Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors

doi:10.1016/j.biopsych.2010.08.006

Biological Psychiatry

Volume 69, Issue 1, 1 January 2011, Pages 12-18

https://doi.org/10.1016/j.biopsych.2010.08.006 Get rights and content

Background

Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates.

Methods

Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg–.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg–1.0 μg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout.

Results

Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg.

Conclusions

These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend.

Section snippets

Subjects

For the acute study, nine adult rhesus macaques (Macaca mulatta; from 6 to approximately 19 years of age) were trained to stability on the spatial delayed response task (see following text). For the multiple ascending dose study, eight adult rhesus macaques (8–17.5 years of age) were trained to stability before inclusion. Note, seven of the animals from the acute study were included in the multiple ascending dose study after a prolonged washout (≥5 weeks) and ascertaining stable baseline levels

PK Analysis

Plasma concentrations of AZD0328 were measured in seven rhesus macaques after IM administration at doses of .048 mg/kg and 1.7 mg/kg. The time to reach maximal plasma exposure at both dose levels was .25 hours after injection. The exposure to AZD0328, as evaluated by the maximum plasma concentration reached, was 1990 ± 274 nM for 1.7 mg/kg and 75 ± 9 nM for .048 mg kg, respectively; the exposure, as evaluated by AUC_(0–t), was 2934 ± 374 nM*h for 1.7 mg/kg and 68.6 ± 13.1 nM*h for .048 mg/kg,

Discussion

This study demonstrated that the dose range for AZD0328 that was predicted to be effective in enhancing spatial working memory on the basis of early preclinical indications from cognitive studies in rodents was excessive in the primate, even at the lowest dose in that range of .48 mg/kg. Only when the dose was titrated down three orders of magnitude was cognitive enhancement observed within a discrete range from .00048 to .0016 mg/kg. The improvement in performance constituted an absolute

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Citation Excerpt :
Through activation of α7 nAChRs, AZD0328 is able to enhance cortical dopamine release in rats and improve novel object recognition (NOR) in mice96,97. AZD0328 also displays efficacy in improving working memory in a spatial delayed response task in Rhesus macaques98. In 2008, AstraZeneca terminated AZD0328 for a phase II clinical trial for being “unlikely to meet the current target product profile”130.
The alpha-7 nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca²⁺-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the α7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of α7 nAChR modulators used in clinical trials.

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Archival ReportImmediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors

Background

Methods

Results

Conclusions

Section snippets

Subjects

PK Analysis

Discussion

Schizophr Res

Eur J Pharmacol

Neuron

Brain Res Mol Brain Res

J Biol Chem

J Chem Neuroanat

Brain Res

Biochem Pharmacol

Trends Pharmacol Sci

Brain Res

Neuroscience

Brain Res

Biochem Pharmacol

Neuron

Cell Calcium

Neuron

Prog Brain Res

Schizophr Res

Smoking in chronic schizophrenia

Br J Psychiatry

Normalization of auditory physiology by cigarette smoking in schizophrenic patients

Am J Psychiatry

Schizophrenia, sensory gating, and nicotinic receptors

Schizophr Bull

Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus

Proc Natl Acad Sci U S A

Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients

Neuropsychopharmacology

Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine

J Neurosci

Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores

Proc Natl Acad Sci U S A

Action potential-independent and nicotinic receptor-mediated concerted release of multiple quanta at hippocampal CA3-mossy fiber synapses

J Neurosci

Synaptic plasticity and the neurobiology of learning and memory

Acta Biol Med

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization

J Comp Neurol

Archival Report
Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors