The effects of lobeline on nicotine withdrawal-induced depression-like behavior in mice

Rationale

Evidence suggests that neuronal nicotinic acetylcholine receptor (nAChR) ligand lobeline has antidepressant-like properties.

Objectives

The present study investigated the effects of lobeline on nicotine withdrawal-induced depression-like behavior.

Methods

Adult C57BL/6J mice were exposed to nicotine (200 μg/ml) in drinking solution for 3 weeks. During withdrawal, depression-like behavior was measured by the forced swim test (FST). We also determined norepinephrine (NE) levels in the prefrontal cortex (PFC) and hippocampus during nicotine withdrawal. Furthermore, we determined the effects of repeated treatment with lobeline or a selective α4β2 nAChR ligand 3-(pyridine-3?-yl)-cytisine on brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding (p-CREB) protein expression in the hippocampus.

Results

Withdrawal from chronic nicotine increased immobility time in the FST, a measure for depression-like behavior. Pretreatment with lobeline significantly decreased immobility time during nicotine withdrawal. In addition, pretreatment with lobeline attenuated nicotine withdrawal-induced increased NE levels in the PFC and hippocampus. Further, repeated treatment with lobeline or 3-(pyridine-3?-yl)-cytisine decreased immobility time in the FST and reduced withdrawal-induced increased BDNF and p-CREB expression in the hippocampus.

Conclusions

Taken together, our results indicate that lobeline attenuated nicotine withdrawal-induced depression-like behavior likely by targeting brain nAChRs, noradrenergic neurotransmission, and/or hippocampal BDNF. Thus, lobeline may have some potential to prevent smoking relapse by counteracting nicotine withdrawal-induced depression in humans.     

Cerebellar Inhibitory Output Shapes the Temporal Dynamics of Its Somatosensory Inferior Olivary Input

The cerebellum is necessary and sufficient for the acquisition and execution of adaptively timed conditioned motor responses following repeated paired presentations of a conditioned stimulus and an unconditioned stimulus. The underlying plasticity depends on the convergence of conditioned and unconditioned stimuli signals relayed to the cerebellum by the pontine nucleus and the inferior olive (IO), respectively. Adaptive timing of conditioned responses relies on the correctly predicted onset of the unconditioned stimulus, usually a noxious somatosensory stimulus. We addressed two questions: First, does the IO relay information regarding the duration of somatosensory stimuli to the cerebellum? Multiple-unit recordings from the IO of anesthetized rats that received periorbital airpuffs of various durations revealed that sustained somatosensory stimuli are invariably transformed into phasic IO outputs. The phasic response was followed by a post-peak depression in IO activity as compared to baseline, providing the cerebellum with a highly synchronous signal, time-locked to the stimulus’ onset. Second, we sought to examine the involvement of olivocerebellar interactions in this signal transformation. Cerebello-olivary inhibition was interrupted using temporary pharmacological inactivation of cerebellar output nuclei, resulting in more sustained (i.e., less synchronous) IO responses to sustained somatosensory stimuli, in which the post-peak depression was substituted with elevated activity as compared to baseline. We discuss the possible roles of olivocerebellar negative-feedback loops and baseline cerebello-olivary inhibition levels in shaping the temporal dynamics of the IO’s response to somatosensory stimuli and the consequences of this shaping for cerebellar plasticity and its ability to adapt to varying contexts.     

Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens

This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen intermediates (RNI) in mammalian immunity. Reflections on redundancy in immunity help explain an apparent paradox: the phagocyte oxidase and inducible nitric oxide synthase are each nonredundant, and yet also mutually redundant, in host defense. In combination, the contribution of these two enzymes appears to be greater than previously appreciated. The remainder of this review focuses on a relatively new field, the basis of microbial resistance to RNI. Experimental tuberculosis provides an important example of an extended, dynamic balance between host and pathogen in which RNI play a major role. In diseases such as tuberculosis, a molecular understanding of host-pathogen interactions requires characterization of the defenses used by microbes against RNI, analogous to our understanding of defenses against reactive oxygen intermediates. Genetic and biochemical approaches have identified candidates for RNI-resistance genes in Mycobacterium tuberculosis and other pathogens.     

Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.

Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)(2)D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993-2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75-1.45; P(trend) = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)(2)D compared with the lowest was 1.23 (95% CI, 0.91-1.68; P(trend) = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (> or =60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)(2)D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure.