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1.
Although microdialysis measurements suggest that extracellular dopamine concentrations in the rat striatum are in the low nanomolar range, some recent voltammetry studies suggest that the concentration may be considerably higher, perhaps in the micromolar range. The presence of such high dopamine levels in the extracellular space has to be rationalized with the rapid, linear clearance of extracellular dopamine observed after electrical stimulation of the medial forebrain bundle. Kinetic analysis of dopamine clearance after evoked release suggests that the basal extracellular dopamine concentration is below the K(M) of dopamine uptake, which is near 0.2 microm. However, dopamine clearance after pressure ejection of dopamine into the rat striatum is slow and non-linear, which may alternatively be a sign that basal dopamine release is only slightly slower than the maximal velocity of dopamine uptake, Vmax. A high basal extracellular dopamine concentration would exist if basal dopamine release were only slightly slower than the Vmax of uptake. This report introduces a new kinetic analysis of dopamine uptake that sheds light on the possible source of the different clearance rates observed following evoked dopamine release and dopamine pressure ejection. Furthermore, the analysis rationalizes the rapid dopamine clearance after evoked release with the possibility that basal extracellular dopamine levels are above the K(M) of the transporter.  相似文献   

2.
The central dopamine systems are involved in several aspects of normal brain function and are implicated in a number of human disorders. Hence, it is important to understand the mechanisms that control dopamine release in the brain. The striatum of the rat receives both dopaminergic and glutamatergic projections that synaptically target striatal neurons but not each other. Nevertheless, these afferents do form frequent appositional contacts, which has engendered interest in the question of whether they communicate with each other despite the absence of a direct synaptic connection. In this study, we used voltammetry in conjunction with carbon fiber microelectrodes in anesthetized rats to further examine the effect of the ionotropic glutamate antagonist, kynurenate, on extracellular dopamine levels in the striatum. Intrastriatal infusions of kynurenate decreased extracellular dopamine levels, suggesting that glutamate acts locally within the striatum via ionotropic receptors to regulate the basal extracellular dopamine concentration. Infusion of tetrodotoxin into the medial forebrain bundle or the striatum did not alter the voltammetric response to the intrastriatal kynurenate infusions, suggesting that glutamate receptors control a non-vesicular release process that contributes to the basal extracellular dopamine level. However, systemic administration of the dopamine uptake inhibitor, nomifensine (20 mg/kg i.p.), markedly decreased the amplitude of the response to kynurenate infusions, suggesting that the dopamine transporter mediates non-vesicular dopamine release. Collectively, these findings are consistent with the idea that endogenous glutamate acts locally within the striatum via ionotropic receptors to control a tonic, impulse-independent, transporter-mediated mode of dopamine release. Although numerous prior in vitro studies had suggested that such a process might exist, it has not previously been clearly demonstrated in an in vivo experiment.  相似文献   

3.
Electrically evoked dopamine release as measured by voltammetry in the rat striatum is heterogeneous in both amplitude and temporal profile. Previous studies have attributed this heterogeneity to variations in the density of dopamine (DA) terminals at the recording site. We reach the alternate conclusion that the heterogeneity of evoked DA release derives from variations in the extent to which DA terminals are autoinhibited. We demonstrate that low-amplitude, slow evoked DA responses occur even though recording electrodes are close to DA terminals. Moreover, the D2 agonist and antagonist, quinpirole and raclopride, respectively, affect the slow responses in a manner consistent with the known functions of pre-synaptic D2 autoreceptors. Recording sites that exhibit autoinhibited responses are prevalent in the dorsal striatum. Autoinhibition preceded electrical stimulation, which is consistent with our prior reports that the striatum contains a tonic pool of extracellular DA at basal concentrations that exceed the affinity of D2 receptors. We conclude that the striatum contains DA terminals operating on multiple time courses, determined at least in part by the local variation in autoinhibition. Thus, we provide direct, real-time observations of the functional consequence of tonic and phasic DAergic signaling in vivo .  相似文献   

4.
Amphetamine (AMPH) is thought to disrupt normal patterns of action potential-dependent dopaminergic signaling by depleting dopamine (DA) vesicular stores and promoting non-exocytotic DA efflux. Voltammetry in brain slices concurrently demonstrates these key drug effects, along with competitive inhibition of neuronal DA uptake. Here, we perform comparable kinetic and voltammetric analyses in vivo to determine whether AMPH acts qualitatively and quantitatively similar in the intact brain. Fast-scan cyclic voltammetry measured extracellular DA in dorsal and ventral striata of urethane-anesthetized rats. Electrically evoked recordings were analyzed to determine K(m) and V(max) for DA uptake and vesicular DA release, while background voltammetric current indexed basal DA concentration. AMPH (0.5, 3, and 10 mg/kg i.p.) robustly increased evoked DA responses in both striatal subregions. The predominant contributor to these elevated levels was competitive uptake inhibition, as exocytotic release was unchanged in the ventral striatum and only modestly decreased in the dorsal striatum. Increases in basal DA levels were not detected. These results are consistent with AMPH augmenting action potential-dependent dopaminergic signaling in vivo across a wide, behaviorally relevant dose range. Future work should be directed at possible causes for the distinct in vitro and in vivo pharmacology of AMPH.  相似文献   

5.
Zhou FM  Liang Y  Salas R  Zhang L  De Biasi M  Dani JA 《Neuron》2005,46(1):65-74
The striatum receives rich dopaminergic and more moderate serotonergic innervation. After vesicular release, dopamine and serotonin (5-hydroxytryptamine, 5-HT) signaling is controlled by transporter-mediated reuptake. Dopamine is taken up by dopamine transporters (DATs), which are expressed at the highest density in the striatum. Although DATs also display a low affinity for 5-HT, that neurotransmitter is normally efficiently taken up by the 5-HT transporters. We found that when extracellular 5-HT is elevated by exogenous application or by using antidepressants (e.g., fluoxetine) to inhibit the 5-HT transporters, the extremely dense striatal DATs uptake 5-HT into dopamine terminals. Immunohistochemical results and measurements using fast cyclic voltammetry showed that elevated 5-HT is taken up by DATs into striatal dopamine terminals that subsequently release 5-HT and dopamine together. These results suggest that antidepressants that block serotonin transporters or other factors that elevate extracellular 5-HT alter the temporal and spatial relationship between dopamine and 5-HT signaling in the striatum.  相似文献   

6.
The release of striatal dopamine (DA) and its metabolites in response to locally-induced K+ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P<0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P<0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P<0.05). Furthermore, the basal level of extracellular HVA in chloral hydrateanesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.  相似文献   

7.
Symptoms of Parkinson's disease do not present until the degeneration of nigrostriatal dopaminergic neurons is nearly complete. Maintenance of dopaminergic tone governing striatal efferents is postulated to preserve motor control during the presymptomatic phase, but the neuroadaptation responsible for normalization is not completely understood. In particular, the prevailing view that surviving dopaminergic neurons compensate by up-regulating release has been difficult to demonstrate directly. Here we investigate dopaminergic neurotransmission in the hemiparkinsonian rat using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Electrical stimulation was used to elicit extracellular dopamine levels mimicking the steady-state dynamics of tonic dopaminergic signaling. In agreement with microdialysis studies, evoked steady-state dopamine levels remained constant over the entire lesion spectrum (0 to approximately 85%) observed during the presymptomatic stage. Kinetic analysis of the voltammetric recordings demonstrated that evoked dopamine concentrations were normalized without plasticity of dopamine release and uptake, suggesting that the primary mechanisms controlling ambient levels of extracellular dopamine were not actively altered. In the present study, we formalize this neuroadaptation as "passive stabilization" . We further propose that passive stabilization is mediated by the simple physical principles of diffusion and steady state, is predicated on extrasynaptic transmission, and forms the basis for a new compensation model of preclinical parkinsonism.  相似文献   

8.
The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of α-methyl-para-tyrosine (αMT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.  相似文献   

9.
Morris G  Arkadir D  Nevet A  Vaadia E  Bergman H 《Neuron》2004,43(1):133-143
Midbrain dopamine and striatal tonically active neurons (TANs, presumed acetylcholine interneurons) signal behavioral significance of environmental events. Since striatal dopamine and acetylcholine affect plasticity of cortico-striatal transmission and are both crucial to learning, they may serve as teachers in the basal ganglia circuits. We recorded from both neuronal populations in monkeys performing a probabilistic instrumental conditioning task. Both neuronal types respond robustly to reward-related events. Although different events yielded responses with different latencies, the responses of the two populations coincided, indicating integration at the target level. Yet, while the dopamine neurons' response reflects mismatch between expectation and outcome in the positive domain, the TANs are invariant to reward predictability. Finally, TAN pairs are synchronized, compared to a minority of dopamine neuron pairs. We conclude that the striatal cholinergic and dopaminergic systems carry distinct messages by different means, which can be integrated differently to shape the basal ganglia responses to reward-related events.  相似文献   

10.
The highly reactive nature of dopamine renders dopaminergic neurons vulnerable to oxidative damage. We recently demonstrated that loss-of-function mutations in the Drosophila gene Catecholamines up (Catsup) elevate dopamine pools but, paradoxically, also confer resistance to paraquat, an herbicide that induces oxidative stress-mediated toxicity in dopaminergic neurons. We now report a novel association of the membrane protein, Catsup, with GTP cyclohydrolase rate-limiting enzyme for tetrahydrobiopterin (BH(4)) biosynthesis and tyrosine hydroxylase, rate-limiting enzyme for dopamine biosynthesis, which requires BH(4) as a cofactor. Loss-of-function Catsup mutations cause dominant hyperactivation of both enzymes. Elevated dopamine levels in Catsup mutants coincide with several distinct characteristics, including hypermobility, minimal basal levels of 3,4-dihydroxy-phenylacetic acid, an oxidative metabolite of dopamine, and resistance to the vesicular monoamine transporter inhibitor, reserpine, suggesting that excess dopamine is synaptically active and that Catsup functions in the regulation of synaptic vesicle loading and release of dopamine. We conclude that Catsup regulates and links the dopamine synthesis and transport networks.  相似文献   

11.
The striatum can be divided into four anatomically and functionally distinct domains: the dorsolateral, dorsomedial, ventral and the more recently identified caudolateral (tail) striatum. Dopamine transmission in these striatal domains underlies many important behaviours, yet little is known about this phenomenon in the tail striatum. Furthermore, the tail is divided anatomically into four divisions (dorsal, medial, intermediate and lateral) based on the profile of D1 and D2 dopamine receptor-expressing medium spiny neurons, something that is not seen elsewhere in the striatum. Considering this organisation, how dopamine transmission occurs in the tail striatum is of great interest. We recorded evoked dopamine release in the four tail divisions, with comparison to the dorsolateral striatum, using fast-scan cyclic voltammetry in rat brain slices. Contributions of clearance mechanisms were investigated using dopamine transporter knockout (DAT-KO) rats, pharmacological transporter inhibitors and dextran. Evoked dopamine release in all tail divisions was smaller in amplitude than in the dorsolateral striatum and, importantly, regional variation was observed: dorsolateral ≈ lateral > medial > dorsal ≈ intermediate. Release amplitudes in the lateral division were 300% of that in the intermediate division, which also exhibited uniquely slow peak dopamine clearance velocity. Dopamine clearance in the intermediate division was most dependent on DAT, and no alternative dopamine transporters investigated (organic cation transporter-3, norepinephrine transporter and serotonin transporter) contributed significantly to dopamine clearance in any tail division. Our findings confirm that the tail striatum is not only a distinct dopamine domain but also that each tail division has unique dopamine transmission characteristics. This supports that the divisions are not only anatomically but also functionally distinct. How this segregation relates to the overall function of the tail striatum, particularly the processing of multisensory information, is yet to be determined.

  相似文献   


12.
The influence of L-DOPA and reserpine on extracellular dopamine (DA) levels in the striatum of intact and dopaminergic denervated rats was studied using the brain microdialysis technique. In intact rats, reserpine (5 mg/kg s.c.) reduced extracellular DA levels to 4% of basal values. L-DOPA (50 mg/kg i.p.) had no effect on extracellular DA levels in reserpine-pretreated rats. In rats with 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic system, basal levels of extracellular DA were low but markedly increased by L-DOPA (50 mg/kg i.p.). In 6-hydroxydopamine-lesioned rats, pretreatment with reserpine (5 mg/kg s.c.) diminished L-DOPA (50 mg/kg i.p.)-induced increases in extracellular DA levels to 16% of those obtained in denervated animals not pretreated with reserpine (p<0.01). These results suggest that in the intact striatum, extracellular DA stems mainly from vesicular storage sites and that in the striatum with dopaminergic denervation, a large part of the L-DOPA-derived extracellular DA is also derived from a vesicular pool that is released by an exocytosis mechanism.  相似文献   

13.
Vesicular sequestration is important in the regulation of cytoplasmic concentrations of monoamines such as dopamine. Moreover, recent evidence suggests that increases in cytoplasmic dopamine levels, perhaps attributable to changes in vesicular monoamine transporter function, contribute to methamphetamine-induced dopaminergic deficits. Hence, we examined whether striatal vesicular uptake is altered following methamphetamine treatment. Multiple administrations of methamphetamine rapidly (within 1 h) decreased vesicular dopamine uptake and dihydrotetrabenazine binding, an effect that (a) persisted at least 24 h, (b) was associated with dopamine and not serotonin neurons, and (c) was unrelated to residual drug introduced by the original methamphetamine treatment. These data suggest that methamphetamine rapidly decreases vesicular monoamine transporter function in dopaminergic neurons, a phenomenon that may be associated with the long-term damage caused by this stimulant.  相似文献   

14.
ATP-sensitive K(+) (K(ATP)) channels are composed of pore-forming subunits, typically Kir6.2 in neurons, and regulatory sulfonylurea receptor subunits. In dorsal striatum, activity-dependent H(2)O(2) produced from glutamate receptor activation inhibits dopamine release via K(ATP) channels. Sources of modulatory H(2)O(2) include striatal medium spiny neurons, but not dopaminergic axons. Using fast-scan cyclic voltammetry in guinea-pig striatal slices and immunohistochemistry, we determined the time window for H(2)O(2)/K(ATP)-channel-mediated inhibition and assessed whether modulatory K(ATP) channels are on dopaminergic axons. Comparison of paired-pulse suppression of dopamine release in the absence and presence of glibenclamide, a K(ATP)-channel blocker, or mercaptosuccinate, a glutathione peroxidase inhibitor that enhances endogenous H(2)O(2) levels, revealed a time window for inhibition of 500-1000 ms after stimulation. Immunohistochemistry demonstrated localization of Kir6.2 K(ATP)-channel subunits on dopaminergic axons. Consistent with the presence of functional K(ATP) channels on dopaminergic axons, K(ATP)-channel openers, diazoxide and cromakalim, suppressed single-pulse evoked dopamine release. Although cholinergic interneurons that tonically regulate dopamine release also express K(ATP) channels, diazoxide did not induce the enhanced frequency responsiveness of dopamine release seen with nicotinic-receptor blockade. Together, these studies reveal subsecond regulation of striatal dopamine release by endogenous H(2)O(2) acting at K(ATP) channels on dopaminergic axons, including a role in paired-pulse suppression.  相似文献   

15.
Abstract: Intrastriatal microdialysis was used to administer muscarinic drugs in freely moving rats for 40 min at a flow rate of 2 µl/min. Administration of the nonselective agonist pilocarpine at 10 m M increased striatal dopamine release and decreased extracellular GABA and glutamate overflow. Perfusion with the muscarinic M2 antagonist methoctramine at 75 µ M increased extracellular dopamine and glutamate concentrations but exerted no changes on extracellular GABA levels. Intrastriatal administration of the M1 antagonist pirenzepine at 0.05 µ M decreased extracellular dopamine overflow. Application of pirenzepine (0.05 and 5 µ M ) exerted no effects on the measured GABA or glutamate levels. There are thus important differences in applied doses of muscarinic drugs needed to obtain modulatory effects. High doses of agonists are probably needed to superimpose on the background of tonic influences of striatal acetylcholine, whereas antagonists can block the receptors in small doses. We further suggest that M1 receptors might tonically facilitate striatal dopamine release, that M2 receptors might tonically inhibit striatal glutamate efflux, and that acetylcholine does not exert tonic effects on striatal GABA release. The link with the pilocarpine animal model for temporal lobe epilepsy will be discussed.  相似文献   

16.
The strength and duration of extracellular dopamine concentrations are regulated by the presynaptic dopamine transporter (DAT) and dopamine D2 autoreceptors (D2autoRs). There is a functional interaction between these two proteins. Activation of D2autoRs increases DAT trafficking to the surface whereas disruption of this interaction compromises activities of both proteins and alters dopaminergic transmission. Previously we reported that DAT expression and activity are subject to modulation by protein kinase Cβ (PKCβ). Here, we further demonstrate that PKCβ is integral for the interaction between DAT and D2autoR. Inhibition or absence of PKCβ abolished the communication between DAT and D2autoR. In mouse striatal synaptosomes and transfected N2A cells, the D2autoR‐stimulated membrane insertion of DAT was abolished by PKCβ inhibition. Moreover, D2autoR‐stimulated DAT trafficking is mediated by a PKCβ‐extracellular signal‐regulated kinase signaling cascade where PKCβ is upstream of extracellular signal‐regulated kinase. The increased surface DAT expression upon D2autoR activation resulted from enhanced DAT recycling as opposed to reduced internalization. Further, PKCβ promoted accelerated DAT recycling. Our study demonstrates that PKCβ critically regulates D2autoR‐activated DAT trafficking and dopaminergic signaling. PKCβ is a potential drug target for correcting abnormal extracellular dopamine levels in diseases such as drug addiction and schizophrenia.  相似文献   

17.
Cannabinoid drugs are known to affect dopaminergic neurotransmission in the basal ganglia circuitry. In this study, we used in vitro and in vivo techniques to investigate whether cannabinoid agonists and antagonist could affect dopaminergic transmission in the striatum by acting at the dopamine transporter. Incubation of striatal synaptosomes with the cannabinoid agonists WIN55,212-2 or methanandamide decreased dopamine uptake (IC(50) = 2.0 micromol/L and 3.1 micromol/L, respectively). A similar inhibitory effect was observed after application of the inactive WIN55,212-2 isomer, S(-)WIN55,212-3. The CB(1) antagonist AM251 did not reverse WIN55,212-2 effect but rather mimicked it. WIN55,212-2 and AM251 partially displaced the binding of the cocaine analog [(3)H]WIN35,428, thus acting as dopamine transporter pseudo-substrates in the high micromolar range. High-speed chronoamperometry measurements showed that WIN55,212-2 (4 mg/kg, i.p.) caused significant release of endogenous dopamine via activation of CB(1) receptors, followed by a reduction of dopamine clearance. This reduction was CB(1)-independent, as it was mimicked by S(-)WIN55,212-3. Administration of AM251 (1 and 4 mg/kg, i.p.) increased the signal amplitude and reduced the clearance of dopamine pressure ejected into the striatum. These results indicate that both cannabinoid agonists and antagonists inhibit dopamine transporter activity via molecular targets other than CB(1) receptors.  相似文献   

18.
A network model of simplified striatal principal neurons with mutual inhibition was used to investigate possible interactions between cortical glutamatergic and nigral dopaminergic afferents in the neostriatum. Glutamatergic and dopaminergic inputs were represented by an excitatory synaptic conductance and a slow membrane potassium conductance, respectively. Neuronal activity in the model was characterized by episodes of increased action potential firing rates of variable duration and frequency. Autocorrelation histograms constructed from the action potential activity of striatal model neurons showed that reducing peak excitatory conductance had the effect of increasing interspike intervals. On the other hand, the maximum value of the dopamine-sensitive potassium conductance was inversely related to the duration of firing episodes and the maximal firing rates. A smaller potassium conductance restored normal firing rates in the most active neurons at the expense of a larger proportion of neurons showing reduced activity. Thus, a homogeneous network with mutual inhibition can produce equally complex dynamics as have been proposed to occur in a striatal network with two neuron populations that are oppositely regulated by dopamine. Even without mutual inhibition it appears that increased dopamine concentrations could partially compensate for the effects of reduced glutamatergic input in individual neurons.  相似文献   

19.
Nigrostriatal dopaminergic neurons release dopamine from dendrites in substantia nigra and axon terminals in striatum. The cellular mechanisms for somatodendritic and axonal dopamine release are similar, but somatodendritic and nerve terminal dopamine release may not always occur in parallel. The current studies used in vivo microdialysis to simultaneously measure changes in dendritic and nerve terminal dopamine efflux in substantia nigra and ipsilateral striatum respectively, following intranigral application of various drugs by reverse dialysis through the nigral probe. The serotonin releasers (+/-)-fenfluramine (100 micro m) and (+)-fenfluramine (100 micro m) significantly increased dendritic dopamine efflux without affecting extracellular dopamine in striatum. The non-selective serotonin receptor agonist 1-(m-chlorophenyl)-piperazine (100 micro m) elicited a similar pattern of dopamine release in substantia nigra and striatum. NMDA (33 micro m) produced an increase in nigral dopamine of a similar magnitude to mCPP or either fenfluramine drug. However, NMDA also induced a concurrent increase in striatal dopamine. The D2 agonist quinpirole (100 micro m) had a parallel inhibitory effect on dopamine release from dendritic and terminal sites as well. Taken together, these data suggest that serotonergic afferents to substantia nigra may evoke dendritic dopamine release through a mechanism that is uncoupled from the impulse-dependent control of nerve terminal dopamine release.  相似文献   

20.
Precise regulation of dopaminergic activity is of obvious importance for the physiology and pathology of basal ganglia. We report here that nanomolar concentrations of the astrocyte-derived neuroinhibitory metabolite kynurenic acid (KYNA) potently reduce the extracellular levels of striatal dopamine in unanesthetized rats in vivo. This effect, which is initiated by the KYNA-induced blockade of alpha7 nicotinic acetylcholine receptors, highlights the functional relevance of glia-neuron interactions in the striatum and indicates that even modest increases in the brain levels of endogenous KYNA are capable of interfering with dopaminergic neurotransmission.  相似文献   

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