Pharmacological Modulation of Belief Salience
Condition: Haloperidol; Placebo; L-DOPA
Study type: Interventional
Phase: Phase 1

Summary: 
      To provide an initial test of the hypothesis that dopamine mediates the motivational salience
      of stimuli beyond simple stimulus-reinforcement associations, the researchers propose to
      undertake a study of the modulation of a) levels of agreement or disagreement with; b) the
      perceived self- relevance; and c) the perceived interest of propositions expressing beliefs
      and values in healthy male volunteers using Ii) a dopamine antagonist (the D2-blocker
      haloperidol), and (ii) a dopamine precursor L-Dopa to increase CNS dopamine transmission.

      The researchers will also administer the Salience Attribution Task (SAT) which will allow
      researchers to assess reward-learning processing of simple stimuli using a reaction-time
      game. This task was utilised by Roiser et al in order to explore whether delusions in
      medicated patients with schizophrenia were related to impairments in associative learning.
      The authors hypothesised that associative learning was influenced by D2 receptor blockade.
      The researchers extend this approach to examine the effect of dopamine modulation on the SAT
      as a measure of associative learning, a basic neuropsychological process that may be involved
      in the attribution of salience to beliefs.

      Finally, the researchers will ask participants to perform a within-subjects dictator game to
      understand the influence of dopaminergic manipulation of the live attribution of harm
      intention to partners. The task has been previously validated online. Participants will play
      against 3 partners in a random order in each drug condition. Each partner will play the
      participant for 6 trials. One partner will always be fair, one will always be unfair, and one
      will be 50% unfair. We aim to understand whether potentiating dopamine has an additive effect
      on the harm intention attributions toward partners, regardless of the behaviour of the
      partner.
    

Detailed description: 
      Delusions in psychiatry are viewed as a form of aberrant belief. Consequently it is important
      to understand the cognitive and neural processes involved in beliefs to provide insights into
      how these processes go awry in the formation of delusions. Beliefs have been defined as 'a
      disposition to express, assent to, or otherwise act in accordance with some proposition'.
      Some beliefs are widely held within a given society (e.g the earth revolves around the sun;
      eating humans is wrong), whereas others vary in association with subcultural and individual
      differences (e.g God created the universe; abortion is wrong). Similarly, the conviction or
      agreement with which an individual's beliefs and values are held may change over time, to the
      extent that some beliefs and values may be lost, and others acquired. Also, the perceived
      relevance of beliefs and values to oneself may vary. For example, beliefs that the 'earth
      revolves around the sun' and that 'global warming is occurring' may both be held with
      conviction, but the latter may be perceived as having higher relevance to the self in terms
      of risk, and potential life-style changes. Hence, self-relevance is a dimension of beliefs
      that is potentially dissociable from the conviction (level of agreement) with which a belief
      is held. Further, some propositions expressing beliefs and values may be regarded as more
      interesting than others. This raises the question of what neurobiological processes
      contribute to the sense of conviction for, and perceived self-relevance and interest of
      beliefs and values?

      The mesolimbic dopamine system is a candidate neural system implicated in mediating the
      motivational salience of perceptions and ideas, 'whereby events and thoughts come to grab
      attention, drive action, and influence goal-directed behaviour because of their association
      with reward or punishment'. In human studies, haloperidol has been used to show that dopamine
      activity influences action-value estimates represented in the striatum during instrumental
      conditioning, as would be expected from earlier studies of feedback-based learning. Still
      other data suggest that brain regions rich in dopaminergic inputs play a role in processing
      the salience of rewarding events. What is not known is if these dopaminergic rich regions
      also modulate the motivational salience of more complex 'stimuli' including ideas and
      beliefs.

      Main hypothesis:

      Prediction 1:

      At a neurobiological level, the hypothesis is that the mesolimbic dopamine system is
      recruited to tag representations (ideas and beliefs) as motivationally salient. Potentiation
      of dopamine transmission should increase salience of beliefs (as indicated by increases in
      agreement, self-relevance and interest toward propositions within science, paranormal,
      politics, moral, and religious themes in the Beliefs and Values Inventory while attenuation
      of dopamine transmission should be associated with decreased salience. Answers of items
      within themes will be summed to create summary scores that will be split by agreement,
      interest, and self-relevance dimensions.

      Prediction 2:

      Potentiating dopamine be associated with increased attribution of harmful intent to partners
      across all trials (but trait paranoia will not be associated with variation in attributions
      of self-interest) of a within-subjects dictator game.

      Prediction 3:

      Attribution of harmful intent to different dictators will follow a dose-response relationship
      (fair < partially fair < unfair) across all ranges of dopamine potentiation. However, L-Dopa
      conditions will have a higher baseline of average harmful intent. There will be no
      interaction between dopamine manipulations and dictator fairness on attribution of harmful
      intent.

      If these hypotheses receive empirical support, it would be relevant to understanding the role
      of the dopamine system in normal cognitive processes involved in expressing or acting in
      accordance with beliefs. It would also be relevant to determining the role of dopamine
      dysregulation in psychosis (in delusion formation). Also, reduced levels of the
      meaningfulness of experience following antipsychotic administration (as indexed by reduced
      agreement for and perceived self- relevance and interest of beliefs and values) would
      identify a potential reason for non-compliance with antipsychotic treatment.

      Supplementary hypotheses:

      There will be an interaction between condition (placebo, dopamine blockade, dopamine
      potentiation) x dimension (agreement, self-relevance, interest), whereby self-relevance and
      interest are affected more by dopamine modulation than agreement. This might explain why
      patients with delusions who are given antipsychotics will continue to say that they believe
      'x,' but don't think about it as much, and cease to act upon it.

      Aims:

      To provide an initial test of the hypothesis that dopamine mediates the motivational salience
      of stimuli beyond simple stimulus-reinforcement associations, we propose to undertake a study
      of the modulation of a) levels of agreement or disagreement with; b) the perceived self-
      relevance; and c) the perceived interest of propositions expressing beliefs and values in
      healthy male volunteers using i) a dopamine antagonist (the D2-blocker haloperidol), and (ii)
      a dopamine precursor L-Dopa to increase CNS dopamine transmission.

      The researchers will also administer the Salience Attribution Task (SAT) which will allow the
      researchers to assess reward-learning processing of simple stimuli using a reaction-time
      game. This task was utilised by Roiser et al. in order to explore whether delusions in
      medicated patients with schizophrenia were related to impairments in associative learning.
      The authors hypothesised that associative learning was influenced by D2 receptor blockade. We
      extend this approach to examine the effect of dopamine modulation on the SAT as a measure of
      associative learning, a basic neuropsychological process that may be involved in the
      attribution of salience to beliefs.

      Finally, the researchers will ask participants to perform a within-subjects dictator game to
      understand the influence of dopaminergic manipulation of the. Participants will play against
      3 partners in a random order in each drug condition. Each partner will play the participant
      for 6 trials. One partner will always be fair, one will always be unfair, and one will be 50%
      unfair. We aim to understand whether potentiating dopamine has an additive effect on the harm
      intention attributions toward partners, regardless of the behaviour of the partner.
    

Intervention name(s): Placebo - Cap; L-dopa; Haloperidol
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Administration of Placebo by pill.; Administration of L-dopa by pill.; Administration of Haloperidol by pill.
Intervention MeSH terms: Haloperidol; Haloperidol decanoate
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Placebo x Haloperidol x LDOPA
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science