Impulsivity, a risk factor in relapse to substance use disorder: investigating neural substrates before and after pharmacological challenges.

During the development of substance dependence, drug-associated stimuli become
increasingly relevant to the substance user. Studies on these motivational
processes have greatly contributed to our understanding of the neurobiology of
addiction, but so far the pharmacological and psychotherapeutic manipulation of
these motivationally relevant drug cues have been moderately successful at
best, and relapses after treatment are the rule rather than the exception.
In addition to the role of motivational cues, there is growing evidence that
deficits in cognitive functioning play a key role in the development, course,
and relapse of substance use disorders. In particular, cognitive functions that
involve control over one*s own behaviour, and thus also over behaviour when
confronted with motivationally relevant drug cues, appear to be crucial. In
human studies, higher impulsivity (disinhibition), diminished planning and
decision making abilities are present in both alcohol- and drug dependent
persons .
Although impulsivity and the motivational properties of drugs have been studied
with various paradigms clinically and preclinically, the relations between
these processes and their influence on the course of addiction and treatment
success have been largely ignored. In this study, we will therefore study these
two processes and their interaction, since it is likely that a diminished
control over behaviour (impulsivity) will also influence behaviour that a
(former) substance dependent person displays when confronted with
motivationally relevant drug cues. For instance, the presence of a glass of
beer will have a higher impact on behaviour when (a) a higher response to
relevant alcohol cues is present, and (b) higher impulsivity is present,
compared to someone who has normal impulsivity, and thus has better control
over the response to motivationally relevant drug cues. We will employ
neuroimaging techniques to shed more light on the neural substrate of abnormal
emotion processing and cognitive deficits in drug addicts and the predictive
value of aberrant brain activation patterns in relapse into drug abuse.
The postulated interrelation between poor impulse control, motivational
relevance of drug cues, and vulnerability to relapse predicts that improving
cognitive performance may represent a promising new approach in the treatment
of addictive behaviours. We therefore propose pharmacological challenges with
(1) a known cognitive enhancer that has been studied in humans with cocaine
dependence (modafinil), and (2) an agent influencing the motivationally
relevance of drug cues in animals (N-acetylcysteine). By including these
pharmacological challenges, we will be able to determine their effect on
impulsivity, motivational relevance of drug cues, and on the prevention of
relapse.

The goals of the proposed study are: (1) to further elucidate the relations
between impulse control, motivational strength of drug cues, and brain
activation patterns (using fMRI); (2) to examine the relative strength by which
these processes are linked to vulnerability to relapse; and (3) to explore
whether pharmacological approaches that improve cognitive functioning may
provide new vistas for intervention strategies in the clinical management of
alcohol and drug dependence (using pharmacological challenges with modafinil
and N-acetylcysteine).

Alcohol dependent patients, cocaine dependent patients and healthy controls
will be tested using relevant neurocognitive tasks on impulsivity and
motivational value of drug cues in a fMRI study both with acute administration
with placebo and one of the two mediactions (participants in year 1 will
receive modafinil and participants in year 2 will receive N-acetylcysteine) in
a randomised double blind cross-over design. In addition, subjects will fill
out questionnaires and DNA samples will be taken in order to examine genetic
polymorphisms.

During the first year of the study, in our randomised double blind cross-over
design study, half of each group of participants (healthy controls, cocaine
dependent patients and alcohol dependent patients) will receive a single dose
of modafinil (200 mg) during the first fMRI session and placebo during the
second fMRI session. The other half of the group will receive placebo during
the first fMRI session and modafinil during the second fMRI session.

The participants who will be included in the second year of the study will
receive N-acetylcysteine (2400 mg) instead of modafinil.

The first session will take place in the research facility, requires about 5
hours and will include diagnostic interviews, questionnaires, behavioral tasks
inside and outside the scanner and taking DNA samples. During this session,
before performing the tasks in the MRI scanner, a single dose of placebo or one
of the two medications (year 1 modafinil or year 2 N-acetylcysteine) will be
administered. The second session will also take place in the research facility
and requires about 4 hours. During this session, questionnaires will be
administered and tasks will performed inside and outside the scanner. Again,
before scanning, during this second session, a single dose of placebo or one of
the two medications will be administered. No adverse health consequences are
known using functional MRI scans. The medications can have side-effects, but
the chance on having side-effects is expected to be small, because a single
dose is administered. Knowledge generated by this study can be of great
importance for treatment of addictive disorders.