A preliminary study suggests that nicotine and prefrontal dopamine affect cortico‐striatal areas in smokers with performance feedback

Nicotine and tonic dopamine (DA) levels [as inferred by catechol‐O‐methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico‐striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy .     

The role of attention in visual processing

Attention to a visual stimulus typically increases the responses of cortical neurons to that stimulus. Because many studies have shown a close relationship between the performance of individual neurons and behavioural performance of animal subjects, it is important to consider how attention affects this relationship. Measurements of behavioural and neuronal performance taken from rhesus monkeys while they performed a motion detection task with two attentional states show that attention alters the relationship between behaviour and neuronal response. Notably, attention affects the relationship differently in different cortical visual areas. This indicates that a close relationship between neuronal and behavioural performance on a given task persists over changes in attentional state only within limited regions of visual cortex.     

Nicotine-induced memory impairment by increasing brain oxidative stress

Male Wistar rats were subjected to chronic nicotine treatment (0.3 mg/kg; 7 continuous days) and their memory performance was studied by means of Y-maze and multi-trial passive avoidance tasks. Nicotine significantly decreased spontaneous alternation in Y-maze task and step-through-latency in the multi-trial passive avoidance task, suggesting effects on both short-term memory and long-term memory, respectively. In addition, nicotine induced neuronal apoptosis, DNA fragmentation, reduced antioxidant enzymes activity, and increased production of lipid peroxidation and reactive oxygen species, suggesting pro-oxidant activity. Our results provide further support that nicotine-induced memory impairment is due to an increase in brain oxidative stress in rats.     

Nicotine enhances delayed matching-to-sample performance by primates

The non-human primate provides an excellent model for studies of learning and memory, and one particular test, the delayed matching-to-sample task, is performed in a similar manner by both humans and non-human primates. Five young adult macaques were employed in this study, displaying variable capacities for retention in the task. Baseline performance was very consistent and three levels of performance difficulties (95-100%, 80-85% and 65-75% correct choices) were employed by including several delay intervals (0-60 sec) in each session. A reproducible enhancement in performance by nicotine in macaques performing a delayed matching-to-sample task was demonstrated. Nicotine enhanced performance with an average increase of 10% at the longest retention delay interval. This beneficial effect of nicotine was abolished in animals pretreated with a low dose (0.5 mg/kg) of mecamylamine to block central nicotinic receptors. Selective blockade of peripheral nicotinic receptors with hexamethonium was without effect on the nicotine response. A high dose (2 mg/kg) of mecamylamine itself induced a marked inhibition of performance, while an equivalent dose of hexamethonium was without effect. These experiments point to the possibility that central nicotinic receptors may be exploited pharmacologically to enhance memory performance. In this respect it is interesting that nicotine was most effective at enhancing performance when recall was more difficult, that is, on the longer retention interval delays. This could signify that nicotine might be particularly effective in the most impaired individuals. Lastly, it is encouraging that the mecamylamine induced decrease in cognitive performance might provide a new model of memory impairment from which to study the pathogenesis and develop new pharmacological strategies for the dementias.     

Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes

Cognitive and neuronal effects of nicotine show high interindividual variability. Recent findings indicate that genetic variations that affect the cholinergic and dopaminergic neurotransmitter system impact performance in cognitive tasks and effects of nicotine. The current pharmacogenetic functional magnetic resonance imaging (fMRI) study aimed to investigate epistasis effects of CHRNA4/DRD2 variations on behavioural and neural correlates of visuospatial attention after nicotine challenge using a data driven partial least squares discriminant analysis (PLS-DA) approach. Fifty young healthy non-smokers were genotyped for CHRNA4 (rs1044396) and DRD2 (rs6277). They received either 7 mg transdermal nicotine or a matched placebo in a double blind within subject design prior to performing a cued target detection task with valid and invalid trials. On behavioural level, the strongest benefits of nicotine in invalid trials were observed in participants carrying both, the DRD2 T- and CHRNA4 C+ variant. Neurally, we were able to demonstrate that different DRD2/CHRNA4 groups can be decoded from the pattern of brain activity in invalid trials under nicotine. Neural substrates of interindividual variability were found in a network of attention-related brain regions comprising the pulvinar, the striatum, the middle and superior frontal gyri, the insula, the left precuneus, and the right middle temporal gyrus. Our findings suggest that polymorphisms in the CHRNA4 and DRD2 genes are a relevant source of individual variability in pharmacological studies with nicotine.     

The potential role of cotinine in the cognitive and neuroprotective actions of nicotine

Cotinine is a primary metabolite of nicotine that has been suggested in many studies in animals and in humans to exert measurable effects on aspects of on-going behavior or on cognitive function. Much of the interest in cotinine derives from its long pharmacological half-life (15-19 hours) relative to nicotine (2-3 hours). Despite decades of study focusing on nicotine as the predominant behaviorally active component of tobacco, there continue to be aspects of the pharmacology of the drug that have yet to be explained. For example, nicotine can evoke a protracted behavioral response, i.e., in great excess of the presence of the drug in the plasma. Also, there is often a striking differential between the potency for nicotine-induced behavioral responses in humans and animals, and its potency as a cholinergic agonist, neurochemically. One possibility that may explain one or more of these properties of nicotine is the presence of a long-lived bioactive metabolite or breakdown product of nicotine such as cotinine. Preliminary data in support of this hypothesis are consistent with the ability of cotinine to improve performance accuracy on delayed matching task by macaque monkeys, and in reversing apomorphine-induced deficits in prepulse inhibition of acoustic startle in rats. The drug also was shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype. This new appreciation for the role of cotinine in nicotine's actions, and as a pharmacological agent in its own right, particularly in aspects of cognitive function and for neuroprotection, ultimately may be applied towards the treatment of Alzheimer's disease and related disorders, and for various psychiatric syndromes.     

nAChR-mediated calcium responses and plasticity in Drosophila Kenyon cells

In Drosophila, nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory synaptic transmission in mushroom body Kenyon cells, a neuronal population involved in generation of complex behaviors, including responses to drugs of abuse. To determine whether activation of nAChRs can induce cellular changes that contribute to functional plasticity in these neurons, we examined nicotine-evoked responses in cells cultured from brains of late stage OK107-GAL4 pupae. Kenyon cells can be identified by expression of green fluorescent protein (GFP+). Nicotine activates alpha-bungarotoxin-sensitive nAChRs, causing a rapid increase in intracellular calcium levels in over 95% of the Kenyon cells. The nicotine-evoked calcium increase has a voltage-gated calcium channel (VGCC) dependent component and a VGCC-independent component that involves calcium influx directly through nAChRs. Thapsigargin treatment reduces the nicotine response consistent with amplification by calcium release from intracellular stores. The response to nicotine is experience-dependent: a short conditioning pulse of nicotine causes a transient 50% reduction in the magnitude of the response to a test pulse of nicotine when the interpulse interval is 4 h. This cellular plasticity is dependent on activation of the VGCC-component of the nicotine response and on cAMP-signaling, but not on protein synthesis. These data demonstrate that activation of nAChRs induces a calcium-dependent plasticity in Kenyon cells that could contribute to adult behaviors involving information processing in the mushroom bodies including responses to nicotine.     

COMT polymorphism modulates the resting‐state EEG alpha oscillatory response to acute nicotine in male non‐smokers

Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol‐O‐methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting‐state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non‐smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double‐blind, placebo‐controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT.     

Mental Fatigue Affects Visual Selective Attention

Mental fatigue is a form of fatigue, induced by continuous task performance. Mentally fatigued people often report having a hard time keeping their attention focussed and being easily distracted. In this study, we examined the relation between mental fatigue, as induced by time on task, and attention-related changes in event-related potentials (ERPs). EEG, reaction times and response accuracies were obtained from 17 healthy volunteers during two hours of task performance on an adapted Eriksen flanker task. In this task, the size of targets and flankers was manipulated to discern neuronal processes that are related to processing of relevant information from processes related to the processing of irrelevant information. The ERP data showed that effects induced by target size manipulation were not affected by time on task, while an initial effect of flanker size manipulation decreased gradually with increasing time on task. We conclude that attention was affected by mental fatigue, in the form of a decrease in the ability to suppress irrelevant information. In behavioural results, this was reflected by a tendency of participants to increasingly base their response decision on irrelevant information, resulting in decreased response accuracies.     

Randomised controlled trial of nicotine chewing-gum.

The effectiveness of 2 mg nicotine chewing-gum as an aid to stopping smoking was compared with a placebo containing 1 mg nicotine, but unbuffered, in a double-blind randomised trial. Of 58 subjects given the active gum, 27 (47%) were not smoking at one-year follow-up compared with 12 (21%) of the 58 subjects treated with placebo (p less than 0.025). By the most stringent criterion of outcome, 18 (31%) subjects in the active treatment group and eight (14%) in the placebo group had not smoked at all from the start of treatment to follow-up at one year (p less than 0.05). Subjects receiving the active gum experienced less severe withdrawal symptoms and rated their gum as more helpful than did the placebo group. Minor side effects were common but only gastric symptoms were more frequent with the active gum. Subjects receiving active gum used it for longer than those receiving placebo but most stopped using it within six months and only four (7%) developed longer-term dependence. The number of gums used daily correlated significantly with pretreatment blood nicotine concentrations in the active treatment group and with pretreatment cigarette consumption in the placebo group. A lower pretreatment blood nicotine value was the best predictor of success at one year (p less than 0.001) but there was no significant relation to cigarette consumption, sex, and social class. The results clearly confirm the usefulness of nicotine chewing-gum as an aid to stopping smoking and imply a definite role for nicotine in cigarette dependence and withdrawal. Successful use of the gum requires careful attention to subjects'' expectations and clear instructions on how to use it.     

Isobaric Tag‐Based Protein Profiling of a Nicotine‐Treated Alpha7 Nicotinic Receptor‐Null Human Haploid Cell Line

Nicotinic acetylcholine receptors (nAChR), the primary cell surface targets of nicotine, have implications in various neurological disorders. Here we investigate the proteome‐wide effects of nicotine on human haploid cell lines (wildtype HAP1 and α7KO‐HAP1) to address differences in nicotine‐induced protein abundance profiles between these cell lines. We performed an SPS‐MS3‐based TMT10‐plex experiment arranged in a 2‐3‐2‐3 design with two replicates of the untreated samples and three of the treated samples for each cell line. We quantified 8775 proteins across all ten samples, of which several hundred differed significantly in abundance. Comparing α7KO‐HAP1 and HAP1wt cell lines to each other revealed significant protein abundance alterations; however, we also measured differences resulting from nicotine treatment in both cell lines. Among proteins with increased abundance levels due to nicotine treatment included those previously identified: APP, APLP2, and ITM2B. The magnitude of these changes was greater in HAP1wt compared to the α7KO‐HAP1 cell line, implying a potential role for the α7 nAChR in HAP1 cells. Moreover, the data revealed that membrane proteins and proteins commonly associated with neurons were predominant among those with altered abundance. This study, which is the first TMT‐based proteome profiling of HAP1 cells, defines further the effects of nicotine on non‐neuronal cellular proteomes.     

Targeting heavy smokers in general practice: randomised controlled trial of transdermal nicotine patches.

OBJECTIVES--(a) To evaluate the efficacy of transdermal nicotine patches as an aid to stopping smoking when used as an adjunct to brief advice and support in a general practice setting; (b) to see whether an increase in nicotine patch dosage enhances the rate of initial cessation. DESIGN--Randomised double blind placebo controlled parallel group study with one year of follow up. SETTING--30 general practices in 15 English counties. SUBJECTS--600 dependent heavy smokers (> or = 15 cigarettes daily) who were well motivated to give up. INTERVENTIONS--Brief general practitioner advice, booklet, and 16 hours per day patch treatment for 18 weeks with brief support and follow up at one, three, six, 12, 26, and 52 weeks. MAIN OUTCOME MEASURES--Self reported complete abstinence for up to one year with biochemical validation at all follow up points. RESULTS--Nicotine patches reduced the severity of craving and adverse mood changes in the first weeks of withdrawal and doubled the rate of initial cessation at week 3 (nicotine group 36% of patients (144/400), placebo group 16.5% of patients (33/200)) and of continuous abstinence throughout one year (nicotine group 9.3% (37), placebo group 5.0% (10)). A dose increase at week 1 among patients experiencing difficulty in quitting increased the proportion who achieved abstinence at week 3. There were no adverse systemic effects attributable to nicotine, but the incidence of moderate or severe local irritation or itching at the patch site was 16.4% (63 patients), compared with 3.8% (seven) with placebo. CONCLUSION--Transdermal nicotine patches used as an adjunct to brief advice and support in a general practice setting are an effective aid to long term cessation of smoking in highly dependent smokers.     

Neuronal migration is transiently delayed by prenatal exposure to intermittent hypoxia

BACKGROUND: Neonatal neurodevelopment is influenced by a variety of external factors, although the mechanisms responsible are poorly understood. Prenatal hypoxia, from physiological or chemical sources, can have no discernible effect, or can result in a broad spectrum of abnormalities. METHODS: To mimic some of the maternal effects of smoking, we developed a model that investigates the effects of intermittent hypoxia (IH), with or without concurrent nicotine in timed pregnant Sprague-Dawley rats. RESULTS: We found no significant differences between litter sizes or birthweight of pups from any treatment group, but animals exposed to IH (with or without nicotine) showed long term diminished body weights. Animals subjected to IH consistently showed a transient delay in neuronal migration early in the postpartum period, which was amplified by concurrent nicotine administration. We observed increased c-Abl protein levels in animals from the IH treatment groups. Multiple proteins involved in the intricate control of neuronal migration were also altered in response to this treatment, primarily the downstream targets of c-Abl: Cdk5, p25, and the cytoskeletal elements neurofilament H and F-actin and catalase. Catalase activity and protein levels, already elevated in response to IH, were further amplified by simultaneous nicotine exposure. CONCLUSIONS: This new model provides a novel system for investigating the effects of low grade IH in the developing brain and suggests that concurrent nicotine further aggravates many of the deleterious effects of IH.     

Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial

Background

Modafinil is a medication licensed for the treatment of narcolepsy. However, it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning. Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers, numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks. Interestingly, several clinical and preclinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times. This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil. The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test (HSCT).

Methodology

Sixty-four healthy volunteers received either a single dose (200 mg) of modafinil (n = 32) or placebo (n = 32) in a randomized, double-blind, placebo-controlled, parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT.

Principal Findings

Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo. However, participants in both groups made a similar number of errors on each of these measures, indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo.

Conclusions

This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT, a task that is highly sensitive to prefrontal executive function, without enhancing accuracy of performance. This finding may provide important clues to defining the limitations of modafinil as a putative cognitive enhancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02051153","term_id":"NCT02051153"}}NCT02051153     

Effects of inhaled nicotine on instrumental learning of blood pressure responses.

The present study investigated the effects of biofeedback of arterial blood pressure on cortical, peripheral, and psychological measures and the dependence of these effects on nicotine. Four groups of subjects, nonsmokers, and habitual smokers who smoked cigarettes during the experimental sessions containing 0.3, 0.8, or 1.5 mg nicotine, respectively, participated in a feedback paradigm in which continuous feedback of mean blood pressure was provided for intervals of 8 s each. While tonic blood pressure did not differ between the groups, the ability to modulate blood pressure (under feedback conditions) was restricted in smokers as compared to nonsmoking subjects; increasing nicotine dosage was accompanied by poorer performance. Independently of habitual smoking and nicotine doses, heart rate increased during feedback and under conditions of blood pressure increase. In smokers, activity in the alpha band was reduced in a dose-dependent manner. Slow cortical potentials (SCPs) during the feedback interval varied with self-induced blood pressure changes in nonsmokers (blood pressure increase was accompanied by reduced surface-negative potential shifts and vice versa), while SCP variations during feedback conditions were small in smokers, more so under the influence of 0.3 and 0.8-mg nicotine, less so under 1.5 mg. Verbal reports suggest that awareness of performance strategies may not be a necessary variable for performance on the blood pressure regulation task.     

Nitric oxide mediates the interleukin-1beta- and nicotine-induced hypothalamic-pituitary-adrenocortical response during social stress.

We investigated the role of nitric oxide (NO) in the interleukin 1beta (IL-1beta) and nicotine induced hypothalamic-pituitary-adrenal axis (HPA) responses, and a possible significance of CRH and vasopressin in these responses under basal and social stress conditions. Male Wistar rats were crowded in cages for 7 days prior to treatment. All compounds were injected i.p., nitric oxide synthase (NOS) inhibitors, alpha-helical CRH antagonist and vasopressin receptor antagonist 15 min before IL-1beta or nicotine. Identical treatment received control non-stressed rats. Plasma ACTH and serum corticosterone levels were measured 1 h after IL-1beta or nicotine injection. L-NAME (2 mg/kg), a general nitric oxide synthase (NOS) inhibitor, considerably reduced the ACTH and corticosterone response to IL-1beta (0.5 microg/rat) the same extent in control and crowded rats. CRH antagonist almost abolished the nicotine-induced hormone responses and vasopressin antagonist reduced ACTH secretion. Constitutive endothelial eNOS and neuronal nNOS inhibitors substantially enhanced the nicotine-elicited ACTH and corticosterone response and inducible iNOS inhibitor, aminoguanidine, did not affect these responses in non-stressed rats. Social stress significantly attenuated the nicotine-induced ACTH and corticosterone response. In crowded rats L-NAME significantly deepened the stress-induced decrease in the nicotine-evoked ACTH and corticosterone response. In stressed rats neuronal NOS antagonist did not alter the nicotine-evoked hormone responses and inducible NOS inhibitor partly reversed the stress-induced decrease in ACTH response to nicotine. These results indicate that NO plays crucial role in the IL-1beta-induced HPA axis stimulation under basal and social stress conditions. CRH and vasopressin of the hypothalamic paraventricular nucleus may be involved in the nicotine induced alterations of HPA axis activity. NO generated by eNOS, but not nNOS, is involved in the stress-induced alterations of HPA axis activity by nicotine.     

Effects of inhaled nicotine on instrumental learning of blood pressure responses

The present study investigated the effects of biofeedback of arterial blood pressure on cortical, peripheral, and psychological measures and the dependence of these effects on nicotine. Four groups of subjects, nonsmokers, and habitual smokers who smoked cigarettes during the experimental sessions containing 0.3, 0.8, or 1.5 mg nicotine, respectively, participated in a feedback paradigm in which continuous feedback of mean blood pressure was provided for intervals of 8 s each. While tonic blood pressure did not differ between the groups, the ability to modulate blood pressure (under feedback conditions) was restricted in smokers as compared to nonsmoking subjects; increasing nicotine dosage was accompanied by poorer performance. Independently of habitual smoking and nicotine doses, heart rate increased during feedback and under conditions of blood pressure increase. In smokers, activity in the alpha band was reduced in a dose-dependent manner. Slow cortical potentials (SCPs) during the feedback interval varied with self-induced blood pressure changes in nonsmokers (blood pressure increase was accompanied by reduced surface-negative potential shifts and vice versa), while SCP variations during feedback conditions were small in smokers, more so under the influence of 0.3 and 0.8-mg nicotine, less so under 1.5 mg. Verbal reports suggest that awareness of performance strategies may not be a necessary variable for performance on the blood pressure regulation task.This experiment was supported by Reemtsma Inc. Hamburg, which also provided the experimental cigarettes.     

Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task

The use of stimulants (methylphenidate and amphetamine) as cognitive enhancers by the general public is increasing and is controversial. It is still unclear how they work or why they improve performance in some individuals but impair it in others. To test the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby reduce cerebral activity by increasing efficiency, we measured the effects of methylphenidate on brain glucose utilization in healthy adults. We measured brain glucose metabolism (using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose) in 23 healthy adults who were tested at baseline and while performing an accuracy-controlled cognitive task (numerical calculations) given with and without methylphenidate (20 mg, oral). Sixteen subjects underwent a fourth scan with methylphenidate but without cognitive stimulation. Compared to placebo methylphenidate significantly reduced the amount of glucose utilized by the brain when performing the cognitive task but methylphenidate did not affect brain metabolism when given without cognitive stimulation. Whole brain metabolism when the cognitive task was given with placebo increased 21% whereas with methylphenidate it increased 11% (50% less). This reflected both a decrease in magnitude of activation and in the regions activated by the task. Methylphenidate's reduction of the metabolic increases in regions from the default network (implicated in mind-wandering) was associated with improvement in performance only in subjects who activated these regions when the cognitive task was given with placebo. These results corroborate prior findings that stimulant medications reduced the magnitude of regional activation to a task and in addition document a "focusing" of the activation. This effect may be beneficial when neuronal resources are diverted (i.e., mind-wandering) or impaired (i.e., attention deficit hyperactivity disorder), but it could be detrimental when brain activity is already optimally focused. This would explain why methylphenidate has beneficial effects in some individuals and contexts and detrimental effects in others.     

PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring

Perinatal exposure to maternal smoke is associated with adverse pulmonary effects, including reduced lung function and increased incidence of asthma. However, the mechanisms underlying these effects are unknown, and there is no effective preventive and/or therapeutic intervention. Recently, we suggested that downregulation of homeostatic mesenchymal peroxisome proliferator-activated receptor-γ (PPARγ) signaling following in utero nicotine exposure might contribute to chronic lung diseases such as asthma. We used an in vivo rat model to determine the effect of perinatal nicotine exposure on 1) offspring pulmonary function, 2) mesenchymal markers of airway contractility in trachea and lung tissue, and 3) whether administration of a PPARγ agonist, rosiglitazone (RGZ), blocks the molecular and functional effects of perinatal nicotine exposure on offspring lung. Pregnant Sprague-Dawley rat dams received placebo, nicotine, or nicotine + RGZ daily from embryonic day 6 until postnatal day 21, when respiratory system resistance, compliance, tracheal contractility, and the expression of markers of pulmonary contractility were determined. A significant increase in resistance and a decrease in compliance under basal conditions, with more pronounced changes following methacholine challenge, were observed with perinatal nicotine exposure compared with control. Tracheal constriction response and expression of mesenchymal markers of airway contractility were also significantly increased following perinatal nicotine exposure. Concomitant treatment with RGZ completely blocked the nicotine-induced alterations in pulmonary function, as well as the markers of airway contractility, at proximal and distal airway levels. These data suggest that perinatal smoke exposure-induced asthma can be effectively blocked by PPARγ agonists.