREMENTS: Participants attended eight weekly visits during which they sampled six different VNPs (disposable, rechargeable, eGO, mod, e-Cigar and e-Pipe) with tobacco-flavored e-liquid. Prior to device use, participants completed product-ranking questionnaires. Participants completed controlled puffing sessions during each of the six trials, after which satisfaction questionnaires were completed and blood samples were taken. FINDINGS: Initial perceptions showed that the smallest device (disposable) was ranked as safer compared with a larger device (e-Pipe) (P < 0.05). Participants rated the eGO and mod devices higher on satisfaction and enjoyment from use, taste, pleasantness, harshness ('throat hit') and speed of effect, but lower on perceived health risk and embarrassment from use (P < 0.05). All devices had a lower Cmax than the combustible cigarette (P < 0.05), but there were differences among devices (P < 0.05). The mod, e-Pipe and eGO provided the highest amount of perceived smoking urge relief, and this correlated strongly with Cmax across all devices (R2  = 0.8614, P = 0.007). The perceived speed of urge relief was not correlated with Tmax (R2  = 0.0035, P = 0.911) CONCLUSIONS: Daily cigarette smokers testing six types of vaporized nicotine products (VNPs) reported that they varied in taste, amount of withdrawal relief, harshness, embarrassment from use, perceived health risk and subjective and objective nicotine delivery. The eGO and mod models have properties that may make them most effective for cigarette substitution among smokers who intend to switch to a VNP.