Activation of the α7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709. Electronic address: .
Neuropharmacology (Impact Factor: 5.11). 01/2013; 70. DOI: 10.1016/j.neuropharm.2013.01.004
Source: PubMed

ABSTRACT The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the α7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both α7 and non-α7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the α7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT(1a) receptor antagonist WAY-100135. However the α7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that α7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the α7 receptors.

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    • "These results suggest that PNU is able to improve acquisition in transgenic mice. In relation to this, it has been shown that PNU could reverse spatial deficits evaluated by a 12-arm radial maze test in rats at 3 mg/kg [55]. Moreover, although no effect on acquisition was detected in C57BL/6J, a better retention was noted after administration of 1 mg/kg of PNU [44]. "
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    ABSTRACT: The aim of the present study was to test the effects of PNU-282987 on spatial learning and memory and hippocampal neurogenesis in both intact and chronically stressed transgenic mice. Transgenic mice with susceptibility to Alzheimer's disease (AD) under immobilization stress and not-stressed animals receiving 0 and 1 mg/kg of PNU-282987 (PNU) were evaluated in a water maze task. The effects of PNU and stress on proliferation of new cells in the hippocampus of these animals were also assessed. The latency to escape the platform was significantly higher in transgenic stressed mice compared to those in the wild stressed group, as well as in transgenic animals without PNU compared to control wild group. On retention of the task, differences emerged on stressed wild animals, PNU wild group, and stressed wild mice receiving PNU. However, no significant differences were detected on new cell proliferation. The results of the present study did not show any impact of stress in acquisition of a spatial task both in wild and transgenic mice. No clear effects of PNU on acquisition of a spatial task in transgenic mice with susceptibility to AD were detected. Although PNU and stress effects were detected on retention of the task in wild animals, no changes were noted in transgenic mice.
    08/2013; 2013:952719. DOI:10.1155/2013/952719
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    ABSTRACT: The role of acetylcholine and specific nicotinic receptors in sensorimotor gating and higher cognitive function has been controversial. Here we used a commercially available mouse with a null mutation in the Chrna7(tm1Bay) gene (α7-nAChR knockout (KO) mouse) in order to assess the role of the α7-nicotinic receptor (α7-nAChR) in sensorimotor gating and spatial learning. We examined prepulse inhibition of startle (PPI) and nicotine-induced enhancement of PPI. We also tested short-term and long-term habituation of the startle response as well as of locomotor behaviour in order to differentiate the role of this receptor in the habituation of evoked behaviour (startle) versus motivated behaviour (locomotion). To address higher cognition, mice were also tested in a spatial learning task. Our results revealed a mild but consistent PPI deficit in α7-nAChR KO mice. Furthermore, they did not show nicotine-induced enhancement of startle or PPI. Short-term and long-term habituation was normal in KO mice for both types of behaviours, evoked or motivated, and they also showed normal learning and memory in the Barnes maze. Thorough analysis of the behavioural data indicated a slightly higher degree of anxiety in α7-nAChR KO mice, however, this could only be partially confirmed in an elevated plus maze test. In summary, our data suggests that α7-nAChRs play a minor role in PPI, but seem to mediate nicotine-induced PPI enhancement. We found no evidence to suggest they are important for habituation or spatial learning.
    Genes Brain and Behavior 03/2013; 4(4). DOI:10.1111/gbb.12038 · 3.66 Impact Factor
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the α7 and α4β2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs.
    Biochemical pharmacology 05/2013; 86(8). DOI:10.1016/j.bcp.2013.05.018 · 5.01 Impact Factor
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