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

Abstract

<b><i>Background:</i></b> 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. <b><i>Objectives:</i></b> 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). <b><i>Methods:</i></b> 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 [<sup>18</sup>F]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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> 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.

Neuromodulation in Psychiatric disorders: Experimental and Clinical evidence for reward and motivation network Deep Brain Stimulation: Focus on the medial forebrain bundle

“…NAC, nucleus accumbens; Hipp, hippocampus; VTA, ventral tegmental area; DRN, dorsal raphae nucleus; SNC, substantia nigra pars compacta; CPu, caudate putamen (=dorsal striatum); PFC, prefrontal cortex; Tu, olfactory tubercle. The references used in the figure: 1 (Ewing et al., 1983); 2 (Kuhr et al., 1984); 3 (Stamford et al., 1986); 4 (Stamford et al., 1987); 5 (Kuhr et al., 1987); 6 (Gonon, 1988); 7 (Howard et al., 2013); 8 (Furlanetti, et al., 2015); 9 (Furlanetti et al., 2015); 10 (Bregman et al., 2015); 11 (Klanker et al., 2017); 12 (Dandekar et al., 2017); 13 (Dandekar et al., 2019); 14 (Thiele et al., 2020); 15 (Ashouri Vajari et al., 2020); 16 (Settell et al., 2017); 17 (Friedman et al., 2012)…”

“…The raclopride‐treated mfb DBS animals had increased levels of D1R and D2R mRNA suggestive of stimulation‐mediated upregulation of dopamine receptors. The data indicate that one potential mechanism of chronic mfb DBS is via the modulation of the midbrain dopaminergic system, including its post‐synaptic receptor profile (Thiele et al., 2020).…”

A narrative review on invasive brain stimulation for treatment-resistant depression

“…Similarly, increased mRNA expression of dopamine receptors D1 and D2 was reported following chronic and continuous MFB-DBS. 164 MFB-DBS also triggered dopamine release in the distant NAc region in a rodent model of depression. 165 Moreover, the importance of BDNF and neuroimmune cytokines in a stress-driven chronic depression model has been described, as well as their restoration following chronic MFB-DBS treatment.…”

“The Heart Asks Pleasure First”—Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive–Compulsive Disorder

“…DBS of the slMFB, and its proposed mechanism of action, highlights the role of DA and the greater reward/MAINTENANCE system in depression and OCD genesis, albeit our ideas for pathology are distinct for both pathologies (see above). It is one focus of our research to look at monoaminergic and other transmitters' transmissions in a translational approach [17,20,75,[91][92][93][94]. The region of stimulation-the mesencephalic ventral tegmentum-as the seat of the A10 DA cellular group in conjunction with the mammillary bodies, forms a complex basal regulation center, relevant as a basis for the MAINTENANCE system but also for positive affect display [95].…”