How cigarette smoking may increase the risk of anxiety symptoms and anxiety disorders : a critical review of biological pathways

Multiple studies have demonstrated an association between cigarette smoking and increased anxiety symptoms or disorders, with early life exposures potentially predisposing to enhanced anxiety responses in later life. Explanatory models support a potential role for neurotransmitter systems, inflammation, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophins and neurogenesis, and epigenetic effects, in anxiety pathogenesis. All of these pathways are affected by exposure to cigarette smoke components, including nicotine and free radicals. This review critically examines and summarizes the literature exploring the role of these systems in increased anxiety and how exposure to cigarette smoke may contribute to this pathology at a biological level. Further, this review explores the effects of cigarette smoke on normal neurodevelopment and anxiety control, suggesting how exposure in early life (prenatal, infancy, and adolescence) may predispose to higher anxiety in later life. A large heterogenous literature was reviewed that detailed the association between cigarette smoking and anxiety symptoms and disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress, mitochondrial function, neurotransmitter systems, neurotrophins and neurogenesis. Some preliminary data were found for potential epigenetic effects. The literature provides some support for a potential interaction between cigarette smoking, anxiety symptoms and disorders, and the above pathways; however, limitations exist particularly in delineating causative effects. The literature also provides insight into potential effects of cigarette smoke, in particular nicotine, on neurodevelopment. The potential treatment implications of these findings are discussed in regards to future therapeutic targets for anxiety. The aforementioned pathways may help mediate increased anxiety seen in people who smoke. Further research into the specific actions of nicotine and other cigarette components on these pathways, and how these pathways interact, may provide insights that lead to new treatment for anxiety and a greater understanding of anxiety pathogenesis

Derivation of High Purity Neuronal Progenitors from Human Embryonic Stem Cells

The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use

Visualization of acetylcholine distribution in central nervous system tissue sections by tandem imaging mass spectrometry

Metabolite distribution imaging via imaging mass spectrometry (IMS) is an increasingly utilized tool in the field of neurochemistry. As most previous IMS studies analyzed the relative abundances of larger metabolite species, it is important to expand its application to smaller molecules, such as neurotransmitters. This study aimed to develop an IMS application to visualize neurotransmitter distribution in central nervous system tissue sections. Here, we raise two technical problems that must be resolved to achieve neurotransmitter imaging: (1) the lower concentrations of bioactive molecules, compared with those of membrane lipids, require higher sensitivity and/or signal-to-noise (S/N) ratios in signal detection, and (2) the molecular turnover of the neurotransmitters is rapid; thus, tissue preparation procedures should be performed carefully to minimize postmortem changes. We first evaluated intrinsic sensitivity and matrix interference using Matrix Assisted Laser Desorption/Ionization (MALDI) mass spectrometry (MS) to detect six neurotransmitters and chose acetylcholine (ACh) as a model for study. Next, we examined both single MS imaging and MS/MS imaging for ACh and found that via an ion transition from m/z 146 to m/z 87 in MS/MS imaging, ACh could be visualized with a high S/N ratio. Furthermore, we found that in situ freezing method of brain samples improved IMS data quality in terms of the number of effective pixels and the image contrast (i.e., the sensitivity and dynamic range). Therefore, by addressing the aforementioned problems, we demonstrated the tissue distribution of ACh, the most suitable molecular specimen for positive ion detection by IMS, to reveal its localization in central nervous system tissues

Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats

Epidemiological evidence of early adolescent tobacco use, prior to that of marijuana and other illicit drugs, has led to the hypothesis that nicotine is a “gateway” drug that sensitizes reward pathways to the addictive effects of other psychostimulants. To test this hypothesis, we have compared the effect of a brief, low-dose nicotine pretreatment of adolescent and adult rats on subsequent locomotor response to acute and chronic cocaine. Adolescents, aged postnatal day (P) 28, and adults, aged P86, were given four daily injections of saline or nicotine (0.06 mg/kg, i.v.). At P32 and P90, rats were given acute injections of cocaine (0, 0.4 or 1.0 mg/kg, i.v.) and monitored for locomotor activity in either a habituated or novel test environment. To examine cocaine sensitization, rats were treated for 3 days with saline or cocaine (0.4 mg/kg, i.v.), and, after 1 day of withdrawal, were given a challenge dose of cocaine (0.4 mg/kg, i.v.). Nicotine pretreatment did not affect acute, drug-induced locomotor activity at either age. However, age differences in cocaine response were observed, with adolescent animals showing enhanced locomotor activity in the novel environment. Adolescent controls did not exhibit cocaine-induced locomotor sensitization, whereas adults did. Nicotine pretreatment during adolescence promoted the development and expression of a sensitized response to repeated cocaine exposure similar to that observed in saline-pretreated adult controls. These findings show that brief pretreatment with nicotine, in a low dose comparable to that inhaled in 2–4 cigarettes, enhances cocaine-induced behavioral plasticity in adolescent rats

Effects of Alcohol on the Acquisition and Expression of Fear Potentiated Startle in Mouse Lines Selectively Bred for High and Low Alcohol Preference

Rationale: Anxiety disorders and alcohol-use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. Objectives and Methods: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP\u3eLAP; Barrenha and Chester 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. Results: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. Conclusions: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS

Maternal smoking during pregnancy and offspring smoking initiation: assessing the role of intrauterine exposure

AIMS: To assess whether associations between maternal smoking during pregnancy and offspring smoking initiation are due to intrauterine mechanisms. DESIGN: Comparison of associations of maternal and partner smoking behaviour during pregnancy with offspring smoking initiation using partner smoking as a negative control (n = 6484) and a Mendelian randomization analysis (n = 1020), using a genetic variant in the mothers as a proxy for smoking cessation during pregnancy. SETTING: A longitudinal birth cohort in South West England. PARTICIPANTS: Participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). MEASUREMENTS: Smoking status during pregnancy was self-reported by mother and partner in questionnaires administered at pregnancy. Latent classes of offspring smoking initiation (non-smokers, experimenters, late-onset regular smokers and early-onset regular smokers) were previously developed from questionnaires administered at 14–16 years. A genetic variant, rs1051730, was genotyped in the mothers. FINDINGS: Both mother and partner smoking were similarly positively associated with offspring smoking initiation classes, even after adjustment for confounders. Odds ratios (OR) [95% confidence interval (CI)] for class membership compared with non-smokers were: experimenters: mother OR = 1.33 (95% CI = 1.06, 1.67), partner OR = 1.28 (95% CI = 1.06, 1.55), late-onset regular smokers: mother OR = 1.80 (95% CI = 1.43, 2.26), partner OR = 1.86 (95% CI = 1.52, 2.28) and early-onset regular smokers: mother OR = 2.89 (95% CI = 2.12, 3.94), partner OR = 2.50 (95% CI = 1.85, 3.37). There was no clear evidence for a dose–response effect of either mother or partner smoking heaviness on class membership. Maternal rs1051730 genotype was not clearly associated with offspring smoking initiation class in pre-pregnancy smokers (P = 0.35). CONCLUSION: The association between smoking during pregnancy and offspring smoking initiation does not appear to operate through intrauterine mechanisms