Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies.
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.
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ABSTRACT: Traumatic brain injury (TBI) is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA); hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified. We assessed the functional alterations in inhibitory synaptic transmission in the BLA and one mechanism that modulates excitatory synaptic transmission, the a7 containing nicotinic acetylcholine receptor (a7-nAChR), after mTBI, to shed light on the mechanisms that contribute to increased anxiety-like behaviors. Seven and 30 days after a mild controlled cortical impact (CCI) injury, animals displayed significantly greater anxiety-like behavior. This was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs). Decreases in the mIPSC amplitude were associated with reduced surface expression of a1, b2, and c2 GABAA receptor subunits. However, significant increases in the surface expression and current mediated by a7-nAChR, were observed, signifying increases in the excitability of principal neurons within the BLA. These results suggest that mTBI causes not only a significant reduction in inhibition in the BLA, but also an increase in neuronal excitability, which may contribute to hyperexcitability and the development of anxiety disorders.PLoS ONE 07/2014; 9(7):e102627. · 3.53 Impact Factor
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ABSTRACT: Clinical and pre-clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in attempt to avoid the rapid desensitization properties associated with the α7nAChR following orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on pharmacological characterization of the novel compound RO5126946 (5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide) which allosterically modulates α7nAChR activity. RO5126946 increased ACh-evoked peak current and delayed current decay, but did not affect recovery of α7nAChRs from desensitization. In addition, RO5126946 effects were absent when nicotine-evoked currents were completely blocked by co-application of the α7nAChR-selective antagonist methyllycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. Absence of RO5126946 effects at human α4β2nAChR and 5HT3 receptors, amongst others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable, brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rat. In addition, pro-cognitive effects of RO5126946 were investigated in presence of nicotine to address potential pharmacological interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at sub-threshold doses and did not interfere with pro-cognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive enhancing properties.Journal of Pharmacology and Experimental Therapeutics 06/2014; · 3.86 Impact Factor
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ABSTRACT: Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds, differing only in methyl-substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, 4MP-TQS, together with all other possible combinations of methyl-substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarised as: 1) non-desensitising activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitisation (type I PAMs), 3) potentiation associated with reduced desensitisation (type II PAMs), 4) non-competitive antagonism (NAMs) and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators; SAMs). Several lines of experimental evidence are consistent with all of these compounds acting at a common, mutually exclusive, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as non-desensitising allosteric agonists or as non-desensitising (type II) PAMs are cis-cis diastereoisomers, whereas all of the NAMs, SAMs and type I PAMs are cis-trans diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.Journal of Biological Chemistry 12/2014; · 4.60 Impact Factor