Reinforcement enhancement by nicotine in adult rats: behavioral
selectivity and relation to mode of delivery and blood nicotine
Paul B. S. Clarke
Received: 17 August 2017 /Accepted: 30 October 2017 /Published online: 11 November 2017
Springer-Verlag GmbH Germany, part of Springer Nature 2017
Rationale Reinforcement-enhancing effects of nicotine occur
in human subjects and laboratory rats. However, the doses
used in animal studies typically exceed smoking-associated
levels of exposure, and generalized behavioral activation by
nicotine can potentially confound data interpretation.
Methods During daily 60-min sessions, male adult rats
pressed an Bactive^ lever to illuminate a brief cue light.
Pressing on either the active or inactive lever retracted both
levers for 60 s. Nicotine (0.025–0.2 mg/kg) was given either
by continuous intravenous (IV) infusion, or spaced IV pulses
(3-s or 30-s/pulse), or pre-session subcutaneous (SC)
Results Almost all rats responded preferentially for the cue
light for several weeks. After several home-cage nicotine injec-
tions, reinforcement enhancement occurred even within the first
nicotine test session. Nicotine increased active lever responding
without altering inactive lever responding, with effects reliably
observed at doses as low as 0.1 mg/kg SC or 0.1 mg/kg/session
IV. Within the session, the 0.1 mg/kg dose maximally increased
active lever responding by 2–3-fold, coinciding with serum
levels of 25 ng/ml. Intravenous nicotine (tested at 0.1 mg/kg/
60-min session) was equally effective whether delivered by con-
tinuous infusion or in a series of equally spaced 0.003 mg/kg
pulses each of 3-s or 30-s duration.
Conclusions Low doses of nicotine can potentiate responding
for a primary sensory reinforcer without producing a general-
ized increase in lever pressing. Reinforcer enhancement by
nicotine generalized to several modes of drug delivery, ap-
peared to track circulating levels of drug, and occurred even
at serum levels within the daytime range of moderate cigarette
In the dual-reinforcement model proposed by Caggiula,
Donny and co-workers, nicotine promotes tobacco smoking
principally via (1) a primary positive reinforcing effect and (2)
a reinforcement-enhancing effect, that is, by potentiating the
reinforcing effects of smoking-associated cues (Caggiula et al.
2009; Donny et al. 2003). The positive reinforcing effects of
nicotine are at best weak, once the drug is isolated from asso-
ciated sensory cues—as shown both in animals (Caggiula
et al. 2002;Chaudhrietal.2005;Donnyetal.2003;
Palmatier et al. 2006; Sorge et al. 2009) and in humans
(Duke et al. 2015; Fulton and Barrett 2008; Jensen et al.
2016). In contrast, nicotine can strengthen non-drug rein-
forcers, both in animal and human subjects (Perkins et al.
2017; Rupprecht et al. 2015).
Tobacco smoking aside, reinforcement enhancement appears
critical in maintaining intravenous self-administration (IVSA) of
nicotine in animals (Rupprecht et al. 2015). In conventional
IVSA procedures, each drug infusion is typically paired with a
brief light cue appearing above the lever. Such visual stimuli can
serve as weak unconditioned reinforcers (Caggiula et al. 2002;
Sorge et al. 2009), and they can also become conditioned rein-
forcers by association with the drug (Palmatier et al. 2007a); both
conditioned and unconditioned reinforcers can be strengthened
by nicotine (Rupprecht et al. 2015).
* Paul B. S. Clarke
Department of Pharmacology and Therapeutics, McGill University,
McIntyre Medical Building Rm. 1320, 3655 Promenade Sir William
Osler, Montreal, Quebec H3G 1Y6, Canada
Psychopharmacology (2018) 235:641–650