Double Dissociation of Nicotinic α7 and α4/β2 Sub-receptor Agonists for Enhancing Learning and Attentional Filtering of Distraction

Abstract

Nicotinic acetylcholine receptors (nAChR) modulate attention, memory, and higher executive functioning, but it has remained unclear whether nAChR sub-receptors tap into different neural mechanisms of these functions. We therefore set out to contrast the contributions of selective alpha-7 nAChR and alpha-4/beta-2 nAChR agonists in mediating value learning and attentional filtering of distractors in the nonhuman primate. We found that the alpha-7 nAChR agonist PHA-543613 selectively enhanced the learning speed of feature values but did not modulate how salient distracting information was filtered from ongoing choice processes. In contrast, the selective alpha-4/beta-2 nAChR agonist ABT-089 did not affect learning speed but reduced distractibility. This double dissociation was dose-dependent and evident in the absence of systematic changes in overall performance, reward intake, motivation to perform the task, perseveration tendencies, or reaction times. These results suggest nicotinic sub-receptor-specific mechanisms consistent with (1) alpha-4/beta-2 nAChR specific amplification of cholinergic transients in prefrontal cortex linked to enhanced cue detection in light of interferences, and (2) alpha-7 nAChR specific activation prolonging cholinergic transients, which could facilitate subjects to follow-through with newly established attentional strategies when outcome contingencies change. These insights will be critical for developing function-specific drugs alleviating attention and learning deficits in neuro-psychiatric diseases.

Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys

“…In the VS paradigm we used, short-term memory of the target object is already necessary for performing the easier trials with 3 or 6 distractors, while an attention-specific effect can be inferred when there is greater improvement in performance with increased attentional demands in trials with 9 or 12 distractors. Thus, our study provides strong evidence that donepezil causes specific attentional improvement at higher doses, which supports the neurogenetic model of cholinergic modulation of attention ( 51 ) that recently has received functional support in studies reporting enhanced distractor suppression in nonhuman primates with nicotine receptor–specific ACh modulation ( 52 , 53 , 54 ) and improved suppression of perceptually distracting flankers in human subjects tested with a single dose ( 55 ). We should note, however, that at the high dose, donepezil already caused a nonselective slowing of reaction times indicative of peripheral side effects (see Supplemental Discussion ).…”