A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Abstract

Several lines of evidence suggest a link between the ␣7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the ␣7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human ␣7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by ␣4␤2, ␣3␤4, and ␣9␣10 nAChRs. PNU-120596 increased the channel mean open time of ␣7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of ␣7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances ␣7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

“…The fact that potentiation occurred within seconds and was reversible suggests that incorporation of receptors, whether newly synthesized or drawn from intracellular stores, seems an unlikely explanation. As has been proposed for the potentiating effect of certain compounds on other nAChRs (Conroy et al 2003;Curtis et al 2002;Hurst et al 2005;Krause et al 1998;Zwart et al 2002), the most likely interpretation of the present results is that ryanodine acts as a positive allosteric effector, recognizing a specific binding site within the receptor protein. Another formal possibility is that ryanodine is having its effect through Fconformational coupling_ between hair cell AChRs and ryanodine receptors (RyR) as occurs during calcium release from sarcoplasmic reticulum in skeletal muscle.…”

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…Therefore, to probe for a specific involvement of α7* nAChRs in this process, we employed PNU-120596, an α7* nAChRs selective positive allosteric modulator. 31,32 In WT mice primed by SubSD, acute systemic PNU-120596 produced cellular changes of VTA DA neurons (Figures 4a-c) that are comparable to neuroadaptations induced by SD. Indeed, VTA DA neurons of SubSD mice pretreated with PNU-120596 exhibited increased in vitro excitability and AMPA.R/NMDA.R ratio (Figures 4a and b, respectively), as well as increased in vivo firing frequency and bursting activities (Figure 4c and Supplementary Figure S4c).…”

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Indeed, studies have shown that drugs activating muscarinic or nicotinic acetylcholine receptor (nAChR) subtypes have potential for the treatment of cognitive symptoms in patients with schizophrenia (for review, see Jones et al, 2012). Specifically, nicotine, as well as agonists and positive allosteric modulators of a7 and a4b2 nAChRs, attenuate various cognitive deficits in rodent models of schizophrenia (Boess et al, 2007;Hashimoto et al, 2008;Hauser et al, 2009;Hurst et al, 2005;Pichat et al, 2007;Rushforth et al, 2011;Thomsen et al, 2009;Timmermann et al, 2007;Wallace et al, 2011;Wildeboer and Stevens, 2008;Wishka et al, 2006). Our observations that nicotine reverses the selective CMOR impairment in rats treated with subchronic NMDAR antagonists is consistent with studies using standard object recognition tasks and extends these findings by implicating nAChRs in the potential treatment of multisensory integration deficits in schizophrenia.…”