Attentional effects of nicotinic agonists in rats

Hahn, Britta; Sharples, Christopher G. V.; Wonnacott, Susan; Shoaib, Mohammed; Stolerman, I. P.

doi:10.1016/s0028-3908(03)00099-6

Cited by 125 publications

(123 citation statements)

References 40 publications

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“…The doses of nicotine that improved attention in mice in the present studies are consistent with those reported to improve attention in normal humans Heishman and Henningfield, 2000;Min et al, 2001). In contrast, studies in rats have generally required higher doses of nicotine and the inclusion of lesions or task challenges (Muir et al, 1995;Mirza and Stolerman, 1998;Stolerman et al, 2000;Hahn et al, 2002Hahn et al, , 2003aGrottick et al, 2003). In addition, whereas nicotine reduced omission levels in ostensibly normal mice in the current study, and previously in normal human subjects , in rats, the most consistent manifestation of an improvement in attention was an increase in accuracy (Mirza and Stolerman, 1998;Hahn et al, 2002).…”

Section: Discussionsupporting

confidence: 86%

“…The 5-CSR task was developed to examine sustained attention in rodents (Carli et al, 1983) and is regarded as being analogous to the CPT (Jones and Higgins, 1995). This task has been used extensively with rats, with nicotine generally showing an improvement in attention, but only when lesions or specific task challenges have been introduced to impair performance (Mirza and Stolerman, 1998;Grottick and Higgins, 2000;Stolerman et al, 2000;Mirza and Bright, 2001;Hahn et al, 2002Hahn et al, , 2003aGrottick et al, 2003). A consistent demonstration of a nicotine-induced facilitation of attention in unimpaired rats, unlike observations in humans , has proven challenging (Mirza and Bright, 2001;Terry et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In rodent brains, the two most predominant nAChRs appear to be the heteromeric a4b2 nAChR, and the homomeric a7 nAChR, accounting for 85 and 10% of neuronal nAChRs respectively (Clarke et al, 1985). In rats, the roles that these receptors play in sustained attention is examined using the 5-choice serial reaction-time (5-CSR) task (Mirza and Stolerman, 1998;Grottick and Higgins, 2000;Stolerman et al, 2000;Mirza and Bright, 2001;Hahn et al, 2002Hahn et al, , 2003aTerry et al, 2002;Grottick et al, 2003). While nicotine-induced improvements in sustained attention have been reported in the rat literature, these studies have generally required the additional complexities afforded by brain lesions, poorly performing subjects, or task challenges (Muir et al, 1995;Grottick and Higgins, 2000;Hahn et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Young

Finlayson

Spratt

et al. 2004

Neuropsychopharmacol

209

174

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In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of a7 nAChR knockout (KO) mice in the 5-CSR task. a7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as a7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the a7 nAChR may be involved in mediating these effects of nicotine.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Young

Finlayson

Spratt

et al. 2004

Neuropsychopharmacol

209

174

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“…AR-R 17779, an AstraZeneca product, is an acetylcholine analogue with full agonist properties at the α7 nicotinic cholinergic receptor. This compound does not enhance the inhibition of startle in DBA/2 mice [123,124,125] or improve accuracy and speed of response on a five-choice serial reaction time [126,127]. ABT-418, has some agonist properties at the α7 nicotinic cholinergic receptors, but is a less potent agonist than nicotine [128] and restores deficient auditory gating in DBA/2 mice as well as rats with fimbria-fornix lesions, but similar to nicotine, fails to produce continued improvement with a second dose [54].…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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“…On this same task, nicotine did not improve accuracy, whereas the atypical nicotinic agonist lobeline did significantly improve accuracy [9]. Some investigators did not find ARR 17779 to effectively improve attention on the 5-choice task [10,11]. However, Young et al found that mice with α7 knockout had significant impairments on the 5-choice task [12].…”

Section: Introductionmentioning

confidence: 96%

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

Levin

Rezvani

2007

Biochemical Pharmacology

108

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People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (α7 and α4β2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotineinduced cognitive improvement appears to be its 5HT 2 antagonist properties. The selective 5HT 2 antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

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Attentional effects of nicotinic agonists in rats

Cited by 125 publications

References 40 publications

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Nicotine Improves Sustained Attention in Mice: Evidence for Involvement of the α7 Nicotinic Acetylcholine Receptor

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

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