Deep Brain Stimulation of the Medial Forebrain Bundle in a Rodent Model of Depression: Exploring Dopaminergic Mechanisms with Raclopride and Micro-PET

Abstract

Background: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. Objectives: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). Methods: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [¹⁸F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. Results: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. Conclusion: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.