Casper Schmidt, April 2016

Main supervisor: Arne Møller, Associate Professor

Traditionally, in neuroscientific behavioural research, impulsive and compulsive behaviour has been viewed as opposite ends of a spectrum; impulsivity driven by reward-seeking behaviour and compulsivity by seeking to avoid harm. However, recent evidence suggests that there are shared neuropsychological mechanisms for both impulsivity and compulsivity, in the form of behavioural disinhibition and dysfunctional inhibition of thoughts and behaviour, which is presumed to result either from failures in ‘top-down’ cognitive control of fronto-striatal circuits, or alternatively from over-activity within the striatal circuits of the brain. Although a lot is known about the roles of dopamine and serotonin, no research has been devoted to the basics of these neurochemical mechanisms when exposed to humans in combination.

The present PhD project seeks to delineate the relationship between the roles of dopamine and serotonin in rewards in medicated healthy volunteers and pathological gamblers, as well as to delineate relationship between dopaminergic and serotonergic roles in the neuropsychological measurements of impulsivity and compulsivity, correspondingly.

Testing pathological gamblers can be seen as a useful model of investigating addiction as it explores the neurobiology underlying addiction without the potential confounding effects of repeated substance misuse on brain function. In this light, it is interesting what the causes of the increase of dopamine and the decrease of serotonin will be on the traits of impulsivity and compulsivity in healthy volunteers, and how these results relate to an unmedicated group with profound deficits in impulsivity and compulsivity in the form of pathological gamblers.

The PhD project is threefold and should facilitate the output of three chapters or articles. The operationalization of the experiments will be a between subjects, partly double partly single blinded design, and will contain testing of four arms consisting of 25 healthy volunteers (double blind) and a fifth arm of 25 pathological gamblers (single blind); all participants will be between 18-45 years  and males. This will be done to isolate the neural and behavioural correlates of both increasing dopamine and depleting serotonin to investigate:

(1) How this affects neural activity in a task-based fMRI experiment

(2) Cognitive components of both impulsivity and compulsivity through cognitive behavioural testing

(3) How the two above-mentioned points relate to a placebo group of pathological gamblers, a group that elicits clear behavioural deficits in impulsivity and compulsivity.

By using these patients, it can be shown which of the manipulations to the healthy volunteers are closest to that of the pathological gamblers' neural activity and elicited behaviour in order to isolate the roles of dopamine and serotonin within both general subcomponents of impulsivity and compulsivity as well as how this relates to pathological gambling.

The experimental setup would be examined looking at four different arms or manipulations in healthy volunteers to correlate levels of brain activity and elicited behaviour with a fifth arm consisting of pathological gamblers. The corresponding arms will consist of the following manipulations:

(1) A group exposed to Levodopa Challenge (LC) to increase dopamine synthesis and release

(2) A group exposed to Tryptophan Depletion (TD) to decrease serotonin synthesis and release

(3) A group exposed to both LC and TD

(4) A group receiving a placebo, thus functioning as a control group

(5) A group of pathological gamblers receiving a placebo, functioning as a control group across patient/non-patient groups.

Generally, the hypotheses for the project are elaborate but in most cases, the hypothesis is that the three first arms will show higher components of impulsivity and compulsivity than the fourth arm, and this to a greater extent with the dual intervention relative to the single intervention. We also anticipate that pathological gamblers will have greater impulsive and compulsive behavioural characteristics relative to placebo.

Thus, this PhD project holds great promise to delineate this relationship on a general premise in the case of the healthy volunteers and specifically for knowledge about pathological gambling. Furthermore, the project applies to biomedicine in that it will help elucidate the molecular interactions of dopamine and serotonin and its effects in vivo and specifically on the behavioural level to psychiatric patient groups with profound impulsive and compulsive behavioural deficits. In this project, these processes are to be studied with the perspective of devising new strategies for knowledge about basic biomedical as well as therapeutic mechanisms.