Anti‐manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine

Author:

Varela Roger B.1,Boschen Suelen L.23,Yates Nathanael1,Houghton Tristan1,Blaha Charles D.2,Lee Kendall H.2,Bennet Kevin E.24,Kouzani Abbas Z.5,Berk Michael6,Quevedo João78910ORCID,Valvassori Samira S.10,Tye Susannah J.1111213ORCID

Affiliation:

1. Functional Neuromodulation and Novel Therapeutics Laboratory, Asia Pacific Centre for Neuromodulation Queensland Brain Institute, The University of Queensland Brisbane Queensland Australia

2. Department of Neurologic Surgery, Neural Engineering Laboratories Mayo Clinic Rochester Minnesota USA

3. Department of Neurologic Surgery, Applied Computational Neurophysiology and Neuromodulation Laboratory Mayo Clinic Rochester Minnesota USA

4. Division of Engineering Mayo Clinic Rochester Minnesota USA

5. School of Engineering Deakin University Geelong Victoria Australia

6. School of Medicine IMPACT—The Institute for Mental and Physical Health and Clinical Translation, Barwon Health, Deakin University Geelong Victoria Australia

7. Faillace Department of Psychiatry and Behavioral Sciences, Center for Interventional Psychiatry, McGovern Medical School The University of Texas Health Science Center at Houston (UTHealth Houston) Houston Texas USA

8. Faillace Department of Psychiatry and Behavioral Sciences, Center of Excellence on Mood Disorders, McGovern Medical School The University of Texas Health Science Center at Houston (UTHealth) Houston Texas USA

9. Faillace Department of Psychiatry and Behavioral Sciences, Translational Psychiatry Program, McGovern Medical School The University of Texas Health Science Center at Houston (UTHealth) Houston Texas USA

10. Translational Psychiatry Laboratory, Graduate Program in Health Sciences University of Southern Santa Catarina (UNESC) Criciúma Santa Catarina Brazil

11. Department of Psychiatry and Psychology, Translational Neuroscience Laboratory Mayo Clinic Rochester Minnesota USA

12. Department of Psychiatry University of Minnesota Minneapolis Minnesota USA

13. Department of Psychiatry and Behavioral Sciences Emory University Atlanta Georgia USA

Abstract

AbstractBackgroundTreatment 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.AimThe 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).MethodsWistar rats were given 14 days of m‐amph injections, and on the last day, animals were submitted to 20 min 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 in different groups of animals through open‐field tests and fast‐scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry.ResultsM‐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.ConclusionThese 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.

Funder

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

National Health and Medical Research Council

Publisher

Wiley

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