BACKGROUND AND RATIONALE: Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801). METHODS: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. RESULTS: Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment. CONCLUSIONS: AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.
BACKGROUND AND RATIONALE: Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801). METHODS: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. RESULTS:Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment. CONCLUSIONS:AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.
Authors: J P Changeux; D Bertrand; P J Corringer; S Dehaene; S Edelstein; C Léna; N Le Novère; L Marubio; M Picciotto; M Zoli Journal: Brain Res Brain Res Rev Date: 1998-05
Authors: E D Levin; C K Conners; D Silva; S C Hinton; W H Meck; J March; J E Rose Journal: Psychopharmacology (Berl) Date: 1998-11 Impact factor: 4.530
Authors: William M Howe; Jinzhao Ji; Vinay Parikh; Sarah Williams; Elisabeth Mocaër; Caryn Trocmé-Thibierge; Martin Sarter Journal: Neuropsychopharmacology Date: 2010-02-10 Impact factor: 7.853
Authors: E D Levin; C K Conners; E Sparrow; S C Hinton; D Erhardt; W H Meck; J E Rose; J March Journal: Psychopharmacology (Berl) Date: 1996-01 Impact factor: 4.530
Authors: Kaitlyn E Shaw; Corina O Bondi; Samuel H Light; Lire A Massimino; Rose L McAloon; Christina M Monaco; Anthony E Kline Journal: J Neurotrauma Date: 2013-03-26 Impact factor: 5.269
Authors: Li Wang; Luis E F Almeida; Nicholas A Spornick; Nicholas Kenyon; Sayuri Kamimura; Alfia Khaibullina; Mehdi Nouraie; Zenaide M N Quezado Journal: Psychopharmacology (Berl) Date: 2015-09-04 Impact factor: 4.530
Authors: Aurelija Jucaite; John Öhd; Alexandra S Potter; Judith Jaeger; Pär Karlsson; Kristin Hannesdottir; Emma Boström; Paul A Newhouse; Björn Paulsson Journal: Psychopharmacology (Berl) Date: 2013-05-03 Impact factor: 4.530