Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

Abstract

(1) The treatment of choice for Parkinson's disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.

Serotonergic neurotransmission in early Parkinson's disease: A pilot study to assess implications for depression in this disorder

“…It could be concluded that, on the one hand, L -dopa therapy infl uences serotonin function and, on the other hand, that specifi c serotonergic treatment might improve adverse effects of L -dopa therapy. However, another animal study showed decreased 5-HT levels after long-term L -dopa treatment suggesting further necessity of distinguishing between different stages of PD (Borah and Mohanakumar 2007). Taylor et al (2009) showed symptoms of depression in mice with a reduction in vesicular monoamine transporter expression (VMAT2-defi cient), thus establishing a model of depression and other nonmotor symptoms in PD which also includes interaction between serotonergic and dopaminergic neurotransmission.…”

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

“…Chronic L-dopa specifically affected the caudal extent of the dorsal DRN and the PFC, two brain regions involved in affective behaviors (Lowry et al, 2005(Lowry et al, , 2008Warden et al, 2012;Albert et al, 2014). The crosstalk between these two regions is involved in fear and anxiety responses in rats (Hashimoto et al, 1999;Bishop et al, 2004;Amat et al, 2005;Forster et al, 2006) and several preclinical and clinical studies propose that chronic L-dopa therapy for Parkinson's disease could result in mood disturbances, such as anxiety and depression (Damasio et al, 1971;Choi et al, 2000;Borah and Mohanakumar, 2007;Eskow Jaunarajs et al, 2010. These mood disturbances may be attributable to an underlying dysregulation of the monoaminergic systems within limbic regions as demonstrated in rats (Eskow Jaunarajs et al, 2012) and more recently in monkeys (Engeln et al, 2014).…”

“…Previous studies have shown dopamine degradation and oxidation are toxic to serotonergic cells in culture (Stansley and Yamamoto, 2013) and to tryptophan hydroxylase (TPH), the rate-limiting enzyme for 5-HT synthesis (Kuhn and Arthur, 1998). Furthermore, rats treated chronically with L-dopa exhibit decreases in 5-HT tissue content in several brain regions (Borah and Mohanakumar, 2007;Eskow Jaunarajs et al, 2012) and decreased L-dopa-induced dopamine release by 5-HT terminals (Navailles et al, 2010a(Navailles et al, , 2011a. These reports suggest that chronic L-dopa leads to the accumulation of dopamine within 5-HT neurons that is detrimental to 5-HT system physiology and function.…”

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

“…In vivo, chronic L-dopa has been shown to reduce the number of 5-HT neurons in the DRN by similar oxidative mechanisms (Stansley and Yamamoto 2014). In addition to decreases in the number of 5-HT cell soma, chronic L-dopa depletes 5-HT content in several brain regions including the DRN, striatum, hippocampus, amygdala and PFC (Borah and Mohanakumar 2007; Navailles, Bioulac et al 2011; Eskow Jaunarajs, George et al 2012; Stansley and Yamamoto 2014). Importantly, proper 5-HT function in these regions is crucial for normal behavioral physiology (Lowry, Johnson et al 2005; Maier and Watkins 2005; Berger, Gray et al 2009; Monti 2011) such that 5-HT deficits in these areas result in impaired memory consolidation, executive cognitive dysfunction, fear, depression and anxiety (Lowry, Hale et al 2008; Soh, McGinley et al 2011; Euston, Gruber et al 2012; Izumi, Ohmura et al 2012).…”