Effects of nicotinic antagonists on working memory performance in young rhesus monkeys

Abstract

Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.

Keywords: Monkey; Nicotinic; Prefrontal; Working memory.

Fig 1.

Spatial delayed response task schematic. The monkey views a reward placed in one of two wells. The wells are then covered by opaque plaques and a screen is placed between the monkey for a variable delay. The screen is subsequently raised, and the monkey moves a plaque to make a selection.

Fig 2.

Spatial delayed response performance by delay for vehicle and each drug condition. (A) Performance following mecamylamine injection for each case across all tested delay intervals. (B) Performance after methyllycaconitine injection across delays. (C) Performance after dihydro-β-erythroidine injection across delays. Data are represented as mean performance ± sem. VEH: vehicle, MEC: mecamylamine, MLA: methyllycaconitine, DHbE: dihydro-β-erythroidine.

Fig 3.

Change in baseline delayed response performance following each drug dose across cases. (A) Change from mean performance under vehicle after administration of mecamylamine across the group of four monkeys. (B) Change from vehicle performance following methyllycaconitine across monkeys. (C) Change from vehicle performance following dihydro-β-erythroidine across monkeys. (D) For comparison, change from vehicle performance following scopolamine in the same group of monkeys as shown in B and C (Wilcoxon signed-rank test; 0.01 mg/kg SCOP: p = .0078, 0.02 mg/kg SCOP: p = .0019). (E) Total task time for sessions with 5–20s delays. (F) Total task times for sessions with 5–30s delays. VEH: vehicle, MEC: mecamylamine, MLA: methyllycaconitine, DHbE: dihydro-β-erythroidine. * p < .05, ** p < .01; p value adjustment: Tukey method.