Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors.
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.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Stacy A
SA
Castner
Gennady N
GN
Smagin
Timothy M
TM
Piser
Yi
Y
Wang
Jeffrey S
JS
Smith
Edward P
EP
Christian
Ladislav
L
Mrzljak
Graham V
GV
Williams
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D011812:Quinuclidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D005663:Furans; D018697:Nootropic Agents; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C543642:spiro(1-azabicyclo(2.2.2)octane-3,2'(3H)-furo(2,3-b)pyridine)