Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

Abstract

AimsTo investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery.Materials and MethodsIn this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury.ResultsSequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion.ConclusionChronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.

Amantadine preserves dopamine level and attenuates depression-like behavior induced by traumatic brain injury in rats

“…Moreover, DA metabolites (DOPAC and HAV) increased significantly in the amantadine-treated rats at this time point, which may be associated with residual DA neurons hyperfunction and increased DA release metabolism [53]. The transient increase of DA at the subacute phase (1-2 weeks after surgery) may result from the spontaneous regrowth of DAergic fibers [54,55] and decreased dopamine transporters (DAT) which play a key role in extracellular DA reuptake [51,56]. Our study revealed that post-TBI depression may be related to the dopaminergic concentration in the striatum, and hence preserving the normal concentration level may be a potential target for post-TBI depression therapy [Figs.…”

Executive (dys)function after traumatic brain injury: special considerations for behavioral pharmacology

“…Several of these drugs show promise in reducing chronic signaling deficits following injury, such as increasing DA levels in the striatum and substantia nigra while also reducing neuronal death ( Zhu et al , 2000 ; Wagner et al , 2008 , 2009 ; Rau et al , 2012 ; Huang et al , 2014a , 2014b ; Wang et al , 2014 ; Tan et al , 2015 ; Phelps et al , 2017 ). In turn, performance is improved acutely for TBI animals on traditional tasks for assessing cognitive deficits, such as the MWM and novel-object recognition tasks, following administration of such therapeutic agents ( Zhu et al , 2000 ; Wagner et al , 2008 , 2009 ; Rau et al , 2012 ; Huang et al , 2014a , 2014b ; Wang et al , 2014 ; Tan et al , 2015 ; Leary et al , 2017 ; Phelps et al , 2017 ). At the same time, pharmacotherapies that reduce DA signaling, such as haloperidol and resperidone, exacerbate acute MWM deficits, in both TBI and non-TBI animals ( Wilson and Hamm, 2002 ; Kline et al , 2007 , 2008 ; Hoffman et al , 2008 ), giving support for a significant contribution of reduced DA signaling in cognitive dysfunction.…”

Psychotropics and Neuroprotection: Literature Review and Case Series Report

“…Pramipexole has neuroprotective effect against glutamate-induced neurotoxicity [84]. Amantadine leads to recovery and decreases dopamine-release deficits in TBI patients [85,86]. Chronic use of benzodiazepines offers no neuroprotection while immediate administration after ischemia is neuroprotective [87].…”