Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement

The question of the subtype(s) of the nicotinic acetylcholine receptor (nAChR) mediating the attention-enhancing effects of nicotine is still unsettled. While early studies pointed towards subtypes other than the homomeric alpha 7 nAChR, pro-cognitive effects of alpha 7 nAChR agonists have since been demonstrated. This study tested whether the performance-enhancing effects of nicotine in a rodent model of attention could be reversed by the alpha 4 beta 2, alpha 4 beta 4, alpha 3 beta 2, and alpha 2 beta 2 nAChR antagonist dihydro-beta-erythroidine (DH beta E), or the alpha 7 antagonist methyllycaconitine (MLA). In repeated tests, 12 rats trained to perform the 5-choice serial reaction time task were systemically injected with nicotine or vehicle in the presence of increasing doses of DH beta E or MLA. DH beta E did not antagonize the attention-enhancing effects of nicotine reflected by measures of accuracy and omission errors, suggesting that its previously reported antagonism of nicotine effects on latency and anticipatory responses specifically reflected the stimulant effects of nicotine. MLA dose-dependently reversed the reduction in omission errors by nicotine. In the absence of nicotine, low doses of MLA (0.4 and 1.3 mg/kg) not previously tested on attention improved response accuracy, resulting in an inverted U-shape dose-response function. nAChR subtypes involved in the performance-enhancing effects of nicotine appear to vary depending on the function assessed. Our findings suggest a greater involvement of alpha 7 nAChRs in the effects of nicotine on attention than first suggested by preclinical studies, with different optimal receptor tones for aspects of stimulus detection and response readiness to task stimuli.