D2 autoreceptors provide an important regulatory mechanism of dopaminergic neurotransmission. However, D2 receptors are also expressed as heteroreceptors at postsynaptic membranes. The expression and the functional characteristics of both, D2 auto- and heteroreceptors, differ between brain regions. Therefore, one would expect that also the net response to a D2 antagonist, i.e. whether and to what degree overall neural activity increases or decreases, varies across brain areas. In the current study we systematically tested this hypothesis by parametrically increasing haloperidol levels (placebo, 2 and 3 mg) in healthy volunteers and measuring brain activity in the three major dopaminergic pathways. In particular, activity was assessed using fMRI while participants performed a working memory and a reinforcement learning task. Consistent with the hypothesis, across brain regions activity parametrically in- and decreased. Moreover, even within the same area there were function-specific concurrent de- and increases of activity, likely caused by input from upstream dopaminergic regions. In the ventral striatum, for instance, activity during reinforcement learning decreased for outcome processing while prediction error related activity increased. In conclusion, the current study highlights the intricacy of D2 neurotransmission which makes it difficult to predict the function-specific net response of a given area to pharmacological manipulations.
