Abstract
Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). Wistar rats were given 14 days of m-amph injections, in the last day animals were submitted to 20 minutes of VTA DBS in two different patterns: intermittent low frequency stimulation (LFS) or continuous high frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated separately through open-field test and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.
Competing Interest Statement
RBV, NY, and SJT were supported the Asia Pacific Centre for Neuromodulation and Medtronic (Australia). MB was supported by a Senior Principal Research Fellowship (1156072). JQ received clinical research support from LivaNova; has speaker bureau membership with Myriad Neuroscience, Janssen Pharmaceuticals, and Abbvie; is stockholder at Instituto de Neurociencias Dr. Joao Quevedo; and receives copyrights from Artmed Editora, Artmed Panamericana, and Elsevier/Academic Press. The other authors have nothing to disclose.
Footnotes
Statistical data description were updated. Dopamine peak and reuptake time for each timepoint were individually corrected by the baseline values for each animal. The data was reanalysed and presented as percentage change from baseline in the new version of the manuscript. Figure 4 was modified to show the data in the new format, and a new figure (Figure 5) demonstrates the direct comparison of DBS effects across the experimental groups.
