Unilateral Dopamine Depletion Research Articles

Using microdialysis to monitor dopaminergic support of limb-use control following mesencephalic neurosphere transplantation in a rodent model of Parkinson's Disease

Controlled nigrostriatal dopamine release supports effective limb use during locomotion coordination that becomes compromised after this pathway deteriorates in Parkinson’s Disease (PD). How dopamine release relates to active ongoing behavior control remains unknown. Restoring proper release strategy appears important to successful PD treatment with transplanted dopamine-producing stem cells. This is suggested by apparently distinct behavioral support from tonic or phasic release and corresponding requirements of requisite afferent control exhibited by intact nigrostriatal neurons. Our laboratory previously demonstrated that transplanted dopaminergic cells can elicit skilled movement recovery known to depend on phasic dopamine release. However, efforts to measure this movement-related dopamine release yielded seemingly paradoxical, incongruent results. In response, here we explored whether those previous observations derived from rapid reuptake transport into either transplanted cells or residual, lesion-surviving terminals. We confirmed this using minimal reuptake blockade during intrastriatal microdialysis. After unilateral dopamine depletion, rats received transplants and were subjected to our swimming protocol. Among dopamine-depleted and transplanted rats, treatment supported restoration of limb movement symmetry. Interestingly, subsequent reuptake-restricted microdialysis confirmed distinct swimming-induced dopamine increases clearly occurred among these lesioned/transplanted subjects. Thus, phasic firing control appears to contribute to transplant-derived recovery in Parkinsonian animals.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.

Striatal mechanisms of turning behaviour following unilateral dopamine depletion in mice.

Unilateral dopamine (DA) depletion produces ipsiversive turning behaviour, and the injection of DA receptor agonists can produce contraversive turning, but the underlying mechanisms remain unclear. We conducted in vivo recording and pharmacological and optogenetic manipulations to study the role of DA and striatal output in turning behaviour. We used a video-based tracking programme while recording single unit activity in both putative medium spiny projection neurons (MSNs) and fast-spiking interneurons (FSIs) in the dorsal striatum bilaterally. Our results suggest that unilateral DA depletion reduced striatal output from the depleted side, resulting in asymmetric striatal output. Depletion systematically altered activity in both MSNs and FSIs, especially in neurons that increased firing during turning movements. Like D1 agonist SKF 38393, optogenetic stimulation in the depleted striatum increased striatal output and reversed biassed turning. These results suggest that relative striatal outputs from the two cerebral hemispheres determine the direction of turning: Mice turn away from the side of higher striatal output and towards the side of the lower striatal output.

Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.

Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia.

Regulator of G-protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l-Dopa-induced dyskinesia. HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small-molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and l-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403-mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l-Dopa. l-Dopa acutely up-regulated RGS4 in the lesioned striatum. RGS4 physiologically inhibits NOP receptor signalling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up-regulation occurring during dyskinesia expression. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Imaging of cerebral tryptophan metabolism using 7-[18F]FTrp-PET in a unilateral Parkinsonian rat model

Degradation products of the essential amino acid tryptophan (Trp) are important signaling molecules in the mammalian brain. Trp is metabolized either through the kynurenine pathway or enters serotonin and melatonin syntheses. The aim of the present work was to examine the potential of the novel PET tracer 7-[18F]fluorotryptophan ([18F]FTrp) to visualize all three pathways in a unilateral 6-OHDA rat model. [18F]FDOPA-PET scans were performed in nine 6-OHDA-injected and six sham-operated rats to assess unilateral dopamine depletion severity four weeks after lesion placement. Afterwards, 7-[18F]FTrp-PET scans were conducted at different timepoints up to seven months after 6-OHDA injection. In addition, two 6-OHDA-injected rats were examined for neuroinflammation using [18F]DAA1106-PET. 7-[18F]FTrp-PET showed significantly increased tracer uptake at the 6-OHDA injection site which was negatively correlated to time after lesion placement. Accumulation of [18F]DAA1106 at the injection site was increased as well, suggesting that 7-[18F]FTrp uptake in this region may reflect kynurenine pathway activity associated with inflammation. Bilaterally in the dorsal hippocampus, 7-[18F]FTrp uptake was significantly decreased and was inversely correlated to dopamine depletion severity, indicating that it reflects reduced serotonin synthesis. Finally, 7-[18F]FTrp uptake in the pineal gland was significantly increased in relation with dopamine depletion severity, providing evidence that melatonin synthesis is increased in the 6-OHDA rat model. We conclude that 7-[18F]FTrp is able to detect alterations in both serotonin/melatonin and kynurenine metabolic pathways, and can be applied to visualize pathologic changes related to neurodegenerative processes.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson's Disease.

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

Proliferation of Inhibitory Input to the Substantia Nigra in Experimental Parkinsonism.

The substantia nigra pars reticulata (SNr) is one of the output nuclei of the basal ganglia (BG) and plays a vital role in movement execution. Death of dopaminergic neurons in the neighboring nucleus, the substantia nigra pars compacta (SNc), leads to Parkinson's disease. The ensuing dopamine depletion affects all BG nuclei. However, the long-term effects of dopamine depletion on BG output are less characterized. In this in vitro study, we applied electrophysiological and immunohistochemical techniques to investigate the long-term effects of dopamine depletion on GABAergic transmission to the SNr. The findings showed a reduction in firing rate and regularity in SNr neurons after unilateral dopamine depletion with 6-OHDA, which we associate with homeostatic mechanisms. The strength of the GABAergic synapses between the globus pallidus (GP) and the SNr increased but not their short-term dynamics. Consistent with this observation, there was an increase in the frequency and amplitude of spontaneous inhibitory synaptic events to SNr neurons. Immunohistochemistry revealed an increase in the density of vGAT-labeled puncta in dopamine depleted animals. Overall, these results may suggest that synaptic proliferation can explain how dopamine depletion augments GABAergic transmission in the SNr.

Selective Regulation of 5-HT1B Serotonin Receptor Expression in the Striatum by Dopamine Depletion and Repeated L-DOPA Treatment: Relationship to L-DOPA-Induced Dyskinesias.

Dopamine and serotonin in the basal ganglia interact in a bidirectional manner. On the one hand, serotonin (5-HT) receptors regulate the effects of dopamine agonists on several levels, ranging from molecular signaling to behavior. These interactions include 5-HT receptor-mediated facilitation of dopamine receptor-induced gene regulation in striatal output pathways, which involves the 5-HT1B receptor and others. Conversely, there is evidence that dopamine action by psychostimulants regulates 5-HT1B receptor expression in the striatum. To further investigate the effects of dopamine and agonists on 5-HT receptors, we assessed the expression of 5-HT1B and other serotonin receptor subtypes in the striatum after unilateral dopamine depletion by 6-OHDA and subsequent treatment with L-DOPA (5mg/kg; 4weeks). Neither dopamine depletion nor L-DOPA treatment produced significant changes in 5-HT2C, 5-HT4, or 5-HT6 receptor expression in the striatum. In contrast, the 6-OHDA lesion caused a (modest) increase in 5-HT1B mRNA levels throughout the striatum. Moreover, repeated L-DOPA treatment markedly further elevated 5-HT1B expression in the dopamine-depleted striatum, an effect that was most robust in the sensorimotor striatum. A minor L-DOPA-induced increase in 5-HT1B expression was also seen in the intact striatum. These changes in 5-HT1B expression mimicked changes in the expression of neuropeptide markers (dynorphin, enkephalin mRNA) in striatal projection neurons. After repeated L-DOPA treatment, the severity of L-DOPA-induced dyskinesias and turning behavior was positively correlated with the increase in 5-HT1B expression in the associative, but not sensorimotor, striatum ipsilateral to the lesion, suggesting that associative striatal 5-HT1B receptors may play a role in L-DOPA-induced behavioral abnormalities.

Effects of subthalamic deep brain stimulation on striatal metabolic connectivity in a rat hemiparkinsonian model.

ABSTRACTDeep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular. We used ipsilesional STN stimulation in a hemiparkinsonian rat model in combination with [18F]FDOPA-PET, [18F]FDG-PET and metabolic connectivity analysis. STN-DBS reversed ipsilesional hypometabolism and contralesional hypermetabolism in hemiparkinsonian rats by increasing metabolic activity in the ipsilesional ventrolateral striatum and by decreasing it in the contralesional hippocampus and brainstem. Other STN-DBS effects were subject to the magnitude of dopaminergic lesion severity measured with [18F]FDOPA-PET, e.g. activation of the infralimbic cortex was negatively correlated to lesion severity. Connectivity analysis revealed that, in healthy control animals, left and right striatum formed a bilateral functional unit connected by shared cortical afferents, which was less pronounced in hemiparkinsonian rats. The healthy striatum was metabolically connected to the ipsilesional substantia nigra in hemiparkinsonian rats only (OFF condition). STN-DBS (ON condition) established a new functional striatal network, in which interhemispheric striatal connectivity was strengthened, and both the dopamine-depleted and the healthy striatum were functionally connected to the healthy substantia nigra. We conclude that both unilateral dopamine depletion and STN-DBS affect the whole brain and alter complex interhemispheric networks.

Stress and corticosterone alter synaptic plasticity in a rat model of Parkinson’s disease

As a major influence on neuronal function and plasticity, chronic stress can affect the progression and symptoms of neurodegenerative conditions, such as Parkinson’s disease (PD). Here we investigated the influence of unilateral dopamine depletion and stress on dopamine-related hallmarks of stress response and neuronal plasticity in a rat model of PD. Animals received either restraint stress or a combination of adrenalectomy and corticosterone (CORT) supplementation to clamp circulating glucocorticoid levels for three weeks prior to unilateral nigrostriatal dopamine depletion. Rats were tested in skilled and non-skilled motor function up to three weeks post-lesion. Midbrain mRNA expression assessments included markers of dopamine function and neuroplasticity, such as tyrosine hydroxylase (TH), synaptophysin (SYN), calcyon, and glucocorticoid receptor (GR). Along with impaired motor performance, stress and clamped CORT partially preserved TH expression in both substantia nigra (SN) and ventral tegmental area (VTA), but differentially modulated the expression of SYN, calcyon, and GR mRNA in midbrain and cortical areas. Stress reduced synaptophysin mRNA expression in SN/VTA, and elevated calcyon mRNA optical density in both non-lesion and lesion hemispheres. Stress and CORT increased GR mRNA in the non-lesion SN/VTA, while in the lesion hemisphere GR mRNA was only elevated by CORT. In the motor cortex and striatum, however, GR was higher in both hemispheres under both experimental conditions. These findings suggest that stress and stress hormones differentially affect dopaminergic function and neuroplasticity in a rat model of PD. The findings suggest a role for stress in motor and non-motor symptoms of PD and stress response.

Study of the Neuropeptide Function in Parkinson’s Disease Using the 6-Hydroxydopamine Model of Experimental Hemiparkinsonism

Parkinson’s disease, one of the most common neurodegenerative diseases, characterized by unilateral brain dopamine damage in its initial stages, remains unknown in many respects. It is especially necessary to improve the early diagnosis and, in order to improve the treatment, to go thoroughly into the knowledge of its pathophysiology. To do this, it is essential to perform studies in appropriate animal models of the disease. One of those is generated by the unilateral intracerebral administration of the neurotoxic 6-hydroxydopamine that produces clear asymmetrical cerebral dopamine depletion. Currently the neuronal coexistence of several neurotransmitters is obvious. Particularly interesting is the coexistence of dopamine with various neuropeptides. If the neuronal content of dopamine is asymmetrically altered in the early stages of the Parkinson’s disease, the coexisting neuropeptides may also be asymmetrically altered. Therefore, their study is important to appropriately understand the pathogenesis of the Parkinson’s disease. The function of the neuropeptides can be studied through their metabolism by neuropeptidases whose activity reflects the functional status of their endogenous substrates as well as the one of the peptides resulting from their hydrolysis. Here we review the 6-hydroxydopamine model of experimental hemiparkinsonism as an appropriate model to study the initial asymmetric stages of the disease. In particular, we analyze the consequences of unilateral brain dopamine depletions on the functionality of brain neuropeptides through the study of the activity of cerebral neuropeptidases.

Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model.

Preclinical and clinical evidence suggests that depression might be associated with a dysfunction in the reward/motivation circuitry. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has been shown in a recent clinical trial to provide a prompt and consistent improvement of depressive symptoms in treatment-resistant patients. In order to better understand the underlying mechanisms of neuromodulation in the context of depression, the effects of chronic bilateral MFB-DBS were assessed in a combined rodent model of depression and Parkinson’s disease. Female Sprague-Dawley rats received unilateral 6-OHDA injection in the right MFB and were divided into three groups: CMS-STIM, CMS-noSTIM and control group. The CMS groups were submitted to chronic unpredictable mild stress (CMS) protocol for 6 weeks. MFB-DBS was applied only to the CMS-STIM group for 1 week. All groups were repeatedly probed on a series of behavioral tasks following each intervention, and to a postmortem histological analysis. CMS led to an increase in immobility in the forced swim test, to a decrease in sucrose solution consumption in the sucrose preference test, as well as to an increased production of ultrasonic vocalizations in the 22 kHz range, indicating increased negative affect. MFB-DBS reversed the anhedonic-like and despair-like behaviors. The results suggest that unilateral dopamine depletion did not preclude MFB-DBS in reversing depressive-like and anhedonic-like behavior in the rodent. Further understanding of the importance of hemispheric dominance in neuropsychiatric disorders is essential in order to optimize stimulation as a therapeutic strategy in these diseases.

Neural mechanism underlying hyperalgesic response to orofacial pain in Parkinson's disease model rats

To investigate the neural mechanism of pain originating from the orofacial region in PD patients, we used PD model rats produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. We investigated effects of nigrostriatal lesions on the behavioral response (face rubbing) to formalin injection into the upper lip. We also examined expression of c-Fos and phosphorylated extracellular signal-regulated kinase (pERK) in the trigeminal spinal subnucleus caudalis (Vc) and expression of c-Fos in the periaqueductal gray matter (PAG).Face rubbings following formalin injection showed a biphasic profile, with the first phase for the first 5min and the second phase from 10 to 90min. Rats with 6-OHDA lesions showed increased face rubbings in the second phase when formalin was injected ipsilaterally to the lesion, and c-Fos expression in the Vc increased. When formalin was injected contralaterally, face rubbings were reduced in the first phase, however, expression levels of c-Fos and pERK in the Vc were unchanged. No significant difference was found in c-Fos expression in the PAG between 6-OHDA- and saline-injected rats.These results suggest that unilateral dopamine depletion in the nigrostriatal pathway may be involved in hypersensitivity to noxious stimulation delivered to the orofacial region.

Subthalamic nucleus lesion improves cell survival and functional recovery following dopaminergic cell transplantation in parkinsonian rats

Subthalamic nucleus (STN) modulation is currently the gold standard in the treatment of Parkinson's disease (PD) cases refractory to medication. Cell transplantation is a tissue-restorative approach and is a promising strategy in the treatment of PD. One of the obstacles to overcome in cell therapy is the poor dopaminergic cell survival. Our experiment investigates the impact of a partial subthalamotomy prior to ventral mesencephalic (VM) embryonic cell transplantation on dopaminergic cell survival and functional outcome. Unilateral dopamine depletion was carried out in rats, via medial forebrain bundle (MFB) injection of 6-hydroxydopamine, and half of the animals went on to receive unilateral excitotoxic lesions of the STN/Zone Incerta (ZI) causing partial lesion of these structures on the same side as the MFB lesion. All MFB-lesioned animals, with or without the STN/ZI lesion, received striatal ipsilateral embryonic VM cell grafts. The data suggest that the STN/ZI lesion could boost the dopamine cell survival in the grafts by 2.6-fold compared with the control grafted-only group. Moreover, performance on the drug-induced rotation and the spontaneous behavior tests were ameliorated on the STN/ZI-lesioned group to a significantly greater extent than the grafted-only group. These data suggest that the STN/ZI partial lesion optimized the striatal environment, promoting an improvement in cell survival. Further studies are needed to see whether the synergy between STN modulation via deep brain stimulation and cell therapy might have clinical applications in the management of PD.

Targeted Motor Rehabilitation Dissociates Corticobulbar Versus Corticospinal Dysfunction in an Animal Model of Parkinson’s Disease

Background. Recent evidence suggests that motor training may be beneficial for slowing the onset of motor impairments in Parkinson’s disease (PD). Objective. To examine the impact of targeted rehabilitation on limb motor and cranial motor function and the corresponding corticospinal and corticobulbar circuits in a rodent model of PD. Methods. Baseline performance of limb (reaching) and cranial (licking) motor function were established prior to and 6 weeks following unilateral intrastriatal 6-hydroxydopamine (6-OHDA) infusions. Animals then received 6 weeks of limb motor rehabilitation (LMR) or cranial motor rehabilitation (CMR), after which motor performance was reassessed. Intracortical microstimulation (ICMS) was used to generate motor maps of corresponding corticospinal (forelimb) and corticobulbar (tongue) movement representations within the motor cortex ipsilateral to the 6-OHDA infusion. Quantitative tyrosine hydroxylase (TH) immunohistochemistry was performed to determine levels of striatal TH depletion in 6-OHDA animals using near infrared densitometry. Results. (1) unilateral intrastriatal dopamine depletion impaired both reaching accuracy and lick force; (2) targeted LMR ameliorated impairments in reaching performance; however, CMR did not improve lick force impairments; (3) unilateral dopamine depletion significantly reduced forelimb but not tongue motor map topography; (4) LMR partially restored forelimb motor maps, whereas CMR did not alter tongue motor maps; and (5) significant correlations were observed between skilled reaching accuracy, forelimb motor map area, and TH depletion, but no relationships were revealed for cranial motor function, motor maps, or TH depletion. Conclusions: These data demonstrate dissociation between striatal dopamine depletion, limb versus cranial motor function, and targeted motor rehabilitation in a rodent model of PD.

Striatal Glutamate Release in l-DOPA-Induced Dyskinetic Animals

l-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-l-alanine (l-DOPA) in Parkinson's disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local l-DOPA application in the striatum. In addition, effects from the 5-HT1A receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OHDPAT; 1 mg/kg) was assessed on glutamate release and on dyskinetic behavior. The results revealed a bilateral ∼30% reduction of basal extracellular glutamate concentration and attenuated potassium-evoked glutamate release after a unilateral dopamine-depletion in l-DOPA naïve animals. In dyskinetic subjects, basal glutamate concentration was comparable to normal controls, although potassium-evoked glutamate release was reduced to similar levels as in drug naïve dopamine-lesioned animals. Furthermore, acute striatal l-DOPA administration attenuated glutamate release in all groups, except in the dopamine-lesioned striatum of dyskinetic animals. Co-administration of 8-OHDPAT and l-DOPA decreased dyskinesia in dopamine-lesioned animals, but did not affect potassium-evoked glutamate release, which was seen in normal animals. These findings indicate altered glutamate transmission upon dopamine-depletion and dyskinesia.

The role of central amygdala dopamine in disengagement behavior.

Unilateral nigrostriatal dopamine depletion in animals induces contralateral sensorimotor deficits that are like symptoms associated with Parkinson's disease (PD). Unilateral nigrostriatal dopamine depletion also causes a contralateral deficit in disengagement behavior (e.g., ability to stop an ongoing activity to orient/attend to a new stimulus). This disengagement deficit has been shown to be resistant to treatments that rescued other motor and somatosensory deficits. Thus, disengagement behavior may involve unique sensorimotor information integration potentially important for attentional allocation and may rely strongly on a mechanism that includes extranigrostriatal circuitry. The central nucleus of the amygdala (CeA) and its connections with the nigral dopamine system have been reported to modulate cognitive processes dependent substantially on attentional allocation. CeA dopamine function might be also important for disengagement behavior. In Experiment 1, rats received microinfusions of 6-hydroxydopamine unilaterally to induce dopamine terminal loss in the CeA and were tested for disengagement behavior in addition to several sensorimotor functions. These rats showed deficits in contralateral disengagement behavior and an asymmetry in adhesive dot removal from the paws, but not in forelimb use in a cylinder or amphetamine rotation. In Experiment 2, rats received D1 or D2 antagonists into the CeA unilaterally prior to behavioral tests. The D1 antagonist disrupted disengagement behavior without affecting the other sensorimotor tests examined. The D2 antagonist had no effects on any of the behaviors tested. Our results suggest that CeA dopamine function is involved in modulation of disengagement behavior.

Chronic dopamine depletion augments the functional expression of K-ATP channels in the rat subthalamic nucleus

Symptoms of Parkinson's disease caused by dopamine depletion are associated with burst firing in the subthalamic nucleus (STN). Moreover, regularization or suppression of STN neuronal activity is thought to improve symptoms of Parkinson's disease. We reported recently that N-methyl-d-aspartate (NMDA) receptor stimulation of rat STN neurons evokes ATP-sensitive K+ (K-ATP) current via a Ca2+- and nitric oxide-dependent mechanism. The present studies were done to determine whether or not K-ATP channel function in STN neurons is altered in a model of chronic dopamine depletion. Brain slices were prepared from rats with unilateral dopamine depletion caused by intracerebral 6-hydroxydopamine (6-OHDA) injections. Whole-cell patch-clamp recordings showed that NMDA evoked more outward current at −70mV and greater positive slope conductance in STN neurons located ipsilateral to 6-OHDA treatment compared to neurons located contralateral. Moreover, extracellular, loose-patch recordings showed that NMDA increased spontaneous firing rate in STN neurons in slices from normal rats, whereas NMDA produced a tolbutamide-sensitive inhibition of firing rate in STN neurons located ipsilateral to 6-OHDA treatment. These results show that K-ATP channel function in STN neurons is up-regulated by chronic dopamine deficiency. We suggest that K-ATP channel activation in the STN might benefit symptoms of Parkinson's disease.

Effects of dopamine depletion on LFP oscillations in striatum are task- and learning-dependent and selectively reversed by l -DOPA

A major physiologic sign in Parkinson disease is the occurrence of abnormal oscillations in cortico-basal ganglia circuits, which can be normalized by L-DOPA therapy. Under normal circumstances, oscillatory activity in these circuits is modulated as behaviors are learned and performed, but how dopamine depletion affects such modulation is not yet known. We here induced unilateral dopamine depletion in the sensorimotor striatum of rats and then recorded local field potential (LFP) activity in the dopamine-depleted region and its contralateral correspondent as we trained the rats on a conditional T-maze task. Unexpectedly, the dopamine depletion had little effect on oscillations recorded in the pretask baseline period. Instead, the depletion amplified oscillations across delta (~3 Hz), theta (~8 Hz), beta (~13 Hz), and low-gamma (~48 Hz) ranges selectively during task performance times when each frequency band was most strongly modulated, and only after extensive training had occurred. High-gamma activity (65-100 Hz), in contrast, was weakened independent of task time or learning stage. The depletion also increased spike-field coupling of fast-spiking interneurons to low-gamma oscillations. L-DOPA therapy normalized all of these effects except those at low gamma. Our findings suggest that the task-related and learning-related dynamics of LFP oscillations are the primary targets of dopamine depletion, resulting in overexpression of behaviorally relevant oscillations. L-DOPA normalizes these dynamics except at low-gamma, linked by spike-field coupling to fast-spiking interneurons, now known to undergo structural changes after dopamine depletion and to lack normalization of spike activity following l-DOPA therapy.