Motivation, dopamine and schizophrenia: A multi-modal functional neuroimaging approach.

The goals of this study were to investigate possible alterations in behavior and brain activations resulting from single dose treatment of two different types of antipsychotic drugs, aripiprazole and haloperidol, compared to placebo. The drugs were studied using a functional neuroimaging approach targeting brain functions previously shown to be disturbed in psychosis. The first function studied was the effect of incentive motivational stimuli and the other function was executive functioning. The first task was designed from a frequently used animal model, conditioned avoidance response, in use with functional magnetic resonance imaging (fMRI). The task targeting incentive motivational salience was firstly conducted without drug intervention for validation. We showed that motivationally salient cues predicting aversive events were associated with stronger activations in the mesolimbic system, in particular the ventral striatum, as compared to neutral stimuli. Further, there was a stronger functional connectivity between the ventral striatum and the frontal cortex in the motivated condition. Subsequently, when participants were conducting this task when administered haloperidol the ventral striatum activation was attenuated. Participants given aripiprazole displayed mesolimbic activations intermediate of subjects given placebo and haloperidol. Using the same sample but targeting executive functioning using the Tower of London problem solving task, there were no significant differences in activations in the frontal cortices between participants given haloperidol and participants given aripiprazole. These results showed that activations obtained using fMRI is sensitive to changes from pharmacological manipulation. The group difference in the motivational task implies different effects of haloperidol and aripiprazole which probably is related to dopamine transmission. This effect might be of importance when interpreting neuroimaging studies in medicated patients. Taken together, these results suggest that pharmacological fMRI may be a useful tool for facilitating drug development for the treatment of psychosis.

Schizophrenia is a severe mental disorder with a large impact on global health and very costly for the society. The disorder is regarded as one of the biggest enigma in modern biomedicine, and the pathophysiology is poorly understood. The lack of knowledg e of biological mechanisms makes the development of new pharmacological agents difficult. One of the most studied pathophysiological mechanisms is abnormal dopamine system and it is generally accepted that abnormalities of dopamine neurotransmission of so me form is present in schizophrenia. Furthermore, several lines of evidence implicate that a dysfunctional motivational system, also involving dopamine neurotransmission, could explain several aspects of the clinical picture of schizophrenia. In the prese nt proposal we integrate the existing evidence linking dopamine and motivational defects to schizophrenia, and we suggest to use multi-modal neuroimaging protocols to study the mesolimbic dopamine systems to examine the role in motivational abnormalities and connect it to schizophrenia and antipsychotic drugs. We propose a series of experiments to systematically investigate the role of dopamine relate it to goal-directed behaviour and strategic decision making. To get the necessary information we will use functional neuroimaging methods such as functional magnetic resonance imaging, pharmacological magnetic resonance imaging, perfusion and positron emission tomography. This will provide new knowledge about the mechanisms underlying antipsychotic treatment , which is of large value for the development of more efficacious drugs. Further, it will give us a very detailed but broad insight into the pathophysiology of schizophrenia, the behavioural consequences of abnormal dopamine transmission and the treatmen t of the disorder.