Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson's Disease

The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.Portuguese Foundation for Science and Technology: Ciência 2007 Program and IF Development Grant (IF/00111/2013) to AJS, Portuguese Foundation for Science and Technology PhD scholarships attributed to MMC (SFRH/BD/51061/2010), FLC (SFRH/BD/47311/2008) and CS-C (SFRH/BD/51992/2012), and Post-Doctoral Fellowship to HL-A (SFRH/BPD/80118/2011). Neurochemical analysis was funded from ELKE/UOA: 11650. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

Singing modulates parvalbumin interneurons throughout songbird forebrain vocal control circuitry

<div><p>Across species, the performance of vocal signals can be modulated by the social environment. Zebra finches, for example, adjust their song performance when singing to females (‘female-directed’ or FD song) compared to when singing in isolation (‘undirected’ or UD song). These changes are salient, as females prefer the FD song over the UD song. Despite the importance of these performance changes, the neural mechanisms underlying this social modulation remain poorly understood. Previous work in finches has established that expression of the immediate early gene EGR1 is increased during singing and modulated by social context within the vocal control circuitry. Here, we examined whether particular neural subpopulations within those vocal control regions exhibit similar modulations of EGR1 expression. We compared EGR1 expression in neurons expressing parvalbumin (PV), a calcium buffer that modulates network plasticity and homeostasis, among males that performed FD song, males that produced UD song, or males that did not sing. We found that, overall, singing but not social context significantly affected EGR1 expression in PV neurons throughout the vocal control nuclei. We observed differences in EGR1 expression between two classes of PV interneurons in the basal ganglia nucleus Area X. Additionally, we found that singing altered the amount of PV expression in neurons in HVC and Area X and that distinct PV interneuron types in Area X exhibited different patterns of modulation by singing. These data indicate that throughout the vocal control circuitry the singing-related regulation of EGR1 expression in PV neurons may be less influenced by social context than in other neuron types and raise the possibility of cell-type specific differences in plasticity and calcium buffering.</p></div

Diagram of the connections in songbird vocal control circuitry.

<p>Illustrated are HVC (proper name) and the robust nucleus of the arcopallium (RA) in the vocal motor pathway (white circles) and the basal ganglia nucleus Area X, the dorsolateral anterior thalamic nucleus (DLM), and the cortical nucleus, the lateral magnocellular nucleus of the anterior nidopallium (LMAN) in the anterior forebrain pathway (gray circles). (B) Photomicrograph of PV neurons (green, 488 filter) and EGR1 neurons (red; 596 filter) in Area X during undirected singing. Yellow arrows indicate colocalization. White scale bar = 25 μm.</p

Parvalbumin (PV) luminance is modulated by singing in HVC and Area X.

<p>PV luminance in HVC-lat and Area X differed between non-singing birds (NS; gray bars) and singing birds (female-directed singers, FD; dark green bars; undirected singers, UD; light green bars). Bars represent means, while circles correspond to individual data points. * indicates a significant difference at p<0.05, # indicates a trend toward a difference at p<0.10.</p

Percent of PV neurons expressing EGR1 across nuclei is modulated by singing.

<p>Percent of PV neurons expressing EGR1 in non-singing birds (NS; gray bars), birds producing female-directed song (FD; dark green bars) and birds producing undirected song (UD; light green bars). Box-and-whisker plots for each experimental group. Each box spans the interquartile range, horizontal black lines indicate the median and whiskers show the minima and maxima. Lines above bars indicate significance of post-hoc contrasts for brain areas in which experimental groups significantly differed. * indicates a significant difference at p<0.05; # indicates a trend toward a difference at p<0.10.</p

Modulation of EGR1 protein by singing and social context varies across the song system.

<p>EGR1 expression among non-singing birds (NS; gray bars), birds producing female-directed song (FD; dark green bars) and birds producing undirected song (UD; light green bars). Box-and-whisker plots for each experimental group. Each box spans the interquartile range, horizontal black lines indicate the median and whiskers show the minima and maxima. Lines above bars indicate significance of post-hoc contrasts for brain areas in which experimental groups significantly differed. * indicates a significant difference at p<0.05; # indicates a trend toward a difference at p<0.10.</p

Levodopa prevents the reinstatement of cocaine self-administration in rats via potentiation of dopamine release in the medial prefrontal cortex

Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naïve rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients

Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson's disease

Background: Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. Methods: Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. Results: At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). Conclusions: Our findings demonstrated that abnormal brain connectivity in the three large-scale networks characterizes drug-naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society