Differential effects of alkaloids on memory in rodents

Abstract

Nicotinic acetylcholine receptors (nAChRs) play a critical role in the neuropharmacology of learning and memory. As such, naturally occurring alkaloids that regulate nAChR activity have gained interest for understanding and potentially improving memory function. In this study, we tested the acute effects of three known nicotinic alkaloids, nicotine, cotinine, and anatabine, in suppressing scopolamine-induced memory deficit in rodents by using two classic memory paradigms, Y-maze and novel object recognition (NOR) in mice and rats, respectively. We found that all compounds were able to suppress scopolamine-induced spatial memory deficit in the Y-maze spontaneous alternation paradigm. However, only nicotine was able to suppress the short-term object memory deficit in NOR, despite the higher doses of cotinine and anatabine used to account for their potential differences in nAChR activity. These results indicate that cotinine and anatabine can uniquely regulate short-term spatial memory, while nicotine seems to have more robust and general role in memory regulation in rodents. Thus, nAChR-activating alkaloids may possess distinct procognitive properties in rodents, depending on the memory types examined.

Figure 1

α4β2 and α7 nAChR EC₅₀ values of nicotine, cotinine, and anatabine. α4β2 and α7 nAChRs EC₅₀ values were determined in Chinese hamster ovarian (CHO) cells overexpressing the respective human nAChRs as reported by Alijevic et al.. Nicotine and anatabine are potent, while cotinine is a weak α4β2 nAChR agonist. Nicotine is also a weak α7 agonist. NA not available due to no or low activity.

Figure 2

Effects of alkaloids on Y-maze working memory. (a) Schematic diagram of the Y-maze spontaneous alternation is shown. The test duration was 8 min. Memory indices, expressed as a percentage of vehicle response (Veh/Veh), are presented for (b) nicotine (NIC), (c) cotinine (COT), and (d) anatabine (ANAT). All compounds were able to significantly suppress scopolamine (SCOP)-induced memory deficit. Doses are indicated below each graph in mg/kg b.w. The vehicle in all panels are the same due to the fact all compounds were tested at the same time. **p < 0.01 and ***p < 0.001 compared with vehicle control without scopolamine (Veh/Veh; white bars). ^###p < 0.001 compared with vehicle control with scopolamine (black bars). Grey bars are the lowest, bars with slashes are the medium, and checkered bars are the highest concentrations tested of the respective compounds. Data are expressed as mean ± SEM.

Figure 3

Effects of alkaloids on NOR short-term memory. (a) Schematic diagram of the NOR test is shown. The familiar objects are indicated as squares with stripes, and the new object is indicated as a checkered round object for presentation purposes. The test was conducted 3 h after training. The discrimination ratios (d2) are presented for (b) nicotine (NIC), (c) cotinine (COT), and (d) anatabine (ANAT). Only nicotine was able to significantly suppress scopolamine (SCOP)-induced memory deficit at 0.1 and 0.3 mg/kg. Doses are indicated below each graph in mg/kg b.w. *p < 0.05, **p < 0.01, and ***p < 0.001 compared with vehicle control without scopolamine (white bars). ^##p < 0.001 and ^###p < 0.001 compared with vehicle control with scopolamine (black bars). Grey bars are the lowest, bars with slashes are the medium, and checkered bars are the highest concentrations tested of the respective compounds. Data are expressed as mean ± SEM.