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Rationale: The question of the subtype(s) of the nicotinic acetylcholine receptor (nAChR) mediating the attention-enhancing effects of nicotine is still unsettled. While early studies pointed towards subtypes other than the homomeric α7 nAChR, pro-cognitive effects of α7 nAChR agonists have since been demonstrated., Objectives: This study tested whether the performance-enhancing effects of nicotine in a rodent model of attention could be reversed by the α4β2, α4β4, α3β2, and α2β2 nAChR antagonist dihydro-β-erythroidine (DHβE), or the α7 antagonist methyllycaconitine (MLA)., Methods: In repeated tests, 12 rats trained to perform the 5-choice serial reaction time task were systemically injected with nicotine or vehicle in the presence of increasing doses of DHβE or MLA., Results: DHβE did not antagonize the attention-enhancing effects of nicotine reflected by measures of accuracy and omission errors, suggesting that its previously reported antagonism of nicotine effects on latency and anticipatory responses specifically reflected the stimulant effects of nicotine. MLA dose-dependently reversed the reduction in omission errors by nicotine. In the absence of nicotine, low doses of MLA (0.4 and 1.3 mg/kg) not previously tested on attention improved response accuracy, resulting in an inverted U-shape dose-response function., Conclusions: nAChR subtypes involved in the performance-enhancing effects of nicotine appear to vary depending on the function assessed. Our findings suggest a greater involvement of α7 nAChRs in the effects of nicotine on attention than first suggested by preclinical studies, with different optimal receptor tones for aspects of stimulus detection and response readiness to task stimuli.

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.

Drug discrimination methodology makes possible the objective, quantitative study of the perception of psychoactive drug effects in either human or animal subjects. Investigations of the nicotine discriminative stimulus complex have contributed to our present understanding of nicotine psychopharmacology by defining the origin of its effects at specific subtypes of nicotinic receptor and the role of diverse neurotransmitter systems as mediating and modulating mechanisms. The evidence strongly supports central sites as the origins of the nicotine stimulus, and these are likely to be located in the mesocorticolimbic dopaminergic neurons; the medial prefrontal cortex is primarily involved, with the Nucleus accumbens and ventral tegmental area of secondary importance, while another element of the complex stimulus may arise in the dorsal hippocampus. Additionally, it appears that interactions of nicotine with the dopamine, serotonin, cannabinoid and probably glutamate systems all contribute to the final perceived stimulus. The resemblance between the nicotine discriminative stimulus and those of the psychomotor stimulant drugs amphetamine and cocaine contributes to defining the nature of the addictive properties of nicotine. It is particularly interesting that acute and chronic exposure to caffeine produce quantitative and qualitative changes in the characteristics of the nicotine stimulus. Interactions of nicotine with caffeine and cannabinoids strengthen proposals that the use of one substance serves as a "gateway" in sequential shifts of the target substance for drug-seeking behaviour, with profound implications for the human use of the substances concerned. Drug discrimination is also an important standard technique used in assessments of the abuse liability of novel psychoactive compounds, with relevance to attempts to develop novel nicotinic agonists for use as cognitive enhancers.

Distinct lines of evidence indicate that glutamate plays a primary role in modulating cognitive functions. Notably, competitive glutamate receptor antagonists acting at ionotropic N-methyl-d-aspartate (NMDA) or metabotropic glutamate 5 (mGlu5) receptors impair cognitive performance. Conversely, nicotine and other psychostimulants stimulate glutamatergic mechanisms and can act as cognitive enhancers. Hence we analysed the role of glutamate in performance of an attentional task and in nicotine-induced enhancement of attention by using the rodent five-choice serial reaction time task (5-CSRTT). Rats were trained to criterion performance and were then pre-dosed with either vehicle, the NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP, 0.3-2.0 mg/kg) or the mGlu5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 1.0-9.0 mg/kg) and challenged with nicotine (0.2 mg/kg). Nicotine improved attentional performance, an effect that was weakened by doses of CPP that themselves had little impact on performance; importantly, CPP dose-dependently blunted the ability of nicotine to improve response accuracy, the major measure of signal detection in the paradigm. MPEP dose-dependently impaired signal detection under conditions with a high attentional load, an effect that was reversed by nicotine; thus, MPEP did not block nicotine-induced attentional enhancement. Co-administration of either CPP or MPEP with nicotine also produced a general slowing of performance characterised by increases in omission errors and response latencies and reduced anticipatory responding. It is concluded that activation of NMDA receptors may be an important determinant of the effects of nicotine in the 5-CSRTT. Stimulation of nicotinic receptors may also reverse attentional deficits associated with the impaired function of the glutamate network.

Nicotine appears to enhance attention, while nicotine withdrawal leads to attentional deficits in humans that are ameliorated with nicotine administration. However, there has been much debate as to whether nicotine improves performance under baseline conditions, or only ameliorates attentional deficits. Thus, we studied the effects of acute and chronic nicotine administration and nicotine withdrawal on attentional performance in the 5-choice serial reaction time task (5-CSRTT) in Wistar and Sprague Dawley (SD) rats under baseline conditions. Wistar rats performed with higher accuracy compared to SD rats. Acute nicotine administration induced small increases in accuracy and correct responses, impulsivity and speed of responding, and decreases in omission errors. These effects were more pronounced in less accurate rats or after task modifications were implemented to disrupt the rats' performance. Chronic nicotine administration via minipumps consistently increased accuracy during days 4-6 of nicotine infusion after the effect of nicotine on impulsivity during days 1-3 dissipated. By contrast, nicotine withdrawal induced decreases in correct responses, and increases in omissions and latencies to respond, but had no effect on accuracy. These results provide evidence that chronic, but not acute, nicotine administration induced accuracy improvement under baseline conditions, while nicotine withdrawal produced some limited performance deficits.

Rationale: Understanding the neuropharmacological 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 alpha(1)-adrenoceptor antagonist prazosin that also displays significant affinity at alpha(2B) and alpha(2C)-adrenoceptors and the beta-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 beta-adrenoceptors are involved in mediating the effects of nicotine on signal detection, while activation of alpha-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.

Nicotine can increase stimulus detection, response rate and speed in the five-choice serial reaction time task, a rodent test of attention. In the present experiments, four other nicotinic agonists with different pharmacological profiles were compared in the same procedure. The response profile of epibatidine resembled that previously obtained with nicotine in that response accuracy was enhanced and omission errors and correct response latency decreased. ABT-418 transiently increased accuracy in the first 10 min of test sessions and reduced response latency. Isoarecolone caused a dose-related increase in accuracy, but had no effect on omissions or response latency. This absence of effects on response rate- or speed-related measures may be related to its previously reported reduced ability to release dopamine as compared with nicotine. The alpha7-agonist AR-R17779 was without effect on any measure, indicating that this receptor subtype may not mediate nicotinic effects on attention. Affinity constants of compounds, determined in competition binding assays targeting the alpha4beta2, alpha7, alpha3beta4 and alpha3beta2* nAChR subtypes, could not explain the differential behavioural effects observed. Differences in their functional efficacy at nAChR subtypes may instead be responsible. The finding that attentional performance and response rate and speed can be selectively modulated by nicotinic agonists is encouraging for the development of drugs with therapeutic properties similar to those of nicotine but with reduced unwanted effects.