Chemogenetic inhibition of dopaminergic neurons reduces stimulus-induced dopamine release, thereby altering the hemodynamic response function in the prefrontal cortex

Abstract

Abstract To investigate the effect of endogenously released dopamine on the stimulus-induced blood oxygen level–dependent (BOLD) responses, we used rats expressing inhibitory designer receptors exclusively activated by designer drugs (DREADDs) in neurons of the ventral tegmental area (VTA) and electrically stimulated the fimbria/fornix. This stimulation activates multiple components of the mesolimbic dopamine system, as demonstrated by the BOLD signal changes during functional magnetic resonance imaging (fMRI) and dopamine release in the nucleus accumbens (NAcc) as detected by in vivo fast-scan cyclic voltammetry. Activation of inhibitory DREADDs by clozapine N-oxide (CNO) significantly reduced stimulus-induced dopamine release and the BOLD response in the NAcc. In contrast, the concurrently induced BOLD response in the medial prefrontal cortex (mPFC) was not significantly reduced after CNO administration, but the hemodynamic response was shifted to the left. Specifically, the Granger causality test showed that the temporal relationship between the BOLD signal changes in the hippocampus and the mPFC, changed. Under control conditions (i.e., in the absence of CNO), the BOLD signal changes in the mPFC and NAcc clearly preceded the BOLD signal changes in the right hippocampus, whereas in the presence of CNO this was only the case for the BOLD signal changes in the NAcc. In the control rats, that is, the rats that received a control virus and thus did not express DREADDs in the VTA, this CNO-mediated effect was not present. Our results indicate that activation of the endogenous dopaminergic system has region-specific effects on the stimulus-induced BOLD responses, so there is no generally applicable fMRI parameter that clearly indicates increased activity of the dopaminergic system.