Effects Of Dopamine Depletion Research Articles

Mild forced exercise in young mice prevents anergia induced by dopamine depletion in late adulthood: Relation to CDNF and DARPP-32 phosphorylation patterns in nucleus accumbens

Mesolimbic dopamine (DA) plays a critical role in behavioral activation and exertion of effort in motivated behaviors. DA antagonism and depletion in nucleus accumbens (Nacb) induces anergia in effort-based decision-making tasks. Exercise improves motor function in Parkinson's disease (PD). However, the beneficial effects of physical exercise on anergia, a symptom present in many psychiatric and neurological pathologies needs to be studied. During 9 weeks, young CD1 male mice were trained to run at a moderate speed in automatically turning running wheels (RW) (forced exercise group) or locked in static RWs (control group) in 1 h daily sessions. Both groups were tested in a 3-choice-T-maze task developed for the assessment of preference between active (RW) vs. sedentary reinforcers, and vulnerability to DA depletion-induced anergia was studied after tetrabenazine administration (TBZ; VMAT-2 blocker). Exercise did not change spontaneous preferences, did not affect body weight, plasma corticosterone levels or measures of anxiety, but it increased the cerebral DA neurotrophic factor (CDNF) in Nacb core, suggesting a neuroprotective effect in this nucleus. After TBZ administration, only the non-trained group showed a shift in relative preferences from active to sedentary options, reducing time running but increasing consumption of pellets, thus showing a typical anergic but not anhedonic effect. Moreover, only in the non-trained group, phosphorylation of DARPP-32(Thr34) increased after TBZ administration. These results are the first to show that mild forced exercise carried out from a young age to adulthood could act on Nacb-related functions, and prevent the anergia-inducing effects of DA depletion.

Dopamine depletion and subcortical dysfunction disrupt cortical synchronization and metastability affecting cognitive function in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large‐scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting‐state blood‐oxygen‐level‐dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical–cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.

Impact of Fluoxetine on Behavioral Invigoration of Appetitive and Aversively Motivated Responses: Interaction With Dopamine Depletion.

Impaired behavioral activation and effort-related motivational dysfunctions like fatigue and anergia are debilitating treatment-resistant symptoms of depression. Depressed people show a bias towards the selection of low effort activities. To determine if the broadly used antidepressant fluoxetine can improve behavioral activation and reverse dopamine (DA) depletion-induced anergia, male CD1 mice were evaluated for vigorous escape behaviors in an aversive context (forced swim test, FST), and also with an exercise preference choice task [running wheel (RW)-T-maze choice task]. In the FST, fluoxetine increased active behaviors (swimming, climbing) while reducing passive ones (immobility). However, fluoxetine was not effective at reducing anergia induced by the DA-depleting agent tetrabenazine, further decreasing vigorous climbing and increasing immobility. In the T-maze, fluoxetine alone produced the same pattern of effects as tetrabenazine. Moreover, fluoxetine did not reverse tetrabenazine-induced suppression of RW time but it reduced sucrose intake duration. This pattern of effects produced by fluoxetine in DA-depleted mice was dissimilar from devaluing food reinforcement by pre-feeding or making the food bitter since in both cases sucrose intake time was reduced but animals compensated by increasing time in the RW. Thus, fluoxetine improved escape in an aversive context but decreased relative preference for active reinforcement. Moreover, fluoxetine did not reverse the anergic effects of DA depletion. These results have implications for the use of fluoxetine for treating motivational symptoms such as anergia in depressed patients.

Shedding light on dyskinesias.

Dopamine replacement therapy with L-DOPA remains the most widely prescribed treatment for Parkinson disease. However, prolonged treatment due to disease progression frequently causes unwanted motor movements known as levodopa-induced dyskinesias. Previous studies have established that alterations to the efferent circuitry of the striatum, a principal component of the basal ganglia, are in part responsible for the pathological motor consequences of prolonged levodopa treatment. While the role of the striatal direct pathway is widely accepted, the engagement of the striatal indirect pathway in dyskinetic pathophysiology is still under consideration. However, recent investigations have finally shown that the activity of both striatal pathways changes as a consequence of dopamine depletion and dyskinetic behavioural conditions. In addition, it has been reported that drug-induced structural alterations to indirect pathway medium spiny neurons, together with associated changes in synaptic plasticity and firing patterns, could contribute importantly to the development of dyskinesia. These findings, together with recent opto- and chemogenetic studies, suggest that a critical imbalance in the activity between both striatal pathways is sufficient to cause dyskinesia in both rodent and primate models of Parkinson disease. In animal models, and in human patients, dyskinetic behaviours elicited by this efferent pathway imbalance can be achieved even in the absence of dopamine denervation. In this review, we summarize recent and past findings to better understand this complex pathology with the aim of pursuing specific cell-type therapies to re-balance efferent striatal activity.

Dopamine role in learning and action inference.

This paper describes a framework for modelling dopamine function in the mammalian brain. It proposes that both learning and action planning involve processes minimizing prediction errors encoded by dopaminergic neurons. In this framework, dopaminergic neurons projecting to different parts of the striatum encode errors in predictions made by the corresponding systems within the basal ganglia. The dopaminergic neurons encode differences between rewards and expectations in the goal-directed system, and differences between the chosen and habitual actions in the habit system. These prediction errors trigger learning about rewards and habit formation, respectively. Additionally, dopaminergic neurons in the goal-directed system play a key role in action planning: They compute the difference between a desired reward and the reward expected from the current motor plan, and they facilitate action planning until this difference diminishes. Presented models account for dopaminergic responses during movements, effects of dopamine depletion on behaviour, and make several experimental predictions.

Basal Ganglia: Striosomes and the Link between Motivation and Action

The basal ganglia integrate motivation and action across their circuits; neurons in anatomical modules called striosomes could contribute strongly to this merger. A new method focusing on network interconnections will allow a better understanding of the functional role of striosomes.

Does fatigue in Parkinson's disease correlate with autonomic nervous system dysfunction?

Despite its negative impact on quality of life, fatigue in Parkinson's disease (PD) remains an under-recognized issue and the underlying pathology is undetermined. To contribute at understanding the pathogenesis of fatigue in a naturalistic cohort of cognitively intact PD patients. In a Caucasian population of PD patients (n = 27), we evaluated to what extent fatigue (quantified as PFS-16 score) is associated with PD duration and with autonomic dysfunction, studied by both MIBG scintigraphy and autonomic nervous system testing. The latter included the head-up tilt test, Valsalva maneuver, deep breathing, and handgrip tests. PFS-16 score correlated with disease duration (R = 0.57, p = 0.002). Fatigue showed a clear correlation with deep breathing test (R = - 0.53, p = 0.004) but not with the MIBG H/M ratios. Our data are consistent with a multifactorial pathogenesis of fatigue and with effects of dopamine depletion in PD-related fatigue; on the other hand, our findings do not support a role for sympathetic denervation in PD-related fatigue.

Alterations in Functional Cortical Hierarchy in Hemiparkinsonian Rats.

Parkinson's disease and experimentally induced hemiparkinsonism are characterized by increased beta synchronization between cortical and subcortical areas. This change in beta connectivity might reflect either a symmetric increase in interareal influences or asymmetric changes in directed influences among brain areas. We assessed patterns of functional and directed connectivity within and between striatum and six cortical sites in each hemisphere of the hemiparkinsonian rat model. LFPs were recorded in resting and walking states, before and after unilateral 6-hydroxydopamine lesion. The hemiparkinsonian state was characterized by increased oscillatory activity in the 20-40 Hz range in resting and walking states, and increased interhemispheric coupling (phase lag index) that was more widespread at rest than during walking. Spectral Granger-causality analysis revealed that the change in symmetric functional connectivity comprised profound reorganization of hierarchical organization and directed influence patterns. First, in the lesioned hemisphere, the more anterior, nonprimary motor areas located at the top of the cortical hierarchy (i.e., receiving many directed influences) tended to increase their directed influence onto the posterior primary motor and somatosensory areas. This enhanced influence of "higher" areas may be related to the loss of motor control due to the 6-OHDA lesion. Second, the drive from the nonlesioned toward the lesioned hemisphere (in particular to striatum) increased, most prominently during walking. The nature of these adaptations (disturbed signaling or compensation) is discussed. The present study demonstrates that hemiparkinsonism is associated with a profound reorganization of the hierarchical organization of directed influence patterns among brain areas, perhaps reflecting compensatory processes.SIGNIFICANCE STATEMENT Parkinson's disease classically first becomes manifest in one hemibody before affecting both sides, suggesting that degeneration is asymmetrical. Our results suggest that asymmetrical degeneration of the dopaminergic system induces an increased drive from the nonlesioned toward the lesioned hemisphere and a profound reorganization of functional cortical hierarchical organization, leading to a stronger directed influence of hierarchically higher placed cortical areas over primary motor and somatosensory cortices. These changes may represent a compensatory mechanism for loss of motor control as a consequence of dopamine depletion.

Rat globus pallidus neurons: functional classification and effects of dopamine depletion.

The rat globus pallidus (GP) is homologous to the primate GP externus. Studies with injectable anesthetics suggest that GP neurons can be classified into Type-I and Type-II cells based on extracellularly recorded spike shape, or positively coupled (PC), negatively coupled (NC), and uncoupled (UC) cells based on functional connectivity with the cortex. In this study, we examined the electrophysiology of rat GP neurons using the inhalational anesthetic isoflurane which offers more constant and easily regulated levels of anesthesia than injectable anesthetics. In 130 GP neurons recorded using small-tip glass electrodes (<1 μm), all but one fired Type-II spikes (positive/negative waveform). Type-I cells were unlikely to be inhibited by isoflurane since all GP neurons also fired Type-II spikes under ketamine-induced anesthesia. When recorded with large-tip electrodes (∼2 μm), however, over 70% of GP neurons exhibited Type-I spikes (negative/positive waveform). These results suggest that the spike shape, recorded extracellularly, varies depending on the electrode used and is not reliable in distinguishing Type-I and Type-II neurons. Using dual-site recording, 40% of GP neurons were identified as PC cells, 17.5% NC cells, and 42.5% UC cells. The three subtypes also differed significantly in firing rate and pattern. Lesions of dopamine neurons increased the number of NC cells, decreased that of UC cells, and significantly shifted the phase relationship between PC cells and the cortex. These results support the presence of GP neuron subtypes and suggest that each subtype plays a different role in the pathophysiology of Parkinson's disease. Synapse 69:41-51, 2015. © 2014 Wiley Periodicals, Inc.

The Michelin red guide of the brain: role of dopamine in goal-oriented navigation

Spatial learning has been recognized over the years to be under the control of the hippocampus and related temporal lobe structures. Hippocampal damage often causes severe impairments in the ability to learn and remember a location in space defined by distal visual cues. Such cognitive disabilities are found in Parkinsonian patients. We recently investigated the role of dopamine in navigation in the 6-Hydroxy-dopamine (6-OHDA) rat, a model of Parkinson’s disease (PD) commonly used to investigate the pathophysiology of dopamine depletion (Retailleau et al., 2013). We demonstrated that dopamine (DA) is essential to spatial learning as its depletion results in spatial impairments. Our results showed that the behavioral effect of DA depletion is correlated with modification of the neural encoding of spatial features and decision making processes in hippocampus. However, the origin of these alterations in the neural processing of the spatial information needs to be clarified. It could result from a local effect: dopamine depletion disturbs directly the processing of relevant spatial information at hippocampal level. Alternatively, it could result from a more distributed network effect: dopamine depletion elsewhere in the brain (entorhinal cortex, striatum, etc.) modifies the way hippocampus processes spatial information. Recent experimental evidence in rodents, demonstrated indeed, that other brain areas are involved in the acquisition of spatial information. Amongst these, the cortex—basal ganglia (BG) loop is known to be involved in reinforcement learning and has been identified as an important contributor to spatial learning. In particular, it has been shown that altered activity of the BG striatal complex can impair the ability to perform spatial learning tasks. The present review provides a glimpse of the findings obtained over the past decade that support a dialog between these two structures during spatial learning under DA control.

Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT‐1

Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for >90% of cortical glutamate uptake. The effect of dopamine depletion on glutamate transporters in the prefrontal cortex (PFC) remains unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters. PFC dopamine denervation elicited a marked increase in GLT-1 protein levels, but had no effect on levels of other glutamate transporters; high-affinity glutamate transport was positively correlated with the extent of dopamine depletion. GLT-1 gene expression was not altered. Our data suggest that dopamine depletion may lead to post-translational modifications that result in increased expression and activity of GLT-1 in PFC astrocytes. The glutamate transporter GLT-1 is expressed by astrocytes, which also express dopamine receptors. Regulation of prefrontal cortical (PFC) GLT-1 potentially offers a novel treatment approach to the cognitive deficits of schizophrenia. Partial PFC dopamine deafferentation increased membrane expression of GLT-1 protein and glutamate uptake, but did not alter levels of the other two neocortical glutamate transporters, GLAST and EAAC1.

Influence of Therapy on Some Important Final Products of Oxidation of Lipids, Proteins and Nucleic Acids in Patients with Parkinson’s Diseases

The major clinical disturbances in Parkinson’s disease (PD) are consequence of dopamine depletion in the neostriatum, due to degeneration of dopaminergic neurons. The aim of the present study was to determine whether oxidative stress (OS) occurs during the clinical course of Parkinson’s disease and to evaluate the influence of therapy on the levels of some important final products of oxidation of lipids, proteins and nucleic acids in PD patients with drug therapy. For this purpose, we investigated the levels of malondialdehid (MDA), protein carbonyl content (PCC) and 8-hydroxy-2’-deoxyguanosine quantity (8-OHdG) in PD patients with and without drug therapy. The observed changes in MDA levels, PCC and 8-OHdG quantity in blood of untreated PD patients, suggested impaired antioxidant status and presence of oxidative stress in Parkinson disease. After treatment with Madopar, the elevation in by-products significantly progresses. Our results demonstrate that administration of Madopar causes in greater degree oxidative stress than that induced by Parkinson disease, by itself.

Why am I lost without dopamine? Effects of 6-OHDA lesion on the encoding of reward and decision process in CA3

There is growing evidence that Parkinson's disease, generally characterized by motor symptoms, also causes cognitive impairment such as spatial disorientation. The hippocampus is a critical structure for spatial navigation and receives sparse but comprehensive dopamine (DA) innervation. DA loss is known to be the cause of Parkinson's disease and therefore it has been hypothesized that the associated spatial disorientation could result from hippocampal dysfunction. Because DA is involved in the prediction of reward expectation, it is possible to infer that spatial disorientation in DA depleted subjects results from the loss of the ability to detect the rewarding features within the environment. Amongst hippocampal formation subdivisions, CA3 properties such as the high liability of its place fields make it a serious candidate for interfacing DA reward system and spatial information encoding. We addressed this issue using multiple electrode recordings of CA3 in normal and dopamine depleted rats performing a spatial learning in a Y-maze. Our data confirm that DA is essential to spatial learning as its depletion results in spatial impairments. The present work also shows that CA3 involvement in the detection of spatial feature contextual significance is under DA control. Finally, it also shows that CA3 contributes to the decision making processes of navigation tasks. The data also reveal a lateralization effect of DA depletion underlined by neural correlates.

Semantic disturbance for verbs in Parkinson's disease patients off medication

Word-association tasks are considered useful tools to assess the normal functioning of the lexico-semantic system in healthy people and patients suffering from neurological disorders. Parkinson's Disease (PD) patients usually present some language dysfunction related to the functioning of the semantic system as a consequence of dopamine depletion. The aim of this study was to check if there were differences in the strength of association of the words generated by a group of non-demented PD patients on and off dopamine medication using a word-association task. In the study, 20 PD patients and 20 healthy-matched controls performed a word association task consisting of 10 nouns and 10 verbs matched by psycholinguistic variables. The participants were asked to generate the first word that came to mind given a specific single target. The results revealed that PD patients off medication said words less associated with the target compared with when they were on medication. Interestingly, comparisons between PD off patients and healthy controls revealed statistical differences only in response to verbs, while differences between PD on and controls were not found. Regarding nouns, we did not find any difference between PD off or PD on and healthy controls. This experiment adds more evidence to the assumption that the lexico-semantic system is disrupted in the absence of dopamine, resulting in poor spreading activation among associative words.

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.

Adenosine A2a receptor antagonists attenuate striatal adaptations following dopamine depletion

The motor symptoms of Parkinson's disease (PD) are widely thought to arise from an imbalance in the activity of the two major striatal efferent pathways following the loss of dopamine (DA) signaling. In striatopallidal, indirect pathway spiny projection neurons (iSPNs), intrinsic excitability rises following the loss of inhibitory D2 receptor signaling. Because these receptors are normally counterbalanced by adenosine A2a adenosine receptors, antagonists of these receptors are being examined as an adjunct to conventional pharmacological therapies. However, little is known about the effects of sustained A2a receptor antagonism on striatal adaptations in PD models. To address this issue, the A2a receptor antagonist SCH58261 was systemically administered to DA-depleted mice. After 5days of treatment, the effects of SCH58261 on iSPNs were examined in brain slices using electrophysiological and optical approaches. SCH58261 treatment did not prevent spine loss in iSPNs following depletion, but did significantly attenuate alterations in synaptic currents, spine morphology and dendritic excitability. In part, these effects were attributable to the ability of SCH58261 to blunt the effects of DA depletion on cholinergic interneurons, another striatal cell type that co-expresses A2a and D2 receptors. Collectively, these results suggest that A2a receptor antagonism improves striatal function in PD models by attenuating iSPN adaptations to DA depletion.

Striatal cellular properties conserved from lampreys to mammals

The striatum of the lamprey, the first vertebrate group to appear in evolution, shows striking similarities to that of mammals with respect to histochemical markers, afferent and efferent projections and the effect of dopamine depletion, which leads to hypokinetic motor symptoms. The cellular properties of lamprey striatal neurons were studied here using patch-clamp recordings in acute striatal slices. Sixty-five per cent of recorded neurons were characterised by a prominent inward rectification due to a K+ conductance of the Kir type. They had a ramping response with a long delay to the first action potential due to activation of a low-voltage-activated A-type K+ current. Many such inwardly rectifying neurons (IRNs) had a hyperpolarised resting membrane potential and some had spiny dendrites. The remaining 35% of the neurons (non-IRNs) represent a heterogeneous group, including some with characteristics similar to the fast-spiking interneuron of the mammalian striatum. They showed short-lasting, large after hyperpolarisations (AHPs) and discharged action potentials at high frequency. None of the recorded neurons were spontaneously active but they received GABAergic and glutamatergic synaptic input. The fact that most lamprey striatal neurons display inward rectification indicates that this is a conserved characteristic of striatal neurons throughout vertebrate phylogeny. This is a cellular property of critical importance for the operations of the striatum in mammals.

MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity.

No effect of dopamine depletion on the binding of the high-affinity D2/3 radiotracer [11C]FLB 457 in the human cortex

The use of PET and SPECT endogenous competition-binding techniques has contributed to the understanding of the role of dopamine (DA) in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of changes in synaptic DA have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal-to-noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than that in the striatum. Recently, we published a comparison study of the ability of two high-affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. Our findings support the use of [(11)C]FLB 457 to measure changes in cortical synaptic DA induced by amphetamine. The goal of this study is to examine the effects of DA depletion with α-methyl-para-tyrosine (α-MPT) on [(11)C]FLB 457 binding in the cortex. Six healthy volunteers underwent two PET scans, first under control conditions and subsequently after DA depletion. The simplified reference tissue model as well as kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in seven cortical regions. We found no effect of DA depletion with α-MPT on [(11)C]FLB 457 binding in any of the regions examined. In contrast to the measurement of DA release, the combination of low D(2) receptor density and low basal DA levels in the cortex greatly reduce the power to detect alterations in [(11)C]FLB 457 binding secondary to DA depletion.

Homeostatic Plasticity of Striatal Neurons Intrinsic Excitability following Dopamine Depletion

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, I A. Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of I A represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks.