Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state

Abstract

Bo Fu,1 Shao-Nan Wen,1 Bin Wang,1 Kun Wang,2 Ji-Yan Zhang,3 Xie-Chuan Weng,1 Shao-Jun Liu1 1State Key Laboratory of Proteomics, Department of Neurobiology, Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China; 2Department of Occupational Medicine, Tianjin Institute of Environmental and Occupational Medicine, Tianjin 300050, China; 3Department of Molecular Immunology, Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China Purpose: Ventral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methods: We used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.Results: We used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.Conclusion: The present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder. Keywords: chronic neuropathic pain, depression, dopaminergic neuron, LFP, VTA

Keywords

• Chronic neuropathic pain
• depression
• dopaminergic neuron
• LFP
• VTA