The Role of Nicotine in Smoking: A Dual-Reinforcement Model

Abstract

Models of intravenous nicotine self-administration in laboratory animals are being used to investigate the behavioral and neurobiological consequences of nicotine reinforcement, and to aid in the development of novel pharmacotherapies for smoking cessation. Central to these models is the principle of primary reinforcement, which posits that response-contingent presentation of a primary reinforcer, nicotine, engenders robust operant behavior, whereas response-independent drug delivery does not. This dictum of nicotine as a primary reinforcer has been widely used to explain why people smoke tobacco-smoking results in the rapid delivery of nicotine to the brain, setting up a cascade of neurobiological processes that strengthen subsequent smoking behavior. However, there is mounting evidence that the primary reinforcement model of nicotine self-administration fails to fully explain existing data from both the animal self-administration and human smoking literatures. We have recently proposed a "dual reinforcement" model to more fully capture the relationship between nicotine and self-administration, including smoking. Briefly, the "dual reinforcement" model posits that nicotine acts as both a primary reinforcer and a reinforcement enhancer. The latter action of nicotine had originally been uncovered by showing that a reinforcing VS, which accompanies nicotine delivery, synergizes with nicotine in the acquisition and maintenance of self-administration, and that this synergism can be reproduced by combining operant responding for the reinforcing stimulus with non-contingent (response-independent) nicotine. Thus, self-administration (and smoking) is sustained by three actions: (1) nicotine, acting as a primary reinforcer, can sustain behavior that leads to its delivery; (2) nicotine, acting as a primary reinforcer, can establish neutral environmental stimuli as conditioned reinforcers through Pavlovian associations; and (3) nicotine, acting as a reinforcement enhancer, can magnify the incentive value of accompanying stimuli, be they conditioned or unconditioned reinforcers.

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine

“…Finally, all previous self-administration research in this area has focused on the impact of MAO inhibition on the primary reinforcing effect of nicotine. However, we have previously shown that rats will respond for a visual stimulus (VS) consisting of a 1-s cue light presentation and a 1-min white houselight offset, and that responding for the VS is increased in rats receiving non-contingent infusions of nicotine (Caggiula et al, 2009;Donny et al, 2003;Palmatier et al, 2006;Rupprecht et al, 2015). The action of nicotine to increase the value of other reinforcers is known as reinforcement enhancement.…”

“…The action of nicotine to increase the value of other reinforcers is known as reinforcement enhancement. The reinforcement enhancement effect has been shown to be as important or more important than the primary reinforcing effect of nicotine for nicotine self-administration (Caggiula et al, 2009). The impact of MAO inhibition on the reinforcement enhancing effect of nicotine is unknown.…”

Behavioral and Neural Substrates of Habit Formation in Rats Intravenously Self-Administering Nicotine

“…Here we propose that IV nicotine self-administration may be particularly amenable to devaluation through techniques typically employed with natural rewards (ie, pairing nicotine with lithium-induced nausea) due to the unique characteristics of nicotine self-administration. First, rats are relatively poor at titrating nicotine intake with changing infusion dose, but are highly sensitive to non-pharmacological factors, including physical response requirements (nose poke vs lever press; Clemens et al, 2010) and the presence of nicotine-related cues (Caggiula et al, 2009). Second, nicotine produces strong interoceptive cues that can enter into associations with other stimuli (Charntikov et al, 2012), such as lithium-induced nausea (Pittenger and Bevins, 2013).…”

Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

“…Furthermore, nicotine dramatically increases responding for other reinforcers even when nicotine delivery is not contingent on the animal ' s behavior ( Donny et al, 2003 ) or when nicotine is concurrently available through another operant ( Palmatier et al, 2006 ). These outcomes have led to the dual reinforcement model, which recognizes two actions of nicotine: ( a ) it is a primary reinforcer and ( b ) it enhances the reinforcing effects of concurrently available stimuli ( Caggiula et al, 2009 ). These effects are consistent with data from studies measuring intracranial self-stimulation that show nicotine increases sensitivity of the neural pathways mediating reward ( Bauco & Wise, 1994 ;Huston-Lyons & Kornetsky, 1992 ;Kenny & Markou, 2006 ).…”