Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex

TY - JOUR

T1 - Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex

AU - Wächtler, Christian Ole

AU - Chakroun, Karima

AU - Clos, Mareike

AU - Bayer, Janine

AU - Hennies, Nora

AU - Beaulieu, Jean Martin

AU - Sommer, Tobias

N1 - Copyright © 2020 Elsevier Ltd. All rights reserved.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

U2 - 10.1016/j.euroneuro.2020.04.008

DO - 10.1016/j.euroneuro.2020.04.008

M3 - SCORING: Journal article

C2 - 32439227

VL - 35

SP - 126

EP - 135

JO - EUR NEUROPSYCHOPHARM

JF - EUR NEUROPSYCHOPHARM

SN - 0924-977X

ER -