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. In addition to the role of motivational cues, deficits in cognitive functioning play a key role in addiction. In particular, cognitive functions that involve behavioural control, and also control over behaviour when confronted with motivationally relevant drug cues, appear to be crucial for the development and course of addictive disorders. We will study the neural substrates of these two processes and their interaction. The 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 addiction. We therefore present a pharmacological challenge study with (1) a cognitive enhancer (studied in humans with cocaine dependence: modafinil), and (2) an agent influencing the motivational relevance of drug cues in animals (N-acetylcysteine). Thirty alcohol dependent patients, thirty cocaine dependent patients and thirty healthy controls will be tested using neurocognitive tasks on impulsivity and motivational drug cues in an fMRI study both before and after acute administration with N-acetylcysteine, modafinil, or placebo.

It is expected that the cocaine and alcohol dependent subjects will display higher impulsivity on impulsivity-related tasks in the current study compared to healthy control subjects and show altered frontostriatal activity associated with impulsivity.

N-acetylcysteine is expected to have its primary effect on motivationally relevant cues (i.e. drug cues, reward cues), and is thus expected to influence mesocorticolimbic and orbitofrontal brain functioning.

Several studies have indicated that modafinil strongly reduces impulsive behaviour. Therefore, it is expected that the inclusion of modafinil will primarily exert its effect on brain areas related to cognitive control, such as the dorsolateral prefrontal cortex and the anterior cingulate cortex.

1. First fMRI session with placebo or medication;

2. Second fMRI session with placebo or medication (cross-over design) within two weeks after first session;

3. Follow-up after 3 and 6 months to investigate relapse rate.

Cocaine dependent, alcohol dependent patients and healthy controls will receive an acute administration with both NAC/modafinil and a placebo during two fMRI sessions in a double-blind cross-over design. Subjects will be randomly allocated to receive placebo or medication during the first session. During the two sessions, subjects will perform cognitive tasks inside and outside a MRI scanner. Functional and structural MRI images will be obtained. Subjects will also fill out questionnaires and a diagnostic interview will be administered. In addition, urine and DNA samples will be obtained.