Improvement of attentional function with antagonism of nicotinic receptors in female rats

Abstract

Nicotinic agonists have been shown in a variety of studies to improve cognitive function. Since nicotinic receptors are easily desensitized by agonists, it is not completely clear to what degree receptor desensitization or receptor activation are responsible for nicotinic agonist-induced cognitive improvement. In the current study, the effect of the neuronal nicotinic cholinergic α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) and the α7 nicotinic receptor antagonist methyllycaconitine (MLA) on attentional function was determined. Adult female Sprague-Dawley rats were trained on the visual signal detection task. They were required to discriminate whether or not a light signal occurred on a trial and respond with a lever press on one side after a signal and the opposite side after the absence of a signal in order to receive a food pellet reinforcer. Acute administration of the α4β2 antagonist DHβE improved attentional function either alone or in reversing the attentional impairment caused by the NMDA glutamate antagonist dizocilpine (MK-801). Acute administration of MLA also significantly attenuated the dizocilpine-induced attentional impairment. In previous research we have shown that the α4β2 nicotinic desensitizing agent and partial agonist sazetidine-A also was effective in reversing dizocilpine-induced attentional impairments on the signal detection task and that low doses of the general nicotinic antagonist mecamylamine improved learning and memory. The current studies indicate that blockade of nicotinic receptors can effectively attenuate attentional impairments. Development of drugs that provide a net decrease in nicotinic receptor activity either through antagonism or desensitization could be worth exploring for beneficial effects for treating cognitive impairments.

Figure 1

Nicotine interactions with the nicotinic α4β2 antagonist DHβE, percent correct (mean± S.E.M.). N=11

Figure 2

DHβE reversed the dizocilpine-induced percent correct impairment and nicotine blocked this effect (mean± S.E.M.). N=11

Figure 3

The nicotinic α7 antagonist MLA attenuated the dizocilpine-induced percent correct impairment (mean± S.E.M.). N=12

Figure 4

Nicotine does not block the MLA-induced reversal of the dizocilpine-induced percent correct impairment (mean± S.E.M.). N=12

Figure 5

Nicotine plus dizocilpine impairs percent hit accuracy, while MLA co-administration reverses this effect (mean± S.E.M.). N=12

Figure 6

Dizocilpine impairs percent correct rejection accuracy, an effect that is attenuated by nicotine or MLA (mean± S.E.M.). N=12