Glutamatergic Overactivity Research Articles

Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned malerats.

Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson's disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019). In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum. The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration. Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.

Role of P11 through serotonergic and glutamatergic pathways in LID.

Parkinson's disease is a progressive neurodegenerative disorder caused by the degeneration of dopaminergic neurons. This leads to the pathogenesis of multiple basal ganglia-thalamomotor loops and diverse neurotransmission alterations. Dopamine replacement therapy, and on top of that, levodopa and l-3,4-dihydroxyphenylalanine (L-DOPA), is the gold standard treatment, while it develops numerous complications. Levodopa-induced dyskinesia (LID) is well-known as the most prominent side effect. Several studies have been devoted to tackling this problem. Studies showed that metabotropic glutamate receptor 5 (mGluR5) antagonists and 5-hydroxytryptamine receptor 1B (5HT1B) agonists significantly reduced LID when considering the glutamatergic overactivity and compensatory mechanisms of serotonergic neurons after L-DOPA therapy. Moreover, it is documented that these receptors act through an adaptor protein called P11 (S100A10). This protein has been thought to play a crucial role in LID due to its interactions with numerous ion channels and receptors. Lately, experiments have shown successful evidence of the effects of P11 blockade on alleviating LID greater than 5HT1B and mGluR5 manipulations. In contrast, there is a trace of ambiguity in the exact mechanism of action. P11 has shown the potential to be a promising target to diminish LID and prolong L-DOPA therapy in parkinsonian patients owing to further studies and experiments.

Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity

Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.

Safinamide modulates levodopa induced striatal glutamatergic overactivity in a rat model of Parkinson's disease

Safinamide modulates levodopa induced striatal glutamatergic overactivity in a rat model of Parkinson's disease

Ascorbate prevents cell death from prolonged exposure to glutamate in an in vitro model of human dopaminergic neurons

Ascorbate (vitamin C) is a nonenzymatic antioxidant highly concentrated in the brain. In addition to mediating redox balance, ascorbate is linked to glutamate neurotransmission in the striatum, where it renders neuroprotection against excessive glutamate stimulation. Oxidative stress and glutamatergic overactivity are key biochemical features accompanying the loss of dopaminergic neurons in the substantia nigra that characterizes Parkinson's disease (PD). At present, it is not clear whether antiglutamate agents and ascorbate might be neuroprotective agents for PD. Thus, we tested whether ascorbate can prevent cell death from prolonged exposure to glutamate using dopaminergic neurons of human origin. To this purpose, dopamine-like neurons were obtained by differentiation of SH-SY5Y cells and then cultured for 4 days without antioxidant (antiaging) protection to evaluate glutamate toxicity and ascorbate protection as a model system of potential factors contributing to dopaminergic neuron death in PD. Glutamate dose dependently induced toxicity in dopaminergic cells largely by the stimulation of AMPA and metabotropic receptors and to a lesser extent by N-methyl-D-aspartate and kainate receptors. At relatively physiological levels of extracellular concentration, ascorbate protected cells against glutamate excitotoxicity. This neuroprotection apparently relies on the inhibition of oxidative stress, because ascorbate prevented the pro-oxidant action of the scavenging molecule quercetin, which occurred over the course of prolonged exposure, as is also seen with glutamate. Our findings show the relevance of ascorbate as a neuroprotective agent and emphasize an often underappreciated role of oxidative stress in glutamate excitotoxicity. Occurrence of a glutamate-ascorbate link in dopaminergic neurons may explain previous contradictions regarding their putative role in PD.

Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation

Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. This study was aimed to examine several brain chemical mediators, including Glx (glutamate + glutamine), using (1)H magnetic resonance spectroscopy (MRS) in medicated patients with schizophrenia, with and without psychotic exacerbation. (1)H MRS was acquired in 24 patients with schizophrenia, with psychotic exacerbation; 22 patients without exacerbation; and 27 age- and sex-matched healthy volunteers. The levels of metabolites were measured in the left frontal and inferior parietal white matter and compared across the three groups. The Glx level was significantly elevated in the left inferior parietal white matter in the patients with psychotic exacerbation in comparison with that in the healthy volunteers and the patients without exacerbation (P < 0.05). We also detected that there was a significant correlation between Positive and Negative Syndrome Scale-positive scale and Glx level in the left parietal white matter (r = 0.51, P < 0.001). Higher than normal Glx levels indicate glutamatergic overactivity in the left inferior parietal white matter with schizophrenic exacerbation, a finding that is in accordance with the glutamatergic hypothesis in schizophrenia. The Glx level measured by (1)H MRS could be a biomarker for exacerbation in schizophrenia.

Inhibition of sigma-1 receptor reduces N-methyl- d-aspartate induced neuronal injury in methamphetamine-exposed and -naive hippocampi

Acute and prolonged methamphetamine (METH) exposure has been reported to moderate the function of N-methyl- d-aspartate type glutamate receptors (NMDAr) in the hippocampus. These effects have been found to be associated with enhanced NMDAr-dependent release of Ca 2+ from IP 3-sensitive intracellular stores. The present studies were designed to extend these findings and examine the role of the endoplasmic membrane (ER) bound orphan receptor, the sigma-1 receptor, in NMDA-induced neuronal injury and METH withdrawal-potentiated NMDA-induced neuronal injury. Organotypic hippocampal slice cultures were exposed to METH (0 or 100 μM) for 6 days and withdrawn for 7 days, then exposed to NMDA (0 or 5 μM) for 24 h. Additional cultures were also exposed to this regimen and were co-incubated with BD1047 (100 μM), a specific inhibitor of ER-bound sigma-1 receptors, for the 24 h NMDA exposure. Cytotoxicity was assessed by analysis of propidium iodide uptake. These studies demonstrated that protracted METH exposure and withdrawal significantly potentiated the neuronal injury produced by NMDA exposure. Further, co-exposure to BD1047 with NMDA markedly attenuated neuronal injury in METH-naïve and METH-withdrawn organotypic cultures. As a whole, these data demonstrate that prolonged METH exposure, even at non-toxic concentrations, significantly alters glutamate receptor signaling. Inhibition of sigma-1 receptor-dependent Ca 2+ release from the ER entirely prevented NMDA-induced toxicity in METH-naïve cultures and markedly reduced METH-potentiated toxicity. These findings demonstrate the importance of Ca 2+-induced intracellular Ca 2+ release in excitotoxic insult and suggest that blockade of glutamatergic overactivity may represent a therapeutic target in the treatment of METH withdrawal.

Extracellular amino acid levels in the striatum of the dtsz mutant, a model of paroxysmal dystonia

The pathophysiology of idiopathic dystonia is still unknown, but it is regarded as a basal ganglia disorder. Previous studies indicated an involvement of a striatal GABAergic disinhibition and a cortico-striatal glutamatergic overactivity in the manifestation of stress-inducible dystonic episodes in the dt sz hamster, a model of idiopathic paroxysmal dystonia. These investigations were carried out postmortem or in anesthetized animals. In the present study, in vivo microdialysis in conscious, freely-moving dt sz and non-dystonic control hamsters was used to examine the levels of GABA, aspartate, glutamate, glutamine, glycine and taurine in each animal during following conditions: (1) at baseline in the absence of dystonia, (2) during an episode of paroxysmal dystonia precipitated by stressful stimuli, (3) during a recovery period and (4) at baseline after complete recovery. In comparison to non-dystonic controls, which were treated in the same manner as the dystonic animals, no differences could be detected under basal conditions. The induction of a dystonic episode in mutant hamsters led to higher contents of glycine in these animals in comparison to stressed but non-dystonic controls. Significant changes of glycine levels within the animal groups were not detected. The levels of the excitatory amino acids glutamate, glutamine and aspartate as well as the levels of the inhibitory amino acids GABA and taurine did not differ between the animal groups or between the periods of measurement. The higher levels of glycine might contribute to the manifestation of paroxysmal dystonia in dt sz hamsters, although unaltered glutamate, glutamine and aspartate levels do not support the hypothesis of a critical involvement of a cortico-striatal overactivity. It seems that a deficiency of GABAergic interneurons, found by previous immunohistochemical examinations, does not lead to reduced extracellular GABA levels in the striatum.

Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania

At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio and levels of other metabolites in acute mania and schizophrenia in this exploratory study. Data were obtained from 2 x 2 x 2 cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 Tesla and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and 17 schizophrenia patients with acute psychosis were recruited from an inpatient unit; 21 matched healthy control subjects were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated measures design. Medication effects and relationship to demographic and clinical variables were analyzed. Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy control subjects. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios. The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.

The magnitude of hippocampal long term depression depends on the synaptic location of activated NR2-containing N-methyl-d-aspartate receptors

Activation of N-methyl-d-aspartate receptors (NMDARs) is the first step in the induction of certain forms of synaptic plasticity in the hippocampus. In the adult rat hippocampus, NMDARs are composed almost exclusively of NR1 and NR2 subunits with NR1 subunits being mainly associated with either NR2A and/or NR2B subunits. The role played by the different subunits in synaptic plasticity is still controversial. In the present study, we used two different long term depression (LTD) –inducing protocols (electrical and chemical stimulation) to show that activation of NR2A-containing NMDAR subunits leads to the induction of LTD. We also demonstrated that extrasynaptic NR2B-containing NMDARs regulate the magnitude of LTD by exerting a control over the function of synaptic NR2A-containing NMDARs while having no effect on plasticity in the absence of synaptic receptor activation. Taken as a whole, these experiments demonstrate that NMDAR subunits play different roles according to their nature (NR2A or NR2B) and location (synaptic versus extrasynaptic). This sheds new light on the functional role of extrasynaptic NR2B containing-NMDARs. These results are particularly important for a better understanding of certain pathological disorders associated with glutamatergic overactivity.

Effects of intrastriatal injections of glutamate receptor antagonists on the severity of paroxysmal dystonia in the dtsz mutant

Imbalances of the glutamatergic system are implicated in the pathophysiology of various basal ganglia disorders, but few is known about their role in dystonia, a common neurological syndrome in which involuntary muscle co-contractions lead to twisting movements and abnormal postures. Previous systemic administrations of glutamate receptor antagonists in dt sz hamsters, an animal model of primary paroxysmal dystonia, exerted antidystonic effects and electrophysiological experiments pointed to an enhanced corticostriatal glutamatergic activity. In order to examine the pathophysiological relevance of these findings, we performed striatal microinjections of the α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor antagonist 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) and the N-methyl- d-aspartate (NMDA) receptor antagonists d(−)-2-amino-5-phosphopentanoic acid (AP-5), ( R)-(+)-3-amino-1-hydroxypyrrolidin-2-one (HA-966) and dizocilpine (MK-801). The striatal application of NBQX reduced the severity and increased the latency to onset of dystonia significantly only at a dosage of 0.08 μg per hemisphere, lower (0.03 μg) and higher dosages (0.16 μg and 0.32 μg) failed to exert comparable effects on the severity. None of the striatal injected NMDA receptor antagonists influenced the severity of the dystonic attacks in the mutant hamster. The combined application of NBQX (0.08 μg) with AP-5 (1.0 μg) failed to exert synergistic antidystonic effects, but the beneficial effect on the severity of dystonia of the single application of NBQX was reproduced. Therefore, corticostriatal glutamatergic overactivity mediated by AMPA receptors, but not by NMDA receptors, is possibly important for the manifestation of dystonic attacks in the dt sz hamster mutant.

Blockade of mGluR5 glutamate receptors in the subthalamic nucleus ameliorates motor asymmetry in an animal model of Parkinson's disease

It has been suggested that Group I metabotropic glutamate receptor antagonists could have potential therapeutic value in the treatment of Parkinson's disease. There is evidence that when given systemically, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a metabotropic glutamate receptor type 5 (mGluR5) antagonist, produces anti-parkinsonian effects in animal models, but the site of action has not been directly established. In the present study, we examined whether the subthalamic nucleus (STN) and its output structures may mediate such an effect using a unilateral rat model of Parkinson's disease. A battery of simple behavioral tests, reliably sensitive to dopamine depletion, was applied consecutively: (i) prior to surgery; (ii) 3 weeks following a unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta; (iii) at 1 h, 24 h and 4 days following a microinjection of MPEP, via an indwelling cannula, into the STN, entopeduncular nucleus (EP) or substantia nigra zona reticulata. Unilaterally dopamine-depleted animals typically had severe motor and sensorimotor asymmetries 3 weeks following surgery. Microinjection of 25 nmol MPEP into the STN of these animals significantly attenuated these asymmetries relative to vehicle. Further microinjections of lower doses (5 and 10 nmol) revealed a dose-response effect. Microinjection of MPEP into either the EP or substantia nigra zona reticulata was without effect. These data suggest that MPEP may act at the level of the STN to reduce glutamatergic overactivity and thereby induce anti-parkinsonian effects.

Subthalamic nucleus lesion reverses motor abnormalities and striatal glutamatergic overactivity in experimental parkinsonism

Subthalamic nucleus (STN) is a target of choice for the neurosurgical treatment of Parkinson’s disease (PD). The therapeutic effect of STN lesion in PD is classically ascribed to the rescue of physiological activity in the output structures of the basal ganglia, and little is known about the possible involvement of the striatum. In the present study, therefore, we electrophysiologically recorded in vitro single striatal neurons of DA-depleted rats unilaterally lesioned by 6-hydroxydopamine, treated or not with therapeutic doses of levodopa ( l-DOPA), or with a consecutive ipsilateral STN lesion. We show that the beneficial motor effects produced in parkinsonian rats by STN lesion or l-DOPA therapy were paralleled by the normalization of overactive frequency and amplitude of striatal glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Since neither l-DOPA treatment nor STN lesion affected sEPSCs kinetic properties, the reversal of these abnormalities in striatal excitatory synaptic transmission can be attributable to the normalization of glutamate release.

Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism

Levodopa (l-dopa) therapy is still considered the gold-standard in the treatment of Parkinson's disease. However, the synaptic and cellular mechanisms involved in the amelioration of motor symptoms during this treatment are still unclear. To address this issue, we analysed the physiological and pharmacological properties of striatal glutamatergic and GABAergic synaptic transmission in an experimental model of Parkinson's disease. Single-cell recordings were performed in sham-operated rats, in 6-hydroxydopamine-lesioned animals and in rats receiving chronic l-dopa treatment following dopamine (DA) denervation. We utilized a dose of l-dopa (10 mg/kg, twice daily for 21 days) able to reverse motor deficits in about half of parkinsonian animals. In the striatum of parkinsonian animals showing therapeutic benefits following l-dopa treatment, we observed a reversal of glutamatergic overactivity and of the hypersensitivity of presynaptic D2 DA receptors controlling glutamate release from corticostriatal terminals. Conversely, no change was detected in the sensitivity of presynaptic D2 DA receptors modulating striatal GABA transmission in both parkinsonian and l-dopa-treated rats. We suggest that the reversal of striatal glutamatergic overactivity and the normalization of hypersensitive D2 DA receptors modulating excitatory transmission might underlie some of the therapeutic actions of l-dopa in Parkinson's disease.

Polyamines in a genetic animal model of paroxysmal dyskinesia

Previous studies suggested that glutamatergic overactivity contributes to the manifestation of dystonia in the dt sz mutant hamster, a model of idiopathic paroxysmal dyskinesia in which dystonic episodes occur in response to mild stress. Therefore, the role of polyamines, known as positive modulators of NMDA receptors, was examined in the present study. The levels of polyamines (putrescine, spermidine, spermine) were determined in forebrain, cerebellum and brainstem in dt sz hamsters at an age of most marked expression of dystonia (32 days) and in age-matched non-dystonic control hamsters. Spermine was found to be significantly increased in the forebrain (35%) of dystonic animals, while spermidine was unaltered in dystonic brains and only a moderate increase in putrescine (12%) was detected in the cerebellum of dt sz mutants. In view of enhanced spermine levels, the effect of the putative polyamine receptor antagonist ifenprodil on the severity of dystonia was examined in dystonic hamsters. Ifenprodil (5–40 mg/kg i.p.) failed to exert a beneficial effect, but even aggravated dystonia in the dt sz mutant at higher doses. These data together with previous pharmacological findings in mutant hamsters do not completely exclude a pathophysiological role of enhanced polyamine levels but suggest that overstimulation of NMDA receptors which contain NR2B subunits by enhanced spermine levels is not involved in the dystonic syndrome.

Which factors influence therapeutic decisions in Parkinson's disease?

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years, some but not all pathogenetic mechanisms causing dyskinesias in PD have become better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and colocalized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long-acting DA-agonists or highly selective D2-agonists. Another strategy is the use of NMDA antagonists.

Changes in AMPA Receptor Binding in an Animal Model of Inborn Paroxysmal Dystonia

Previous pharmacological studies suggested that glutamatergic overactivity contributes to manifestation of dystonic attacks in mutant hamsters (dtsz), a model of idiopathic paroxysmal dystonia in which episodes of dystonia occur in response to stress. In the present study, [3H]AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor binding was determined by autoradiographic analyses in 41 brain (sub)regions of dtsz hamsters under basal conditions, i.e., in the absence of dystonia, and in a group of mutant hamsters that exhibited severe stress-induced dystonic attacks immediately prior to sacrifice. In comparison to nondystonic control hamsters the basal [3H]AMPA binding was significantly higher in the ventromedial and ventrolateral caudate putamen, the anterior cingulate cortex, the hippocampus, and the lateral septum of dystonic brains. During dystonic attacks the [3H]AMPA binding was significantly lower in the dorsomedial, dorsolateral, and posterior caudate putamen; the ventromedial thalamus; and the frontal cortex of mutant hamsters compared with control animals that were exposed to the same external stimulation. The basal increase in AMPA receptor density within limbic structures may contribute to the susceptibility of stress-inducible dystonic episodes in mutant hamsters. Since AMPA receptor activation is known to cause a fast reduction of the affinity and an internalization of postsynaptic AMPA receptors, the latter finding could reflect a glutamatergic overactivity within the striato-thalamo-cortical circuit during the expression of dystonia, which is in line with previous neurochemical and pharmacological data in dtsz hamsters.

A PET study with [11-C]raclopride in Parkinson's disease: preliminary results on the effect of amantadine on the dopaminergic system.

Amantadine has been proved to be beneficial in Parkinson's disease. Although it is still uncertain which neurochemical events are modified at therapeutic doses, an increase in dopaminergic tone secondary to NMDA receptor blockade and a direct inhibition of the glutamatergic overactivity have been suggested to be involved in its clinical effects. The aim of this study was to evaluate the effects of amantadine on the dopaminergic system by measuring the in vivo binding of [11-C]raclopride to D2 dopamine receptors in the basal ganglia of 6 patients with idiopathic Parkinson's disease. Each patient underwent a PET study, before and after 14 days of treatment with amantadine (200 mg/day). Repeated treatment with therapeutic doses of amantadine induced a moderate increase in the in vivo binding of [11C]raclopride in the putamen of PD patients. This observation indicates that in PD patients, 200 mg/day amantadine does not produce an increase in extracellular levels of dopamine sufficiently to inhibit raclopride binding or that, if present, is it masked by a concurrent increase in receptor availability, as recently reported in rat striatum.

Neuroprotective effects of (+/-)-kavain in the MPTP mouse model of Parkinson's disease.

This is the first study to investigate the potential protective effects of the lipophilic kavapyrone (+/-)-kavain in the experimental MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD). Male C57BL/6 mice were treated with (+/-)-kavain (50, 100, or 200 mg/kg i.p.) or vehicle 60 min before and 60 min after a single administration of MPTP (30 mg/kg s.c.) or saline, respectively. Mice were sacrificed after 7 days and the neostriatum was analyzed for dopamine and its metabolites using HPLC with electrochemical detection. Furthermore, nigral sections were processed for tyrosine hydroxylase (TH) immunocytochemistry. To determine the effects of (+/-)-kavain (200 mg/kg) on MPTP metabolism, HPLC analysis of striatal MPP(+) (1-methyl-4-phenylpyridinium) levels was performed. MPTP treatment alone led to a significant depletion of striatal dopamine levels to 12.61% of saline controls. The lower dosages of (+/-)-kavain (50 and 100 mg/kg) showed only a nonsignificant attenuation of MPTP-induced dopamine depletion, but a high dosage of (+/-)-kavain (200 mg/kg) significantly antagonized the dopamine depletion to 58.93% of saline control values. Remarkably, the MPTP-induced decrease of TH-immunoreactivity as well as the loss of nigral neurons was completely prevented by (+/-)-kavain (200 mg/kg). Striatal MPP(+) levels were not altered by (+/-)-kavain treatment. In conclusion, we found that MPTP metabolism was not influenced by (+/-)-kavain and postulate the antiglutamatergic effects of (+/-)-kavain for its protective effects against MPTP toxicity. (+/-)-Kavain may be a novel candidate for further preclinical studies in animal models of PD and other disorders with glutamatergic overactivity.

Dyskinesia in Parkinson's disease. Pathophysiology and clinical risk factors.

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years some but not all pathogenetic mechanisms causing dyskinesias in PD have been better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and co-localized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long acting DA agonists or highly selective D2 agonists. Another strategy is the use of NMDA antagonists.