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Gestational exposure to environmental toxins such as nicotine may result in detectable gene expression changes in later life. To investigate the direct toxic effects of prenatal nicotine exposure on later brain development, we have used transcriptomic analysis of striatal samples to identify gene expression differences between adolescent Lister Hooded rats exposed to nicotine in utero and controls. Using an additional group of animals matched for the reduced food intake experienced in the nicotine group, we were also able to assess the impact of imposed food-restriction on gene expression profiles. We found little evidence for a role of gestational nicotine exposure on altered gene expression in the striatum of adolescent offspring at a significance level of p<0.01 and |log2 fold change >0.5|, although we cannot exclude the possibility of nicotine-induced changes in other brain regions, or at other time points. We did, however, find marked gene expression differences in response to imposed food-restriction. Food-restriction resulted in significant group differences for a number of immediate early genes (IEGs) including Fos, Fosb, Fosl2, Arc, Junb, Nr4a1 and Nr4a3. These genes are associated with stress response pathways and therefore may reflect long-term effects of nutritional deprivation on the development of the stress system. [ABSTRACT FROM AUTHOR]

Cigarette smoking is associated with a wide variety of adverse reproductive outcomes, including increased infant mortality and decreased birth weight. Prenatal exposure to tobacco smoke, of which nicotine is a major teratogenic component, has also been linked to the acceleration of the risk for different psychiatric disorders, including conduct disorder and attention deficit hyperactivity disorder (ADHD). Whether this increased risk is influenced by the direct effects of gestational nicotine exposure on the developing fetus remains uncertain. In this study we provide experimental evidence for the effects of prenatal nicotine exposure on measures of attention and impulsivity in adult male rats. Offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water (daily consumption: 69.6±1.4 ml/kg; nicotine blood level: 96.0±31.9 ng/ml) had lower birth weight and delayed sensorimotor development measured by negative geotaxis, righting reflex, and grip strength. In the 5-choice serial reaction time test, adult rats showed increased numbers of anticipatory responses and omissions errors, more variable response times, and lower accuracy with evidence of delayed learning of the task demands when the 1 s stimulus duration was introduced. In contrast, prenatal nicotine exposure had no effect on exploratory locomotion or delay-discounting test. Prenatal nicotine exposure increased expression of the D5 dopamine receptor gene in the striatum, but did not change expression of other dopamine-related genes (DRD4, DAT1, NR4A2, and TH) in either the striatum or the prefrontal cortex. These data suggest a direct effect of prenatal nicotine exposure on important aspects of attention, inhibitory control, or learning later in life. [ABSTRACT FROM AUTHOR]

There is evidence that serotonin2C (5-HT2C) receptors can modulate some behavioural effects of nicotine, but the generality of this action is not known. To analyse the influence of the 5-HT2C agonist Ro-60-0175 on responses to nicotine in the five-choice serial reaction time task (5-CSRTT) and on its discriminative stimulus effect; these procedures constitute models for attention-enhancing and subjective effects of nicotine, respectively. In the 5-CSRTT, rats were trained to obtain food reinforcers by detecting light stimuli and then challenged with Ro-60-0175 (0.3–0.8 mg/kg) and nicotine (0.2 mg/kg). For drug discrimination studies, rats were trained to discriminate nicotine (0.2 mg/kg) from saline in a two-lever procedure using a tandem schedule of food reinforcement. In the 5-CSRTT, nicotine positively influenced most response indices, confirming previous results. Ro-60-0175 increased response latencies and omission errors and reduced anticipatory responding but had little effect on response accuracy; importantly, it counteracted the effects of nicotine on response speed and omission errors. Pentobarbitone (10–14 mg/kg) also slowed performance of the 5-CSRTT but did not weaken the nicotine-induced enhancement of performance. In the drug discrimination procedure, Ro-60-0175 was not generalised with nicotine but shifted the nicotine dose–response curve to the right in a dose-related manner. The data suggest that selective occupancy of 5-HT2C receptors can attenuate some effects of nicotine in the 5-CSRTT and weaken the nicotine discriminative stimulus; these effects cannot be explained by a sedative action of Ro-60-0175. [ABSTRACT FROM AUTHOR]

Rationale: Understanding the neuropharmaco-logical mechanisms mediating attentional enhancement by nicotine would help a targeted search for nicotinic compounds with retained therapeutic but reduced unwanted side-effects. Previous studies suggested that the dopamine-releasing effects of nicotine may not be of primary importance for its attention-enhancing properties. Objectives: The present study examined the role of noradrenergic neurotransmission for the effects of nicotine on different response indices of an attentional paradigm. Methods: The effects of systemic injections of the α1-adrenoceptor antagonist prazosin that also displays significant affinity at α2B and α2C-adrenoceptors and the β-adrenoceptor antagonist propranolol were tested in both the presence and absence of nicotine in rats trained in a version of the five-choice serial reaction time task. Results: Nicotine generally enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. At the largest doses tested, both prazosin (1 mg/kg) and propranolol (10 mg/kg) impaired performance. For propranolol, these effects depended on the rate of target signal presentation. The two compounds differentially modulated the effects of nicotine. Propranolol (6 mg/kg and 10 mg/kg) but not prazosin reduced its effects on omission errors and accuracy. By contrast, prazosin (0.5 mg/kg) reversed the nicotine-induced reductions in response latency. Conclusions: The data provide the first evidence that βadrenoceptors are involved in mediating the effects of nicotine on signal detection, while activation of α-adrenoceptors may contribute to its effects on response speed. This is a further indication that, from among nicotine's wide range of neuropharmacological effects, specific facets can be dissociated that are responsible for its attention-enhancing properties. [ABSTRACT FROM AUTHOR]

Rationale: Nicotine can enhance attentional performance in humans, a property that may be of therapeutic utility. Objectives: To identify brain sites mediating nicotine-induced attentional enhancement. Methods: Nicotine (0, 1, 2, 4 and 8 μg) was injected bilaterally into the dorsal hippocampus and the prelimbic area of the prefrontal cortex, brain sites implicated in cognitive functions, of rats performing the five-choice serial reaction time task (5-CSRTT). This rodent model of attention required the detection of light stimuli presented randomly in one of five locations during 30-min sessions. Systemically administered nicotine (0.1 and 0.2 mg/kg SC) was tested alongside local injections as a positive control. Results: Nicotine (SC) enhanced response accuracy, reduced omission errors and shortened response latency. Nicotine injected into the dorsal hippocampus had no effect on any measure of performance except a slight decrease in latency in some animals at lower doses. By contrast, local injections of nicotine into the prefrontal cortex caused a dose-related increase in accuracy, the measure most closely reflecting stimulus detection and attention. Nicotine also increased omission errors selectively in the first 10 min of sessions and slightly reduced premature responding in the intertrial interval. No effects on response latency were observed. Conclusions: The results implicate the prefrontal cortex, but not the dorsal hippocampus, in the attention-enhancing effects of nicotine. The targeting of nicotinic receptor subtypes expressed in the prefrontal cortex may be of particular benefit for the treatment of chronic disease states characterised by attentional dysfunction. [ABSTRACT FROM AUTHOR]

Abstract Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable sell-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50-200 ng/ml) were approximately 2-fold higher than nicotine levels (40-120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. [ABSTRACT FROM AUTHOR]

Abstract Although nicotine has cognitive enhancing effects in both animals and humans, most studies in humans have only shown consistent improvements in sustained attention. Moreover, many studies with smokers have been, since nicotine may simply be relieving withdrawal-induced deficits. The present study investigated the effect of nicotine on sustained attention in drug-naive rats using a five-choice serial reaction time task. Initially, the task was demonstrated to satisfy some of the criteria for the construct validity of a vigilance task: reducing signal length and either increasing or decreasing the inter-trial interval significantly (P<0.05) impaired performance. Whether nicotine (0.05-0.4 mg/kg, SC) reversed the deficits induced by a signal length of 0.25 s (weak signal) or an inter-trial-interval of either 20 s (low event rate) or I s (high event rate) was assessed. Nicotine (0.15 mg/kg) improved accuracy and decreased omission errors under low event rate conditions only. However, nicotine (0.05/0.15 mg/kg) improved reaction time and increased anticipatory responses under both weak signal and low event rate conditions. There was no effect of nicotine on performance under high event rate conditions. Under the low event rate condition, nicotine enhanced the ability of rats to maintain attention (i.e. accuracy) throughout a session. These findings suggest (i) that nicotine's effect on attention depends upon task characteristics; (ii) these effects on attention may reflect self-reports by smokers that nicotine aids concentration, particularly in stressful situations, and (iii) nicotinic agonists may have therapeutic benefits in patient populations suffering from attentional deficits. [ABSTRACT FROM AUTHOR]

It is widely accepted that nicotine serves as a major reinforcer of tobacco use, but how it does so is obscure. Little is known about the nature of the reinforcing effect of nicotine in psychobiological terms, or about the mechanism of reinforcement at the level of neuropharmacology. Several ideas about the nature of the reinforcement are current, including mood changes such as euphoria, learning, memory and attention improvements, ability to help smokers deal with or adapt to stressors, and capacity to terminate symptoms of a nicotine withdrawal syndrome. These psychobiological effects are not mutually exclusive; different effects may be important for different people, or for the same person under different circumstances. Similarly, the neuropharmacology of nicotine reinforcement remains largely unexplored; nicotinic-cholinergic receptors seem to play a primary role but evidence implicating particular subtypes of nicotinic receptor is not available. Evidence points to the release of dopamine as an important link in the chain of events that transduce effects at nicotinic receptors into behaviour and nicotine-seeking responses, but the dopamine hypothesis addresses only one part of a complex system. The possibility has to be faced that neuropharmacologically, several mechanisms are involved that parallel the several psychobiological effects mentioned above; multiple types of receptor, brain structures and indirectly activated neurotransmitter systems may contribute to the maintenance of nicotine-seeking behaviour. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue, including one by Victor De Noble and Paul Mele on interactions among nicotine and other substances including acetaldehyde and mecamylamine.