Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice

Young, Jared W.; Crawford, Nicola; Kelly, John; Kerr, Lorraine E.; Marston, Hugh; Spratt, Christopher; Finlayson, Keith; Sharkey, John

doi:10.1016/j.euroneuro.2006.03.008

Cited by 211 publications

(173 citation statements)

References 68 publications

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“…These results suggest the involvement of functional a7 nAChRs in the pro-cognitive effect of chronic nicotine treatment in DAT KO mice. Such a hypothesis is in agreement with previous studies showing impaired performance of a7 nAChR knockout mice (Young et al, 2004(Young et al, , 2007Keller et al, 2005). Deficit in sensory gating in schizophrenic patients has been suggested to be linked to a7 nAChR (for a review, see Adler et al, 1998) and can be improved by DMXB-A, an a7 nAChR agonist (Olincy et al, 2006).…”

Section: Chronic Nicotine Treatment Did Not Elicit An Anxiogenic Effesupporting

confidence: 80%

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

Weiss

Nosten‐Bertrand

McIntosh

et al. 2007

Neuropsychopharmacol

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Various studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and establish that patients suffering from schizophrenia and attention deficit hyperactivity disorder (ADHD) have a high tobacco consumption, potentially for the purpose of selfmedication. Owing to its neuroprotective and procognitive effects, transdermal nicotine was proposed to be an effective treatment of some neurodegenerative and psychiatric diseases. Mice deficient in the dopamine transporter (DAT KO) exhibit a phenotype reminiscent of schizophrenia and ADHD, including hyperdopaminergia, hyperactivity, paradoxical calming by methylphenidate and cognitive deficits, some of which being improved by antipsychotic agents. We recently demonstrated that nicotinic receptor content and function were profoundly modified in DAT KO mice. In this study, we assessed the effects of a chronic nicotine treatment in the drinking water on the nicotine-induced locomotion, anxiety status and learning performance. Chronically nicotine-treated DAT KO mice were always hypersensitive to the hypolocomotor effect of nicotine without tolerance and did not exhibit the anxiogenic effect of nicotine treatment observed in WT mice. Very interestingly, both acute and chronic nicotine treatments greatly improved their deficits in the cued and spatial learning, without eliciting tolerance. We speculate that the procognitive effects of nicotine in DAT KO mice are related to the upregulation of a7 nicotinic receptors in the hippocampus, amygdala, and prelimbic cortex, all areas involved in cognition. Data from our studies on DAT KO mice shed light on the nicotine self-medication in psychiatric patients and suggest that nicotinic agonists could favorably lead to additional therapy of psychiatric diseases.

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Section: Chronic Nicotine Treatment Did Not Elicit An Anxiogenic Effesupporting

confidence: 80%

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

Weiss

Nosten‐Bertrand

McIntosh

et al. 2007

Neuropsychopharmacol

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“…Of particular relevance to attentional and sensory gating deficits in schizophrenia (Adler et al, 1998;Heinrichs, 2005;Lubow, 2005), a7-nAChR agonists alleviate both types of deficits in humans and animals Olincy et al, 2006;Timmermann et al, 2007;Wishka et al, 2006). A role for the a7-nAChR in these processes is supported by findings that a7-nAChR knock-out mice show attentional and gating impairments (Adams et al, 2008;Hoyle et al, 2006;Young et al, 2004Young et al, , 2007. Finally, there is a diminished expression of a7-nAChR in the hippocampus and frontal cortex in schizophrenia (Freedman et al, 1995;Guan et al, 1999).…”

Section: Introductionsupporting

confidence: 52%

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Barak

Arad

Levie

et al. 2009

Neuropsychopharmacol

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Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of a7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective a7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously nonreinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with a7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in nodrug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

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“…Hence positive allosteric modulators of α7 nAChR have therapeutic potential for restoring cognitive deficits in conditions involving PFC dysfunction [10]. Indeed, a role for α7 nAChRs in PFC function is implicit in the deficits in attention and working memory performance in knockout mice lacking this nAChR subunit [118,119], although it is unclear in these studies if the critical α7 nAChRs are located in the PFC or elsewhere in the brain.…”

Section: The In Vitro Experimentsmentioning

confidence: 96%

Nicotinic acetylcholine receptors and the ascending dopamine pathways

Livingstone

Wonnacott

2009

Biochemical Pharmacology

125

114

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Nicotinic acetylcholine receptors (nAChRs) are widely expressed in midbrain dopamine neurons that project to dorsal striatum, nucleus accumbens and prefrontal cortex. Thus nAChRs can influence the functions of these three pathways; notably motor control, 'reward' and executive function, respectively. Diverse subtypes of nAChRs have been identified on dopamine cell bodies and terminals as well as on neighbouring afferents and interneurons. Here we review the molecular and cellular mechanisms through which nAChRs exert their influence on these pathways in rodents. Page 4 of 40A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 5 IntroductionThe association of nicotine with tobacco addiction has stimulated particular interest in how nicotine interacts with the 'reward' pathways of the brain. Most attention has been given to the ascending dopaminergic pathways that arise in the midbrain and project to aspects of the basal ganglia and prefrontal cortex (PFC; Fig. 1). In addition to mediating the reinforcing properties of addictive substances, dopamine is also central to the fine control of movement governed by the basal ganglia, whereas its actions in the PFC are critically important to 'executive' function [1,2]. This includes working memory, behavioural flexibility and decision making, and the PFC is also involved with the anticipation of reward [3,4]. FIGURE ONE NEAR HERENicotine interacts with the dopamine systems via nicotinic acetylcholine receptors (nAChRs), a family of ligand-gated pentameric cation channels constituted from at least nine α and β subunits (α2-7 and β2-4) expressed in the mammalian brain [5]. nAChR subtypes can differ in their sensitivities to nicotine or acetylcholine (ACh), their channel characteristics (including their propensity to desensitise) and their cellular distribution. A high relative permeability to Ca 2+ , a notable characteristic of the α7 nAChR subtype, enables nAChRs to interface with a variety of intracellular Ca 2+ -dependent mechanisms [6]. The localisation of nAChRs on dopamine cell bodies in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) allows nicotine to directly modulate dopaminergic cell firing. Additionally, nAChRs on dopamine terminals can influence transmitter release. nAChRs present on afferents projecting to the VTA and SNc or to the terminal fields can also influence the activity of dopaminergic neurons. The nicotinic modulation of dopamine release has generated interest in nAChRs as therapeutic targets for conditions involving dopaminergic dysfunction, including schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, Alzheimer's disease and age-related cognitive impairment [7][8][9][10].In this review we focus on the mechanisms through which nAChRs modulate the activity of dopamine neurones of the principal ascending pathways (Fig. 1). We will considerPage 6 of 40A c c e p t e d M a n u s c r i p t 6 nicotinic influences on somatodendritic and terminal fields, with the aim of integratin...

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Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice

Cited by 211 publications

References 68 publications

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Nicotinic acetylcholine receptors and the ascending dopamine pathways

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