Addictive Behaviour

Program committee

Guus Smit (program leader)
Ton Schoffelmeer (program leader)

Huibert Mansvelder
Brenda Penninx
Sabine Spijker
Dick Veltman
Jacqueline Vink
Taco De Vries

Rationale

Addiction is a widely occurring psychiatric disorder that may develop in vulnerable individuals upon repeated voluntary exposure to rewarding/reinforcing stimuli. It is a chronic relapsing disorder of appetitive motivation characterized by obsessive craving for the reinforcer and its consumption, despite awareness of the long-term negative consequences. The central feature of drug addiction is compulsive drug use, i.e. loss of control over apparently voluntary acts of drug-seeking and drug taking. From a neurobiological point of view, the leading hypothesis is that addictive behaviour is caused by persistent changes in neurotransmission in the mesocorticolimbic system, mediating the transition from voluntary to habitual and compulsive drug use. This research program will address the motivational and cognitive processes in the brain underlying the acquisition of addictive behaviour and relapse during abstinence, focusing on tobacco smoking (nicotine addiction) and alcoholism in the coming years. The program Addictive Behaviour is a basic translational research program addressing fundamental principles of addictive behaviour with a human research component. The program is carried out by research groups with an excellent international reputation in animal and human studies on addictive behaviour and other (co-morbid) psychiatric disorders. By means of a highly multidisciplinary approach, this reseach program aims to provide novel vistas for the development of pharmacotherapeutical intervention strategies for the treatment of addiction.

Executive summary

We will address the development of drug and alcohol addiction as well as relapse to compulsive drug- and alcohol-seeking behaviour during abstinence in both laboratory animals (rodents) and humans. The availability of operant animal models to study the motivational and cognitive aspects of addiction, the availability of advanced in vitro and in vivo neurophysiological techniques and that of state-of-the-art genomics/proteomics expertise in this program is unique. Moreover, the availability of genome-wide data in NESDA as well as the Dutch Twin Register allows us to identify genetic risk factors, whereas the application of brain imaging enables us to examine the motivational and cognitive aspects and pharmacotherapy of relapse behaviour in humans. We will examine how individual differences in cognition (such as attention and impulsivity) and emotion (anxiety), primarily addressed in other research programs of the intitute, determine the individual susceptibility to develop addictive behaviour and the individual’s risk to relapse to drug- and alcohol-seeking behaviour during abstinence. In this respect, animal and human studies aimed to identify the genetic basis of addiction proneness (identification of vulnerability genes, including studies in twins), will be initiated. Our animal studies address the psychopharmacology and neurobiology of cue-induced relapse to drug- and food-seeking behaviour as well as that of reconsolidation of drug/food-related memories during abstinence. Clinical studies are being performed in drug addicts, employing brain imaging (fMRI) and pharmacotherapy, in order to examine the functional anatomy and pharmacotherapy of relapse behaviour (predicted by animal studies). The following topics will be addressed:

Consolidation and reconsolidation of reward-related memories

The psychopharmacology, molecular neurobiology (genomics, proteomics) and (ex vivo and in vivo) neurophysiology of cue-induced reinstatement of drug- and food-seeking behaviour is currently under investigation. In this respect, innovative molecular intervention technologies (in vivo gene transfer) will be further developed.

Vulnerability traits

Using behavioural paradigms to quantify attention, distinct measures of impulsivity and behavioural flexibility in rodents, we will study the role of distinct neurocognitive characteristics as risk factors for the acquisition of addictive behaviour and relapse during abstinence. Neuroimaging techniques (primarily fMRI in humans) will be used to examine brain activity in alcoholics and cocaine addicts during performance of operant tasks on impulsivity and motivation, prior to and following chronic treatment with registered anti-craving compounds or cognitive enhancers. The effect of these compounds on relapse will also be monitored in humans.

Genetics of addiction proneness

Employing the Netherlands Twin Register (NTR) and using the differential social and genetic relatedness of mono- and dizygotic twins, siblings, parents and spouses, we will investigate to which extent individual differences in smoking, alcohol drinking and high-calorie food consumption are influenced by genetic factors and explore the chromosomal regions (linkage studies) and candidate genes (association studies) involved. Moreover, taking advantage of the NESDA study and genome-wide data among NESDA responders (with and without addictive behaviours), the genetics of addiction proneness will be examined in patients suffering from depression, including linkage and association studies in close collaboration with NTR.

Future perspectives

We envisage the following major deliverables of our research efforts:

• Identification of genetic risk factors (polymorphisms) for the acquisition of nicotine and alcohol addiction.
• Identification of novel targets (e.g. synaptic proteins) for pharmacotherapeutical intervention of relapse to drug and/or alcohol consumption during abstinence.
• Identification of distinct impulsivity traits as treatable risk factors for the development of compulsive nicotine- and alcohol-seeking behaviour.
• Synthesis and in vivo application of compounds targeting nicotinic and glutamate receptors as putative future medicines.