Modulation of the neurotoxic effects of methamphetamine by the selective kappa-opioid receptor agonist U69593

Kappa-opioid receptor agonists prevent alterations in dopamine neurotransmission that occur in response to repeated cocaine administration. The present microdialysis study examined whether administration of the selective kappa-opioid receptor agonist U69593 with methamphetamine prevents alterations in dopamine levels produced by neurotoxic doses of methamphetamine. Swiss Webster mice were injected intraperitoneally with methamphetamine (10.0 mg/kg) or saline, four times in 1 day, at 2-h intervals. Prior to the first and third injection, they received U69593 (0.32 mg/kg s.c.) or vehicle. Microdialysis was conducted 3, 7, or 21 days later. Basal and K+-evoked (60 and 100 mM) dopamine overflow were reduced 3 days after methamphetamine administration. These effects were long-lasting in that they were still apparent 7 and 21 days after methamphetamine treatment. Intrastriatal (5.0 and 50 microM) or systemic (1.0-10.0 mg/kg) administration of methamphetamine increased dopamine concentrations in control animals. In mice preexposed to methamphetamine, methamphetamine-evoked dopamine overflow was reduced. In animals that had received methamphetamine with U69593, basal dopamine levels did not differ from those of vehicle-treated controls. U69593 treatment attenuated the decrease in K+-evoked dopamine produced by prior methamphetamine exposure. The reduction in methamphetamine-evoked dopamine levels was also attenuated. The administration of U69593 alone did not modify basal or stimulus-evoked dopamine levels. These data demonstrate that repeated methamphetamine administration reduces presynaptic dopamine neuronal function in mouse striatum and that co-administration of a selective kappa-opioid receptor agonist with methamphetamine attenuates these effects. U69593 treatment did not modify the hyperthermic effects of methamphetamine, indicating that this kappa-opioid receptor agonist selectively attenuates methamphetamine-induced alterations in dopamine neurotransmission.     

Effect of intracerebral administration of NMDA and AMPA on dopamine and glutamate release in the ventral pallidum and on motor behavior

The present study investigates the modulation of the ventral tegmental area (VTA)-ventral pallidum (VP) dopaminergic system by glutamate agonists in rats. The glutamate receptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were infused via reversed microdialysis into the VTA, and dopamine (DA), glutamate, and aspartate levels in the VTA and ipsilateral VP were monitored together with motor behavior screened in an open field. NMDA (750 microM) infusion, as well as AMPA (50 microM) infusion, induced an increase of DA and glutamate levels in the VTA, followed by an increase of DA levels in the ipsilateral VP and by enhanced locomotor activity. The increase of DA in the VP was similar after administration of these two glutamate agonists, although motor activity was more pronounced and showed an earlier onset after NMDA infusion. Glutamate levels in the VP were not increased by the stimulation of DA release. It is concluded that DA is released from mesencephalic DA neurons projecting to the VP and that these neurons are controlled by glutamatergic systems, via NMDA and AMPA receptors. Thus, DA in the VP has to be considered as a substantial modulator. Dysregulation of the mesopallidal DA neurons, as well as their glutamatergic control, may play an additional or distinct role in disorders like schizophrenia and drug addiction.     

Simultaneous determination of cholecystokinin,dopamine, glutamate and aspartate in cortex and striatum of the rat using in vivo microdialysis

Summary Extracellular levels of cholecystokinin (CCK), dopamine (DA), glutamate (Glu) and aspartate (Asp) were simultaneously monitored in the frontoparietal cortex and the striatum of halothane-anaesthetized rats using in vivo microdialysis. Under basal conditions, cortical and striatal CCK levels were 3.11 ± 0.39 pM and 2.76 ± 0.15 pM, respectively. Local KCl (10^–1 M) and bicuculline (10^–4 M) co-application in cortex or striatum increased the CCK levels 18-fold and 26-fold, respectively. The DA level in striatum was 3.78 ± 0.28 nM and the local perfusion with KCl + bicuculline led to a 45-fold increase. The cortical and striatal outputs of Glu were of the order of 2 · 10^–6 M and Asp levels were around 6 · 10^–7 M. Local stimulation with KCl (10^–1 M) and bicuculline (10^–4 M) caused a small increase (2 fold) in cortical and striatal levels of Glu and Asp. The addition of KCl (10^–1 M) and bicuculline (10^–4 M) to the cortical perfusion medium did not modify CCK, DA or Glu concentrations in striatum. These results demonstrate that CCK, DA, Glu and Asp may be simultaneously monitored in vivo and support the idea that their extracellular levels recovered in the microdialysis perfusates could be derived from neuronal pools.     

The effect of prolyl oligopeptidase inhibition on extracellular acetylcholine and dopamine levels in the rat striatum

Prolyl oligopeptidase (PREP, EC 3.4.21.26) inhibitors have potential as cognition enhancers, but the mechanism of action behind the cognitive effects remains unclear. Since acetylcholine (ACh) and dopamine (DA) are known to be associated with the regulation of cognitive processes, we investigated the effects of two PREP inhibitors on the extracellular levels of ACh and DA in the rat striatum using in vivo microdialysis. KYP-2047 and JTP-4819 were administered either as a single systemic dose (50 μmol/kg～17 mg/kg i.p.) or directly into the striatum by retrodialysis via the microdialysis probe (12.5, 37.5 or 125 μM at 1.5 μl/min for 60 min). PREP inhibitors had no significant effect on striatal DA levels after systemic administration. JTP-4819 significantly decreased ACh levels both after systemic (by ～25%) and intrastriatal (by ～30-50%) administration. KYP-2047 decreased ACh levels only after intrastriatal administration by retrodialysis (by ～40-50%) when higher drug levels were reached, indicating that higher brain drug levels are needed to modulate ACh levels than to inhibit PREP. This result does not support the earlier hypothesis that the positive cognitive effects of PREP inhibitors in rodents would be mediated through the cholinergic system. In vitro specificity studies did not reveal any obvious off-targets that could explain the observed effect of KYP-2047 and JTP-4819 on ACh levels, instead confirming the concept that these compounds have a high selectivity towards PREP.     

Role of excitatory amino acids in the ventral tegmental area for central actions of non-competitive NMDA-receptor antagonists and nicotine

Summary The putative role of non-NMDA excitatory amino acid (EAA) receptors in the ventral tegmental area (VTA) for the increase in dopamine (DA) release in the nucleus acumbens (NAC) and the behavioural stimulation induced by systemically administered dizocilpine (MK-801) was investigated. Microdialysis was utilized in rats with probes in the VTA and NAC. The VTA was perfused with the AMPA and kainate receptor antagonist CNQX (0.3 or 1.0 mM) or vehicle and dialysates from the NAC were analyzed with high-performance liquid chromatography for DA. Forty min after onset of CNQX or vehicle perfusion of the VTA MK-801 (0.1 mg/kg) was injected subcutaneously (sc). Subsequently, typical MK-801 induced behaviours were assessed. The MK-801 induced hyperlocomotion was associated with a 50% increase of DA levels in NAC dialysates. Both the MK-801 evoked hyperlocomotion and DA release in the NAC were effectively antagonized by CNQX perfusion of the VTA. However, by itself the CNQX or vehicle perusion of the VTA did not affect DA levels in NAC or the rated behaviours. The results indicate that MK-801 induced hyperlocomotion and increased DA release in the NAC are largely elicited within the VTA via activation of non-NMDA EAA receptors, tentatively caused by locally increased EAA release. In contrast, the enhanced DA output in the NAC induced by systemic nicotine (0.5 mg/kg sc) was not antagonized by intra VTA infusion of CNQX (0.3 or 1.0 mM), but instead by infusion of the NMDA receptor antagonist AP-5 (0.3 or 1.0 mM) into the VTA, which by itself did not alter DA levels in the NAC. Thus, the probably indirect, EAA mediated activation of the mesolimbic DA neurons in the VTA by MK-801 and nicotine, respectively, seems to be mediated via different glutamate receptor subtypes.     

Modulation of ventral pallidal dopamine and glutamate release by the intravenous anesthetic propofol studied by in vivo microdialysis

Summary. The intravenous anesthetic propofol is reported to have various psychological side effects as hallucinations, sexual disinhibition, or euphoria. Hedonic and rewarding states like these are modulated by the dopaminergic system in the nucleus accumbens, prefrontal cortex and also in the ventral pallidum and by the glutamatergic system in the neocortex and limbic system. In the present study, propofol was administered either alone or in combination with the GABAA receptor antagonist bicuculline via reverse microdialysis into the ventral pallidum of freely moving rats. Dialysis fractions were taken every 20min and analyzed for dopamine and glutamate using high performance liquid chromatography. Application of propofol decreased dopamine levels in the ventral pallidum. This effect seems to be mainly mediated through GABAA receptors, since it was compensated by the GABAA receptor antagonist bicuculline. Propofol and propofol plus bicuculline exerted no effect on glutamate release in this brain region. The reduced dopamine release in ventral pallidum was most probably mediated through a GABAergic feedback loop from the ventral pallidum via the nucleus accumbens to the dopaminergic neurons of the ventral tegmental area or by long loop feedback. As an increase but not a decrease of dopamine release in the ventral pallidum is involved in hedonic and rewarding properties, similar symptoms induced by propofol seem to be unrelated to an action of propofol in the ventral pallidum.     

Amphetamine increases glutamate efflux in the rat ventral tegmental area by a mechanism involving glutamate transporters and reactive oxygen species

We have shown that amphetamine produces a delayed and sustained increase in glutamate levels in the ventral tegmental area, a region containing dopamine cell bodies important in acute and chronic effects of amphetamine administration. The present study characterized the mechanism underlying amphetamine-induced glutamate efflux. It was abolished by the glutamate uptake inhibitor dihydrokainate, but unaffected by perfusion with a low Ca(2+)/high Mg(2+) solution, implicating glutamate transporters. Because reactive oxygen species inhibit glutamate uptake, we examined the effect of amphetamine on hydroxyl radical formation by perfusing with D-phenylalanine (5 mM) and monitoring p-tyrosine production. Although no increase in hydroxyl radical formation was detected, D-phenylalanine completely prevented the amphetamine-induced increase in glutamate efflux, as did systemic injection of another trapping agent, alpha-phenyl-N-tert-butyl nitrone (60 mg/kg). Thus, amphetamine-induced glutamate efflux may involve reactive oxygen species. In other studies, we found that repeated coadministration of alpha-phenyl-N-tert-butyl nitrone with amphetamine attenuated the development of behavioral sensitization. This supports prior results indicating that the increase in glutamate efflux produced by each amphetamine injection in a chronic regimen is important in triggering drug-induced adaptations in ventral tegmental area dopamine neurons, and that such adaptations may in part represent a response to metabolic and oxidative stress     

Effect of acute and chronic cholinesterase inhibition with diisopropylfluorophosphate on muscarinic, dopamine, and GABA receptors of the rat striatum

The effects of acute and chronic administration of diisopropylfluorophosphate (DFP) to rats on acetylcholinesterase (AChE) activity (in striatum, medulla, diencephalon, cortex, and medulla) and muscarinic, dopamine (DA), and gamma-aminobutyric acid (GABA) receptor characteristics (in striatum) were investigated. After a single injection of (acute exposure to) DFP, striatal region was found to have the highest degree of AChE inhibition. After daily DFP injections (chronic treatment), all brain regions had the same degree of AChE inhibition, which remained at a steady level despite the regression of the DFP-induced cholinergic overactivity. Acute administration of DFP increased the number of DA and GABA receptors without affecting the muscarinic receptor characteristics. Whereas chronic administration of DFP for either 4 or 14 days reduced the number of muscarinic sites without affecting their affinity, the DFP treatment caused increase in the number of DA and GABA receptors only after 14 days of treatment; however, the increase was considerably lower than that observed after the acute treatment. The in vitro addition of DFP to striatal membranes did not affect DA, GABA, or muscarinic receptors. The results indicate an involvement of GABAergic and dopaminergic systems in the actions of DFP. It is suggested that the GABAergic and dopaminergic involvement may be a part of a compensatory inhibitory process to counteract the excessive cholinergic activity produced by DFP.     

Repeated treatment with the kappa opioid receptor agonist U69593 reverses enhanced K+ induced dopamine release in the nucleus accumbens, but not the expression of locomotor sensitization in amphetamine-sensitized rats

The effects after the acute activation of the kappa opioid receptor (KOR) can be distinguished from the effect after repeated administration of KOR agonist. Here, we report the effect of repeated administration of U69593 during abstinence after amphetamine-induced locomotor sensitization. Rats were injected once daily with amphetamine for five consecutive days. From day 6 to 9, rats that developed locomotor sensitization, received once daily injection of U69593 or vehicle. On day 10, all rats were injected with a challenging dose of amphetamine and locomotor activity was measured to assess the expression of sensitization. Microdialysis studies were carried out to assess dopamine extracellular levels in NAc. Rats that develop and express horizontal locomotor sensitization to amphetamine show increased dopamine release in the NAc induced by high K(+). The repeated treatment with U69593 reverses the sensitized depolarization-stimulated dopamine release in the NAc, but not the expression of locomotor sensitization induced by amphetamine. Thus, repeated activation of KORs during early amphetamine withdrawal dissociates the behavioral responses and the neurochemical responses that accompany the expression of sensitization to amphetamine.     

Interactions of glutamate and dopamine in a computational model of the striatum

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.     

Dopamine transporters are involved in the onset of hypoxia-induced dopamine efflux in striatum as revealed by in vivo microdialysis

Although many studies have revealed alterations in neurotransmission during ischaemia, few works have been devoted to the neurochemical effects of mild hypoxia, a situation encountered during life in altitude or in several pathologies. In that context, the present work was undertaken to determine the in vivo mechanisms underlying the striatal dopamine efflux induced by mild hypoxaemic hypoxia. For that purpose, the extracellular concentrations of dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid were simultaneously measured using brain microdialysis during acute hypoxic exposure (10% O₂, 1 h) in awake rats. Hypoxia induced a +80% increase in dopamine. Application of the dopamine transporters inhibitor, nomifensine (10 μM), just before the hypoxia prevented the rise in dopamine during the early part of hypoxia; in contrast the application of nomifensine after the beginning of hypoxia, failed to alter the increase in dopamine. Application of the voltage-dependent Na⁺ channel blocker tetrodotoxin abolished the increase in dopamine, whether administered just before or after the beginning of hypoxia. These data show that the neurochemical mechanisms of the dopamine efflux may change over the course of the hypoxic exposure, dopamine transporters being involved only at the beginning of hypoxia.     

GABAA Receptor Blockade in the Anterior Ventral Tegmental Area Increases Extracellular Levels of Dopamine in the Nucleus Accumbens of Rats

Abstract: Previously, it was shown that microinfusion of the GABA_A antagonist picrotoxin into the anterior ventral tegmental area (VTA) is reinforcing. It was hypothesized that this reinforcing effect of picrotoxin in the anterior VTA is mediated, at least in part, by the activation of the mesoaccumbens dopamine (DA) system. The objective of the present study was to determine if blockade of GABA_A receptors in the anterior VTA can increase extracellular levels of DA in the nucleus accumbens (ACB), using an in vivo microdialysis technique in freely moving rats. Concentrations of picrotoxin (40, 80, and 160 µ M ) that had previously been shown to produce a reinforcing effect increased the extracellular levels of DA and its major metabolites in the ACB. The increased extracellular DA levels induced by intra-VTA injection of picrotoxin was markedly attenuated by coadministration with the GABA_A agonist muscimol, whereas intra-VTA injection of muscimol alone did not have an apparent effect on extracellular DA levels in the ACB. Microinjection of another GABA_A antagonist, bicuculline, into the anterior VTA also increased the extracellular release of DA in the ACB. These results suggest that DA neurons projecting from the anterior VTA to the ACB are tonically inhibited by GABA through its actions at the GABA_A receptors.     

Neuronal dependence of extracellular dopamine,acetylcholine, glutamate,aspartate and gamma-aminobutyric acid (GABA) measured simultaneously from rat neostriatum using in vivo microdialysis: reciprocal interactions

Summary The neuronal origin of extracellular levels of dopamine (DA), acetylcholine (ACh), glutamate (Glu), aspartate (Asp) and gamma-aminobutyric acid (GABA) simultaneously collected from the neostriatum of halothane anaesthetized rats with in vivo microdialysis was studied. The following criteria were applied (1) sensitivity to K⁺-depolarization; (2) sensitivity to inhibition of synaptic inactivation mechanisms; (3) sensitivity to extracellular Ca²⁺; (4) neuroanatomical regionality; sensitivity to selective lesions and (5) sensitivity to chemical stimulation of the characterized pathways.It was found that: (1) Extracellular DA levels found in perfusates collected from the neostriatum fulfills all the above criteria and therefore the changes in extracellular DA levels measured with microdialysis reflect actual release from functionally active nerve terminals, and so reflect ongoing synaptic transmission. (2) Changes in neostriatal ACh levels reflect neuronal activity, provided that a ACh-esterase inhibitor is present in the perfusion medium. (3) Extracellular Glu, Asp and GABA could be measured in different perfusion media in the rat neostriatum and probably reflect metabolic as well as synaptic release. However, (4) the majority of the extracellular GABA levels found in perfusates collected from the neostriatum may reflect neuronal release, since GABA levels were increased, in a Ca²⁺-dependent manner, by K⁺-depolarization, and could be selectively decreased by an intrinsic neostriatal lesion. (5) It was not possible to clearly distinguish between the neuronal and the metabolic pools of Glu and Asp, since neostriatal Glu and Asp levels were only slightly increased by K⁺-depolarization, and no changes were seen after decortication. A blocker of Glu re-uptake, DHKA, had to be included in the perfusion medium in order to monitor the effect of K⁺-depolarization on Glu and Asp levels. Under this condition, it was found (6) that neostriatal Glu and Asp levels were significantly increased by K⁺-depolarization, although only increases in the Glu levels were sensitive to Ca²⁺ in the perfusion medium, suggesting that Glu but not Asp is released from vesicular pools. (7) Evidence is provided that selective stimulations of nigral DA cell bodies may lead to changes in release patterns from DA terminals in the ipsilateral neostriatum, which are in turn followed by discrete changes in extracellular levels of GABA and Glu in the same region. Finally, some methodological considerations are presented to clarify the contribution of neuronal release to extracellular levels of amino acid neurotransmitters in the rat neostriatum.     

Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum

This study investigated, using in vivo microdialysis in the striatum of freely moving rats, the role of striatal serotonin2A (5-HT2A) and 5-HT2C receptor subtypes in the modulation of dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) outflow, both in basal conditions and under activation induced by subcutaneous administration of 0.01 mg/kg haloperidol. The different 5-HT2 agents used were applied intrastriatally at a 1 microM concentration through the microdialysis probe. Basal DA efflux was enhanced (27%) by the 5-HT2A/2B/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and reduced (-30%) by the 5-HT2B/2C antagonist SB 206553. It was unaffected by infusion of the 5-HT2A antagonist SR 46349B. The effect of DOI was abolished by SB 206553 but not modified by SR 46349B. Haloperidol-stimulated DA efflux (65-70%) was reduced by both SR 46349B (-32%) and the 5-HT2A/2B/2C antagonist ritanserin (-30%) but not affected by SB 206553. Conversely, the effect of haloperidol was potentiated (22%) when DOI was coperfused with SB 206553. Also, haloperidol-stimulated DOPAC outflow (40-45%) was reduced (-20%) by SR 46349B and potentiated (25%) by the combination of SB 206553 with DOI. These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic.     

Regulatory effects of D2 receptors in the ventral tegmental area on the mesocorticolimbic dopaminergic pathway

To investigate the regulatory effects of somatodendritic D2 receptors on the terminal's extracellular dopamine (DA) concentration, a D2 antagonist (eticlopride) was infused directly into the ventral tegmental area via a microdialysis probe in chloral hydrate-anesthetized rats. Extracellular DA changes in both the nucleus accumbens (N ACC) and the medial prefrontal cortex (mPFC) were monitored. Infusion of 10.0 fM eticlopride had no effect on DA in the mPFC (110.2 +/- 10.0% of baseline) but significantly increased DA in the N ACC (150.1 +/- 11.7%). Infusion of a higher dose of eticlopride (100.0 or 1,000.0 fM) significantly augmented the DA in the mPFC (121.1 +/- 7.6 and 180.7 +/- 25.8%, respectively) but surprisingly had no effect on DA in the N ACC (111.5 +/- 7.3 and 104.1 +/- 8.7%, respectively). To further investigate whether the bluntness of DA increase in the N ACC was due to DA receptor activation in the mPFC, eticlopride or SCH23390 was infused into the mPFC prior to and during intrategmental eticlopride infusion, and the change of DA in the N ACC was simultaneously monitored. During intra-mPFC 1.0 nM eticlopride infusion but not during 10.0 nM SCH23390 administration (95.5 +/- 6.1%), intrategmental 1,000.0 fM eticlopride infusion could further elevate DA in the N ACC (130.0 +/- 4.6%). Our results indicated that (1) the mesolimbic and the mesocortical pathways were under tonic inhibition by somatodendritic D2 receptors; (2) the DA concentration in the N ACC first increased and then returned to baseline while the intrategmental infusion dose of eticlopride increased; and (3) the bluntness of DA increase in the N ACC resulted from the D2 receptor activation in the mPFC.     

Glutamatergic Regulation of Basal and Stimulus-Activated Dopamine Release in the Prefrontal Cortex

Abstract: The present study was undertaken to determine whether basal and stimulus-activated dopamine release in the prefrontal cortex (PFC) is regulated by glutamatergic afferents to the PFC or the ventral tegmental area (VTA), the primary source of dopamine neurons that innervate the rodent PFC. In awake rats, blockade of NMDA or α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in the VTA, or blockade of AMPA receptors in the PFC, profoundly reduced dopamine release in the PFC, suggesting that the basal output of dopamine neurons projecting to the PFC is under a tonic excitatory control of NMDA and AMPA receptors in the VTA, and AMPA receptors in the PFC. Consistent with previous reports, blockade of cortical NMDA receptors increased dopamine release, suggesting that NMDA receptors in the PFC exert a tonic inhibitory control on dopamine release. Blockade of NMDA or AMPA receptors in the VTA as well as blockade of AMPA receptors in the PFC reduced the dopaminergic response to mild handling, suggesting that activation of glutamate neurotransmission also regulates stimulus-induced increase of dopamine release in the PFC. In the context of brain disorders that may involve cortical dopamine dysfunction, the present findings suggest that abnormal basal or stimulus-activated dopamine neurotransmission in the PFC may be secondary to glutamatergic dysregulation.     

Comparison of alterations in tyrosine hydroxylase,dopamine levels,and dopamine uptake in the striatum of the weaver mutant mouse

Previous reports have shown that among the markers for the nigro-striatal dopamine (DA) system measured in the striatum, dopamine uptake seems to be more severely affected than the others in the weaver mutant mouse. In the present study we examined DA levels, tyrosine hydroxylase (TH) activity, and high-affinity DA uptake to determine if the DA uptake is most affected when all the measurements are made in the same striatal homogenate in the same laboratory. We found that the DA uptake activity was most altered (93% lower) compared to DA levels (68% lower) and TH activity (64% lower). The DA uptake was so low in the weaver that we could not obtain reliable kinetic parameters. For TH activity we found that the Vmax was 36% lower while the Km forl-tyrosine was 92% higher in the weaver striatum. This lower affinity for substrate suggests that the TH enzyme itself may be altered in the nigro-striatal system of the weaver mutant mouse.Special issue dedicated to Dr. Morris H. Aprison.     

Role of glutamate in neurodegeneration of dopamine neurons in several animal models of parkinsonism

Summary Although controversial, studies with methamphetamine and MPTP suggest a link between glutamate-mediated excitotoxicity and degeneration of dopamine cells. Both compounds are thonght to create a metabolic stress. To further explore glutamate actions in DA degeneration, we investigated the effects of other metabolic inhibitors. In mesencephalic cultures, DA cell loss produced by 3-NPA or malonate was potentiated by NMDA and prevented by MK-801. In vivo, striatal DA loss produced by intranigral infusions of malonate was also potentiated by intranigral NMDA and prevented by systemic MK-801. In contrast, systemic MK-801 did not prevent DA loss produced by intrastriatal malonate. Intrastriatal MK-801 or CGS 19755 did attenuate DA loss in METH-treated mice, but was confounded by the findings that METH-induced hyperthermia, an important component in toxicity, was also attenuated. Taken together, the data support the hypothesis of NMDA receptor involvement in degeneration of DA neurons. Furthermore, the data also suggest that this interaction is likely to occur in the substantia nigra rather than in the striatum.