Impulsivity and Stress Response in Nondependent Smokers (Tobacco Chippers) in Comparison to Heavy Smokers and Nonsmokers.

INTRODUCTION: Tobacco chippers are light smokers with stable patterns of smoking that exhibit lower nicotine dependence severity than heavy smokers. Chippers may provide valuable information about the factors influencing drug dependence. Impulsivity and stress are two factors known to influence smoking. By comparing nondependent smokers (tobacco chippers, n = 25) to dependent smokers (heavy smokers, n = 23) and nonsmokers (n = 25), this study examines the relationship between nicotine dependence, impulsivity, chronic stress, and stress reactivity. METHODS: A total of 73 adult participants completed a study visit that included questionnaires to measure nicotine dependence, chronic stress, personality, affect, withdrawal, and craving. Impulsivity was measured with the delay discounting task and the flanker task. Stress reactivity was assessed by monitoring respiration, heart rate, and salivary cortisol during performance of a titrated Stroop task. Effects of acute stress on affect and craving were examined. RESULTS: Tobacco chippers were as impulsive as heavy smokers on the delay discounting task but no different from nonsmokers on the flanker task. Heavy smokers reported higher perceived stress than chippers and nonsmokers. Perceived stress was a significant predictor of discounting only in heavy smokers. Acute stress induced changes in respiration, heart rate, and heart rate variability. Craving and negative affect increased after stress in both smoking groups, but craving was associated with affect only in chippers. CONCLUSIONS: Tobacco chippers do not differ from heavy smokers in impulsivity, but do differ in perceived stress. One's perception and experience of stress might be associated to nicotine dependence resistance and could inform smoking cessation treatments. IMPLICATIONS: By examining impulsivity, chronic stress, and stress reactivity in nondependent smokers (tobacco chippers) compared to dependent smokers and nonsmokers, this study contributes to the understanding of nicotine addiction and informs smoking cessation programs.

Mind-body practices: an alternative, drug-free treatment for smoking cessation? A systematic review of the literature.

OBJECTIVE: The limited success of current smoking cessation therapies encourages research into new treatment strategies. Mind-body practices such as yoga and meditation have the potential to aid smoking cessation and become an alternative drug-free treatment option. The aim of this article is to assess the efficacy of yoga and other meditation-based interventions for smoking cessation, to identify the challenges of clinical trials applying mind-body treatments, and to outline directions for future research on these types of therapies to assist in smoking cessation. METHODS: A systematic review of the scientific literature. RESULTS: Fourteen clinical trials met the inclusion criteria defined for this review. Each article was reviewed thoroughly, and evaluated for quality, design, and methodology. Although primary outcomes differed between studies, the fourteen articles, most with limitations, reported promising effects supporting further investigation of the use of these practices to improve smoking cessation. CONCLUSIONS: The literature supports yoga and meditation-based therapies as candidates to assist smoking cessation. However, the small number of studies available and associated methodological problems require more clinical trials with larger sample sizes and carefully monitored interventions to determine rigorously if yoga and meditation are effective treatments.

Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo.

Pathological or in vitro overexpression of the truncated TrkB (TrkB.T1) receptor inhibits signaling through the full-length TrkB (TrkB.FL) tyrosine kinase receptor. However, to date, the role of endogenous TrkB.T1 is still unknown. By studying mice lacking the truncated TrkB.T1 isoform but retaining normal spatiotemporal expression of TrkB.FL, we have analyzed TrkB.T1-specific physiological functions and its effect on endogenous TrkB kinase signaling in vivo. We found that TrkB.T1-deficient mice develop normally but show increased anxiety in association with morphological abnormalities in the length and complexity of neurites of neurons in the basolateral amygdala. However, no behavioral abnormalities were detected in hippocampal-dependent memory tasks, which correlated with lack of any obvious hippocampal morphological deficits or alterations in basal synaptic transmission and long-term potentiation. In vivo reduction of TrkB signaling by removal of one BDNF allele could be partially rescued by TrkB.T1 deletion, which was revealed by an amelioration of the enhanced aggression and weight gain associated with BDNF haploinsufficiency. Our results suggest that, at the physiological level, TrkB.T1 receptors are important regulators of TrkB.FL signaling in vivo. Moreover, TrkB.T1 selectively affects dendrite complexity of certain neuronal populations.

Developmental analysis of Lingo-1/Lern1 protein expression in the mouse brain: interaction of its intracellular domain with Myt1l.

Lingo-1 (also known as Lern1) is a component of the Nogo receptor complex that mediates intracellular signaling in response to myelin associated inhibitors (MAIs): NogoA, MAG, and Omgp. Signaling through Nogo receptor extends to more than its well known role in preventing axon regeneration after lesion in the CNS, being implicated in neuronal functional maturation. Using Lingo-1-deficient mice, it has been demonstrated that Lingo-1 plays relevant roles in oligodendrocyte differentiation during brain development, and that treatment with Lingo-1 antagonists can improve axon regeneration after lesion in adult mice by decreasing MAI mediated signaling. However, a detailed description of the pattern of expression of Lingo-1 protein in correlation with the other partners of Nogo receptor is missing. Here, we show that components of the Nogo receptor complex, Lingo-1, NgR1, p75, and TROY coexist in mouse brain in a defined time window only at later postnatal stages. We have also determined the Lingo-1 distribution showing expression in particular subsets of neurons, but not in myelinating mature oligodendrocytes. Surprisingly, Lingo-1 is expressed at early developmental stages without NgR1, which supports the notion that Lingo-1 may participate in other activities in developing neurons different from oligodendrocyte maturation or axon extension inhibition in the adult. Finally, we propose that the intracellular domain of Lingo-1 contributes to signaling and show that it interacts with the postmitotic neuronal specific zinc finger protein Myt1l, suggesting that Lingo-1 may regulate Myt1l transcription factor activity by affecting its subcellular localization.

ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3.

The Eph (erythropoietin-producing hepatoma) family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. The transmembrane ephrinB (Eph receptor interactor B) protein is a bidirectional signaling molecule that sends a forward signal through the activation of its cognate receptor tyrosine kinase, residing on another cell. A reverse signal can be transduced into the ephrinB-expressing cell via tyrosine phosphorylation of its conserved C-terminal cytoplasmic domain. Although some insight has been gained regarding how ephrinB may send signals affecting cytoskeletal components, little is known about how ephrinB1 reverse signaling affects transcriptional processes. Here we report that signal transducer and activator of transcription 3 (STAT3) can interact with ephrinB1 in a phosphorylation-dependent manner that leads to enhanced activation of STAT3 transcriptional activity. This activity depends on the tyrosine kinase Jak2, and two tyrosines within the intracellular domain of ephrinB1 are critical for the association with STAT3 and its activation. The recruitment of STAT3 to ephrinB1, and its resulting Jak2-dependent activation and transcription of reporter targets, reveals a signaling pathway from ephrinB1 to the nucleus.

In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model.

Imbalances in neurotrophins or their high-affinity Trk receptors have long been reported in neurodegenerative diseases. However, a molecular link between these gene products and neuronal cell death has not been established. In the trisomy 16 (Ts16) mouse there is increased apoptosis in the cortex, and hippocampal neurons undergo accelerated cell death that cannot be rescued by administration of brain-derived neurotrophic factor (BDNF). Ts16 neurons have normal levels of the TrkB tyrosine kinase receptor but an upregulation of the TrkB.T1 truncated receptor isoform. Here we show that restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death. Moreover, it corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling mediated by full-length TrkB in Ts16 hippocampal neurons. These data provide a direct link between neuronal cell death and abnormalities in Trk neurotrophin receptor levels.

LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex.

Human chromosome 15q24-q26 is a very complex genomic region containing several blocks of segmental duplications to which susceptibility to anxiety disorders has been mapped (Gratacos et al., 2001, Cell, 106, 367-379; Pujana et al., 2001, Genome Res., 11, 98-111). Through an in silico gene content analysis of the 15q24-q26 region we have identifie1d a novel gene, LRRN6A (leucine-rich repeat neuronal 6A), and confirmed its location to the centromeric end of this complex region. LRRN6A encodes a transmembrane leucine-rich repeat protein, LERN1 (leucine-rich repeat neuronal protein 1), with similarity to proteins involved in axonal guidance and migration, nervous system development and regeneration processes. The identification of homologous genes to LRRN6A on chromosomes 9 and 19 and the orthologous genes in the mouse genome and other organisms suggests that LERN proteins constitute a novel subfamily of LRR (leucine-rich repeat)-containing proteins. The LRRN6A expression pattern is specific to the central nervous system, highly and broadly expressed during early stages of development and gradually restricted to forebrain structures as development proceeds. Expression level in adulthood is lower in general but remains stable and significantly enriched in the limbic system and cerebral cortex. Taken together, the confirmation of LRRN6A's expression profile, its predicted protein structure and its similarity to nervous system-expressed LRR proteins with essential roles in nervous system development and maintenance suggest that LRRN6A is a novel gene of relevance in the molecular and cellular neurobiology of vertebrates.