Behavioral impairments and serotonin reductions in rats after chronic L-dopa

Abstract

Rationale L-dopa, the main therapeutic for Parkinson's disease (PD), has been shown to increase brain dopamine concentrations that are necessary for proper motor control; however, PD patients experience non-motor symptoms that are not improved or could be exacerbated by L-dopa. Objectives The purpose of this study is to determine the effects of L-dopa treatment on cognitive and affective behavioral responses of rats, as well their corresponding monoamine brain concentrations. Methods Rats were treated with L-dopa (6 mg/kg; twice daily) for 10 consecutive days. Sodium ascorbate (400 mg/kg), was co-administered with L-dopa to investigate the effects of antioxidant co-treatment on behavior and monoamine concentrations. Rats underwent cognitive and affective behavioral testing. Monoamine concentrations of several brain regions were analyzed. Results L-dopa treatment resulted in significant impairment in the performance in the Barnes maze and improvement in conditioned fear stress paradigms. Specifically, L-dopa caused an increase in latency to find the goal box during Barnes maze testing, and increased freezing behavior in context-induced conditioned fear testing. Furthermore, the rats in the conditioned fear stress experiments showed corresponding depletions in serotonin (5-HT) and its metabolite, 5-HIAA, in the dorsal DRN and the mPFC. The behavioral impairments as well as monoamine depletions were blocked by ascorbate co-treatment. Conclusions Chronic L-dopa may contribute to non-motor symptoms related to spatial memory and fear. These effects may be attributable to a dysregulation of brain 5-HT caused by L-dopa treatment. The results presented here provide further rationale for investigating adjunctive therapeutics to L-dopa for PD, such as antioxidants.

Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients

“…It has been reported that L-dopa therapy may be toxic to serotoninergic neurons in cell cultures by oxidative mechanisms producing highly reactive quinone species that reduce serotoninergic neurons 18 . These findings also have been observed “ in vivo ” by similar oxidative mechanisms producing a significant decrease in serotonin and 5HIAA metabolite 19 , as well as affecting the behaviour and cognitive functions in animal models 19 . However, no differences were observed when compared urinary aMT6s values between naive GTPCH patients and those under L-dopa/carbidopa treatment.…”

Cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention in the rat

“…5-HT play a key role in memory formation by interacting with other neurotransmitters/exerts its effect through their seven (5-HT 1 –5-HT 7 ) subclass of receptors ( Meneses, 1999 , 2007 , 2013 ; Meneses et al, 2011 ; Perez-Garcia and Meneses, 2009 ; Hoyer et al, 2002 ). Although evidence from Aplysia to human points at a functional role of serotonergic transmission in learning and memory, the underlying mechanism is depends on the level of 5-HT ( Barbas et al, 2003 ; Meyer et al, 2009 ), and the depletion of 5-HT could affect the memory formation ( Kaang et al, 1993 ; Barbas et al, 2003 ; Seyedabadi et al, 2014 ; Stansley and Yamamoto, 2015 ).…”

Insomnia and autonomic dysfunction may identify patients at risk for developing early Parkinson's disease dementia

“…Increased oxidative stress also causes mitochondrial dysfunction and DNA damage, adding to the levodopa induced neurotoxicity [30]. A relatively recent study concluded that by a dysregulation of brain 5-hydroxytryptamine chronic levodopa treatment may contribute to non-motor symptoms related to spatial memory and fear [31].…”