Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat

Abstract

Depression and anxiety are prevalent non-motor symptoms that worsen quality of life for Parkinson's disease (PD) patients. While dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. In order to delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-OHDA or sham lesions and were treated daily with L-DOPA (12 mg/kg + benserazide, 15 mg/kg, sc) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One h after final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed via high performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L-DOPA treatment did not improve these effects. While DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced NE levels in the prefrontal cortex, striatum, and hippocampus. Collectively, the present data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve non-motor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary cause neuroplastic changes for improving affect.

Activation of serotonin2C receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat

“…Although depression is a common non-motor symptom in PD, previous studies into depressive-like behaviors in different rat models of PD were less consistent (Winter et al, 2007;Branchi et al, 2008;Tadaiesky et al, 2008;Eskow Jaunarajs et al, 2010Santiago et al, 2010Santiago et al, , 2014Zhang et al, 2011;Delaville et al, 2012;Sourani et al, 2012;Carvalho et al, 2013;Hui et al, 2014). The discrepancy could be related to the site of 6-OHDA injection, the extent of DA depletion, unilateral or bilateral lesions, used depression paradigms and time frame for the behavior tests.…”

“…Previous studies into depressive-like behaviors in 6-hydroxydopamine (6-OHDA)-lesioned rats have been limited and divergent. These studies reported increased or unchanged depressive-like behaviors in different 6-OHDA rat models of PD (Winter et al, 2007;Branchi et al, 2008;Tadaiesky et al, 2008;Eskow Jaunarajs et al, 2010Santiago et al, 2010Santiago et al, , 2014Zhang et al, 2011;Delaville et al, 2012;Sourani et al, 2012;Carvalho et al, 2013;Hui et al, 2014). Further, a dysfunctional 5-HT system is generally regarded as a risk factor for depression, and accumulating lines of evidences also suggest that degeneration of the nigrostriatal pathway leads to an impairment of 5-HT system, with evidence including the loss of 5-HT neurons, reduction of brain 5-HT content, hyperactivity of 5-HT neurons and alterations in various types of 5-HT receptors (Scholtissen et al, 2006;Wang et al, 2009;Huot et al, 2011).…”

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).…”

Pathophysiology of Non-Dopaminergic Monoamine Systems in Parkinson's Disease: Implications for Mood Dysfunction

“…As discussed earlier, neurodegeneration of LC neurons in PD is a well established phenomenon that precedes DA neuronal loss (Braak et al, 2003). It has been postulated that a compromised LC produces significant changes in NE receptors and transporters that may lead to the development or exacerbation of depression/anxiety (Eskow Jaunarajs et al, 2010). Additionally, Remy et al (2005) have reported reduced binding for the DA/NE transporter, suggesting a loss of terminals, in the LC of PD patients suffering from anxiety and depression (Remy et al, 2005).…”

“…In a rodent model of PD, alterations in DA and NE systems in the striatum have been reported to produce anxiety (Tadaiesky et al, 2008), consistent with findings in naïve rats that NE regulates anxiety behavior. Experimental studies have reported depression and anxiety-like behaviors in a 6-OHDA lesion model of PD (Branchi et al, 2010;Eskow Jaunarajs et al, 2010;Tadaiesky et al, 2008). Additionally, concomitant depletion of NE, 5-HT and DA in a unilateral rodent model of PD produced symptoms of depression, suggesting that loss of all three systems contribute to PD-like depression (Delaville et al, 2010).…”