Available online at www.sciencedirect.com
Behavioural Brain Research 186 (2008) 23–31
Serial reversal learning and acute tryptophan depletion
Geoffrey van der Plasse
, Matthijs G.P. Feenstra
Netherlands Institute for Neuroscience (an Institute of the Royal Netherlands Academy of Arts and Sciences),
Meibergdreef 47, 1105 BA Amsterdam ZO, The Netherlands
Department of Anatomy and Neuroscience, VU University Medical Center, Amsterdam, The Netherlands
Received 7 April 2007; received in revised form 13 July 2007; accepted 15 July 2007
Available online 20 July 2007
Cognitive ﬂexibility (i.e. the ability to adapt goal-directed behaviour in response to changed environmental demands) has repeatedly been shown
to depend on the prefrontal cortex (PFC). Recent data from primate studies moreover show that depletion of prefrontal 5-HT impairs reversal
learning of visual stimuli [Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC. Prefrontal serotonin depletion affects reversal
learning but not attentional set shifting. J Neurosci 2005;25:532–8; Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC. Cognitive
inﬂexibility after prefrontal serotonin depletion is behaviorally and neurochemically speciﬁc. Cereb Cortex 2007;17:18–27].
It is not clear however if 5-HT serves a general role in reversal learning or if it is involved only in speciﬁc reversal problems. A ﬁrst aim of these
experiments was to study the role of 5-HT in serial reversal learning of a spatial discrimination. Literature has, moreover, repeatedly shown that the
PFC is involved in the initial acquisition of a reversal problem but hardly when the task is well practiced. A second aim concerns the role of 5-HT
in early versus late reversal learning. With the current experiment, we aim to clarify whether 5-HT is differentially involved in early versus late
reversal learning. To this end, we tested rats on a serial two-lever reversal task and induced a temporary reduction of 5-HT availability in these rats
by restricting dietary intake of the 5-HT precursor tryptophan at an early and a late reversal. Our results indicate that acute tryptophan depletion
(ATD) did not affect either early or late reversal learning, nor extinction and suggest that spatial reversal learning, in contrast to visual reversal
learning, might not be dependent on 5-HT. The data furthermore provide insight in the behavioural strategies employed in serial reversal learning
and suggests the formation of a learning-set.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Serotonin; ATD; Spatial; Learning-set; Perseveration
Cognitive ﬂexibility, or the ability to adapt ongoing behaviour
to environmental changes, depends critically on the prefrontal
cortex (PFC) and its connection with thalamic and striatal areas
[e.g. 4]. Functions that underlie this ability, moreover, like
response selection, inhibition and extinction, as well as encoding
of reward-related information have been shown to be impaired
after lesioning or inactivation of prefrontal cortex (PFC) areas
[for a review, see 12,42].
Corresponding author at: Netherlands Institute for Neuroscience (an Institute
of the Royal Netherlands Academy of Arts and Sciences), Meibergdreef 47, 1105
BA Amsterdam ZO, The Netherlands. Tel.: +31 20 5665500;
fax: +31 20 5666121/6961006.
E-mail address: firstname.lastname@example.org (G. van der Plasse).
In studies of cognitive ﬂexibility, reversal learning is a com-
monly used paradigm in which a previously learned stimulus –
reinforcement or action – outcome association is reversed and
subjects have to adjust their behaviour accordingly. Performance
on various behavioural tasks based on this paradigm have been
shown to depend on the PFC in both primates [1,11,24,31,35]
and rats [7,14,25,28,33,47,48,54].
Previous work stressed the importance of mono-aminergic
innervation of the PFC in cognitive ﬂexibility in general [e.g.
6,27,41] and reversal learning in particular [32,53]. Evidence for
a speciﬁc role of prefrontal 5-HT is suggested by work of Clarke
and collaborators [8–10] in primates. It is not clear however if 5-
HT serves a general role in reversal learning or if its involvement
depends on the particular stimulus modality.
Previously we developed a reversal task  with which we
showed medial PFC dopamine (DA) involvement in reversal
learning of a spatial discrimination. A decreased performance
0166-4328/$ – see front matter © 2007 Elsevier B.V. All rights reserved.