Nicotine improves probabilistic reward learning in wildtype but not alpha7 nAChR null mutants, yet alpha7 nAChR agonists do not improve probabilistic learning

Abstract

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n = 84) were treated with vehicle, 0.03, or 0.3 mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3 mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.

UHPLC-MS/MS combined with microdialysis for simultaneous determination of nicotine and neurotransmitter metabolites in the rat hippocampal brain region: application to pharmacokinetic and pharmacodynamic study

“…[1][2][3][4] Its mode of action involves interacting with various subtypes of acetylcholine receptors, thus modulating neurotransmitter release. 5,6 Consequently, nicotine has emerged as a promising therapeutic candidate for neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD). Notably, a7 nicotinic acetylcholine receptors (a7 nAChRs) rank as the second most prevalent subtype of nicotinic acetylcholine receptors in the brain, regulating the release of multiple neurotransmitters, including g-aminobutyric acid, glutamic acid, and dopamine.…”

Sex-dependant differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice

“…Additionally, even when the same task is used, different designs may result in different aspects of cognition being measured. For example, VD and VDR tasks in previous studies have largely been performed in “classic” operant chambers where the visual cue is a single cue light illuminated above the correct or incorrect lever (Cole et al, 2015; Ortega et al, 2013; Milienne-Petiot et al, 2018). Thus, mice/rats are required only to attend to a single cue and to learn to approach or avoid that cue.…”

“…In humans, a meta-analysis reported positive effects of nicotine or smoking on attention, as well as short-term episodic and working memory (Heishman et al, 2010), while several other studies have similarly demonstrated enhanced performance on tests of continuous attention, computational processing, and memory (DeVito et al, 2014; Myers et al, 2008; Warburton et al, 1992). In rodent studies, nicotine improved VD in rats and three mouse strains (F. Bovet-Nitti, 1966, 1969), and facilitated reversal learning in a probabilistic reversal learning tasks (Milienne-Petiot et al, 2018). However, conversely, nicotine has also been reported to impair reversal learning in VD tasks, suggesting that nicotine may not improve cognitive function indiscriminately (Cole et al, 2015; Ortega et al, 2013).…”

“…Among nAChR subunits, the α7 subunit is known to be necessary for nicotinic enhancement of discrimination learning, and positive allosteric modulation of α7 subunit containing nAChRs enhance recognition memory and cognitive flexibility (Milienne-Petiot et al, 2018; Nikiforuk et al, 2015). Alternatively, the β2 subunit has been implicated in the ability of nicotine to impair cognitive flexibility (Cole et al, 2015).…”

Converging evidence that short-active photoperiod increases acetylcholine signaling in the hippocampus

“…The PRLT is a rodent operant task used to measure reward and punishment learning contingencies as well as behavioral flexibility when these reward/punishment contingencies are switched (Amitai et al, 2014;Milienne-Petiot et al, 2018). In short, the animal must choose between two differentially rewarded options, one with a high probability of reward (80:20) and another with a low probability (20:80).…”