Behavioural and physiological measures of the effects of norepinephrine on adapting to change

Several theorists have suggested that neuromodulatory systems are involved in
the response of the brain to environmental change (Hasselmo & Barkai, 1995;
Lisman & Grace, 2005). One of the neuromodulators of most interest in this
regard is norepinephrine (NE). Microdialysis studies have shown increased
levels of NE in the frontal cortex and the hypothalamus in response to novel
environments (McQuade, Creton, & Stanford, 1999). Moreover,
computational-modeling studies have suggested that NE plays an important role
in optimizing inference and learning in dynamic environments (Yu & Dayan,
2005). However, no study has sought to manipulate norepinephrine levels to
study its effects on responses to change.
Atomoxetine is a very selective norepinephrine reuptake inhibitor (SNRI), in
contrast with other SNRIs that also affect the levels of dopamine and
serotonin. It can therefore be used to investigate the role of norepinephrine
in responding to changes in the environment.

It is not guaranteed that all participants will react in the same way to a
Atomoxetine challenge. In particular, it is likely that the response will vary
as a function of personality and genetic status. We will determine genotypes
for genes related to the NE system and trait anxiety for each participant.
Genetic variation has been shown to modulate responses to noradrenergic drugs
(e.g., de Rover et al., in revision; Hughes, Watkins, Blumenthal, Kuhn, &
Sherwood, 2004; Luksys, Gerstner, & Sandi, 2009; Mizuki, Suetsugi, Ushijima, &
Yamada, 1996; Ressler & Nemeroff, 2000; White & Depue, 1999). Hence, including
these measures may allow us to explain a potentially large part of the
inter-individual variance in the effects of Atomoxetine on cognition.

The present project aims to determine the role of NE transmission in reactions
to environmental change, both behavioral and psychophysiological, in healthy
participants.

Counter balanced within-subject (placebo controlled) design, using behavioral
measures of response accuracy and electroencephalographic measures of brain
activity (EEG) during execution of cognitive tasks. As covariates, personality
traits and genotype will be measured.

Single oral dose of atomoxetine (60 mg), and placebo, double-blind.

Participants will visit the EEG laboratory of the Faculty of Psychology (Van
der Boechorststraat 1 building), on two separate occasions with 7 days in
between to avoid carryover and reduce practice effects.
Pre-Testing: A personality questionnaire will be filled out before the first
session by the internet, as a requirement for registration in the study. Before
the intake of the drug, people will be tested with a memory span task, to
determine their baseline level. Moreover, saliva will be collected to determine
genotype with respect to several polymorphisms related to norepinephrine.
Day 1: First EEG recording. Half of the participants will receive Atomoxetine
(60 mg), and the other half placebo, in a double blinded way. Participants will
be asked to perform three tasks: an audiovisual task to evaluate the Von
Restorff effect, a visual a visual paired comparison task, and a predictive
inference task.
Day 2: Second EEG recording. Same as day one, but the groups receiving a
placebo and Atomoxetine will be inverted.
None of the treatments and measurements causes any significant risk to the
long-term health or well-being of the participants. Possible short-term side
effects of the drug can include fatigue, headache, stomach ache, dizziness,
drowsiness, vomiting, akathisia, and dry mouth.