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

Behavioral Neuroscience Program, Department of Psychology, State University of New York at Binghamton, Binghamton, New York, USA.
Behavioural pharmacology (Impact Factor: 2.15). 10/2010; 21(7):627-37. DOI: 10.1097/FBP.0b013e32833e7e80
Source: PubMed


Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague-Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) 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 hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through 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. Although 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 norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect.

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    • "We also found an imbalance in cortical NA responses to L-Dopa in dyskinetic monkeys in which NA content was unaltered in the motor cortex but decreased in the prefrontal cortex. This phenomenon remains poorly understood, though similar observations have been made in the prefrontal cortex of hemiparkinsonian rats (Eskow Jaunarajs et al. 2010). This opposite pattern of cortical responses of NA and 5-HT may participate in the DA cortical imbalance reported specifically in the prefrontal cortex of dyskinetic monkeys. "
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    ABSTRACT: Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4-dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution.
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    • "Curiously, experimental data in animal models of PD is also inconclusive. While a recent study showed no effect of bilateral MFB lesions on anxiety [33], previous studies had reported a significant anxiolytic effect of bilateral 6-OHDA lesions in the striatum [34], or even higher levels of anxiety in animals with either unilateral MFB lesions [35,36] or bilateral striatal lesions [37]. Our results on the EPM show no signs for the presence of anxiety-like behavior in animals with both incomplete and complete lesions. "
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    ABSTRACT: Background Parkinson’s disease (PD) is a chronic neurodegenerative condition that is characterized by motor symptoms as a result of dopaminergic degeneration, particularly in the mesostriatal pathway. However, in recent years, a greater number of clinical studies have focused on the emergence of non-motor symptoms in PD patients, as a consequence of damage on the mesolimbic and mesocortical dopaminergic networks, and on their significant impact on the quality of life of PD patients. Herein, we performed a thorough behavioral analysis including motor, emotional and cognitive dimensions, of the unilateral medial forebrain bundle (MFB) 6-hydroxidopamine (6-OHDA)-lesioned model of PD, and further addressed the impact of pharmacological interventions with levodopa and antidepressants on mood dimensions. Results Based on apomorphine-induced turning behaviour and degree of dopaminergic degeneration, animals submitted to MFB lesions were subdivided in complete and incomplete lesion groups. Importantly, this division also translated into a different severity of motor and exploratory impairments and depressive-like symptoms; in contrast, no deficits in anxiety-like and cognitive behaviors were found in MFB-lesioned animals. Subsequently, we found that the exploratory and the anhedonic behavioural alterations of MFB-lesioned rats can be partially improved with the administration of both levodopa or the antidepressant bupropion, but not paroxetine. Conclusions Our results suggest that this model is a relevant tool to study the pathophysiology of motor and non-motor symptoms of PD. In addition, the present data shows that pharmacological interventions modulating dopaminergic transmission are also relevant to revert the non-motor behavioral deficits found in the disease.
    Full-text · Article · Apr 2013 · Molecular Neurodegeneration
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    • "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). "

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