Effects of D-cycloserine and (+)-HA-966 on the locomotor stimulation induced by NMDA antagonists and clonidine in monoamine-depleted mice

Summary We have previously observed that an N-methyl-D-aspartate (NMDA) antagonist in combination with the 2-adrenoceptor agonist clonidine produces a marked locomotor stimulation in monoamine-depleted mice. In this paper we report on how the partial glycine agonists D-cycloserine (high intrinsic activity) and (+)-HA-966 [(+)-3-amino-1-hydroxypyrrolid-2-one; low intrinsic activity] affect this response; the interaction with both an uncompetitive and a competitive NMDA antagonist was investigated. (+)-HA-966 was found to counteract the locomotor stimulation produced by clonidine combined with either an uncompetitive (MK-801=dizocilpine) or a competitive [D-CPPene=3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid] NMDA antagonist. D-cycloserine potentiated the locomotor stimulation produced by either NMDA antagonist combined with clonidine, although statistical significance was achieved only in the case of MK-801. If the present hyperactivity model has any relevance for psychosis the prediction based on the present results would be that d-cycloserine, contrary to current hopes, might not be so effective in schizophrenia, whereas (+)-HA-966 might be an interesting candidate.     

Ethanol behaves as an NMDA antagonist with respect to locomotor stimulation in monoamine-depleted mice

Summary Previous studies have shown that administration of NMDA antagonists in combination with the ₂-adrenoceptor agonist clonidine results in a marked locomotor stimulation in monoamine-depleted mice, albeit the pattern of movement produced is highly stereotyped and primitive. Ethanol has recently been suggested to display NMDA antagonistic properties; hence, in the present study the ability of ethanol to produce locomotor activation in monoamine-depleted mice with a movement pattern similar to that produced by NMDA antagonists was investigated. It was found that neither ethanol nor clonidine given alone reversed the akinesia induced by pretreatment with reserpine (10 mg/ kg; 18 h) and -methyl-para-tyrosine (500 mg/kg; 2 h). However, when the drugs were combined a marked stimulatory effect was observed and, indeed, the animals displayed the same primitive locomotor pattern previously observed following treatment with NMDA antagonists in conjunction with clonidine. The locomotor response was effectively blocked by pretreatment with the selective ₂-adrenoceptor antagonists yohimbine (10 mg/kg) or idazoxan (10 mg/ kg) but not with the selective ₁-adrenoceptor antagonist prazosin (1 mg/kg). The present results suggest that ethanol in conjunction with ₂-adrenoceptor stimulation induces locomotion in monoamine-depleted mice via a mechanism that may involve interference with glutamate receptor-mediated neurotransmission.     

The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice

Summary It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and -methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.     

Differential locomotor interactions between dopamine D1/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice

Summary Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilpine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in this interaction. To that end, dizocilpine was given in combination with either the DA D 1 receptor agonist SKF 38393 or the selective DA D 2 receptor agonist quinpirole or the preferential DA D 2 agonist bromocriptine. In general, the locomotor stimulatory effects produced by SKF 38393 were potentiated by dizocilpine, whereas the locomotor stimulation produced by quinpirole and bromocriptine was counteracted. However, baseline activity, which partly depends on how much time is allowed to elapse between administration of the DA agonist and commencement of locomotor recording, and partly on the dose of the DA agonist, seems to be an important factor that determines whether dizocilpine will have a weakening or a potentiating effect. Interestingly, the competitive NMDA antagonist D-CPPene displayed a different pattern of interaction with SKF 38393 and quinpirole in that synergistic effects were observed with both DA agonists, most conspicuously so with the DA D 2 receptor agonist.The results are interpreted in the light of present knowledge of basal ganglia neuroanatomy; they are discussed in relation to the direct and indirect pathways from the striatum to the thalamus, proposed to form part of positive and negative cortico-striato-thalamo-cortical loops, respectively, as well as to the presumed presynaptic D 2 receptors on corticostriatal glutamatergic neurons.     

Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice

Summary Activity of trout pineal HIOMT was found to increase with increase in incubation temperature from 5 to 40 °C although the activation energy remained constant over this range. From examination of the effects of the products of HIOMT catalysis on the enzyme it was apparent that the catalytic mechanism was ordered Bi-Bi with S-adenosylmethionine as the obligatory first substrate. Trout HIOMT was found to methylate all the common pineal hydroxyindoles with hydroxytryptophol having the greatest affinity for the enzyme. The pH optimum for trout HIOMT was found to be about pH 9.0 although routine use of a pH of 7.9 is recommended to limit potentially deliterious effects caused by degradation of S-adenosylmethionine at elevated pHs.     

Centrally-administered glycine antagonists increase locomotion in monoamine-depleted mice

Summary It was shown in the present study that several structurally diverse antagonists of the glycine site of the NMDA receptor, including (R)-HA-966, L 689,560, 5,7-dichlorokynurenic acid, 7-chlorokynurenic acid, and two of ZENECA's novel pyridazinoindole glycine antagonists, caused marked reversal of akinesia when administered intrastriatally to monoamine depleted mice. Coinjection of the glycine agonist D-serine antagonized this locomotor stimulation. In addition, all glycine antagonists tested did not cause significant locomotor stimulation when intrastriatally administered to normal mice. These data suggest that glycine antagonists may offer therapeutic utility in the treatment of idiopathic Parkinson's disease.     

Stimulation of growth-hormone release with clonidine does not distinguish individual cases of idiopathic Parkinson's disease from those with Striatonigral Degeneration

Multiple System Atrophy (MSA) and idiopathic Parkinson's disease (PD) can be difficult to distinguish. There is an ongoing debate about the diagnostic value of the growth-hormone response to clonidine (CGH-test) in PD and MSA. We investigated whether the CGH-test can identify individual patients in the early stages of PD (n = 21) and Striatonigral Degeneration (SND, n = 11), a particular variety of MSA. Patients were diagnosed on the basis of clinical criteria and IBZM-SPECT. Clonidine induced a greater total serum growth-hormone production in PD than in SND (p = 0.01). However, taking the difference in prevalence of PD and SND into account, and because of the low likelihood ratios of the test, an increase of GH after clonidine increases the pre-test probability for PD by about only 5 %, while an absent response of GH also increases the pre-test probability for SND by about 5 %. We conclude that the CGH-test discriminates between groups of patients with PD and SND, but has little practical diagnostic value for identifying individual patients. Received: 6 July 2001, Received in revised form: 15 March 2002, Accepted: 18 March 2002     

Increased corticotropin-releasing factor receptors in rat cerebral cortex following chronic atropine treatment

Rats were treated chronically with atropine (14 days, 20 mg/kg/day, s.c.) and corticotropin-releasing factor (CRF) receptors and CRF-mediated adenylate cyclase activity were measured in discrete brain regions. Chronic atropine treatment produced significant increases in muscarinic cholinergic receptors in the frontoparietal cortex (30% increase) and hippocampus (20% increase). No significant changes in the concentration of [¹²⁵I]Tyr^o-rat CRF binding sites were observed in olfactory bulb, cerebellum, striatum and hippocampus. In contrast, there was a significant and selective increase (35%) in CRF receptors in the frontoparietal cortex of atropine-treated rats. However, no significant corresponding changes in the V_max or EC₅₀ of CRF-stimulated adenylate cyclase activity accompanied the upregulation of CRF receptors in the cerebral cortex. These results demonstrate that (1) CRF receptors in rat brain are subject to receptor regulation, (2) the upregulation of CRF receptors occurs as a consequence of chronic muscarinic cholinergic receptor blockade, and (3) this interaction between acetylcholine and CRF may be limited to the cerebral cortex.     

Synergistic interactions between the NMDA antagonist dizocilpine and the preferential dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 with regard to locomotor stimulation in monoamine-depleted mice

Summary When administered to mice pretreated with the monoamine-depleter reserpine and the catecholamine synthesis inhibitor -methyl-para-tyrosine, the preferential autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 induced weak locomotor stimulation. When either (+)-AJ 76 or (+)-UH 232 was combined with a subthreshold dose of the selective NMDA antagonist dizocilpine (MK-801), a marked locomotor stimulation was produced in monoamine-depleted mice. The mechanism of this stimulation, although reduced by dopamine antagonists, remains to be clarified.     

Dopamine agonists potentiate antiakinetic effects of competitive NMDA-antagonists in monoamine-depleted mice

Summary The competitive NMDA-antagonists SDZ EAA-494 and CGP 37849 and the mixed D-1/D-2 dopamine agonists CI 201-678 and SDZ 205-152 reverse akinesia in monoamine-depleted mice in a dose dependent manner. Combination of threshold doses of NMDA-antagonists with dopamine agonists markedly enhances anti-akinetic effects. CI 201-678 which in addition to D-1 and D-2 receptors stimulates -2 receptors produces a stronger effect than SDZ 205-152 which is devoid of -2 agonist activity. The results indicate that concomitant blockade of NMDA-receptors and activation of dopamine receptors results in synergistic or at least additive motor stimulatory effects.     

Antiparkinsonian effect of flupirtine in monoamine-depleted rats

Summary Excitatory amino acid receptor antagonists lead to marked suppression of parkinsonian-like symptoms in rodent and primate models of Parkinson's disease and are able to potentiate the ability of L-DOPA to reverse akinesia and ameliorate muscular rigidity displayed in these animal models. Flupirtine, which is clinically used as a non-opioid analgesic agent, has some N-methyl-D-aspartate (NMDA) antagonistic properties in several in vivo and in vitro experiments. We now report that in monoamine depleted rats (pretreated with reserpine, 5 mg/kg, and -methyl-para-tyrosine, 250mg/ kg i.p.) flupirtine dose-dependently (1–20mg/kg i.p.) suppressed rigidity, measured as tonic EMG activity in the gastrocnemius muscle, but had no effect on akinesia, measured as locomotor activity. In addition, it potentiated the antiparkinsonian effect of L-DOPA on akinesia and rigidity in this rodent model of Parkinson's disease. These effects of flupirtine are of particular clinical relevance, since flupirtine is devoid of the typical side effects of NMDA-receptor antagonists.     

刺激术和毁损术在双侧立体定向手术治疗帕金森病中的比较

目的比较脑深部刺激术和毁损术在双侧立体定向手术治疗帕金森病中的优缺点。方法69例帕金森病病人进行了双侧手术治疗,其中同期双侧丘脑底核(STN)脑深部刺激术(DBS)11例,同期一侧苍白球腹后部毁损术(PVP),另一侧STNDBS3例,分期一侧PVP或腹中间核(Vim)毁损术、另一侧STN或VimDBS9例;分期双侧PVP或Vim毁损术41例,同期双侧PVP5例。平均随访9.3个月。结果UPDRS评分显示刺激术和毁损术均能显著改善对侧肢体震颤、僵硬和运动迟缓症状,双侧刺激术还能改善步态和姿势症状,但双侧毁损术可加重语言、吞咽及流涎等症状,并发症较高。结论双侧DBS是具有双侧症状的帕金森病病人手术治疗的最佳术式,双侧毁损术并发症较高,应严格慎重采用。     

Effect of chronic treatment with riluzole on the nigrostriatal dopaminergic system in weaver mutant mice

The effects of a chronic treatment with the anti-glutamate and sodium channel modulating neuroprotective agent riluzole on the degeneration of dopamine-containing neurons were studied in the brain of weaver mutant mice. In these animals, as in Parkinson's disease, dopaminergic neurons of the nigro-striatal pathway undergo spontaneous and progressive cell death. Homozygous weaver mice were orally treated twice a day with either 8 mg/kg riluzole or placebo for 2 months. Quantification of tyrosine-hydroxylase and dopamine-transporter axonal immunostaining in the striatum revealed that riluzole significantly increased the density of striatal dopaminergic nerve terminals. These results suggest that riluzole protects dopaminergic processes in the weaver mice and/or promotes their neuroplasticity.     

Enhanced neuroprotective effect by combination of bromocriptine and Hypericum perforatum extract against MPTP-induced neurotoxicity in mice

The present study has been designed to evaluate the combined effect of bromocriptine (BRC) and Hypericum perforatum extract (HPE) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in male Swiss Albino mice, which were randomly divided into seven groups of six animals each. Group I served as control. Groups II and III were given 300 mg/kg HPE (po) and 10 mg/kg BRC (i.p.) respectively, once daily for 7 days. The four doses of MPTP (20 mg/kg) were administered intraperitoneally with an interval of 2 h to the groups IV, V, VI and VII. The drug treatment was given to fifth group (10 mg/kg BRC; i.p), sixth group (300 mg/kg HPE; po) and seventh group (300 mg/kg HPE; po and 10 mg/kg BRC; i.p.) once in a day for 7 days and the dose on the first day was given 30 min prior to first MPTP injection. The rotarod test, hang test and forepaw stride length revealed significant improvement by the combined treatment. Dopamine and DOPAC levels were significantly improved (p<0.05). There was a significant reduction in lipid peroxidation after the combined treatment (p<0.05) and the antioxidant status was improved. These findings suggest that the combined effect of BRC and HPE was more pronounced than BRC or HPE alone. So it is concluded that the combined treatment might be preferable to either BRC (or) HPE alone in the effective clinical management of Parkinson's disease.     

Amphetamine-induced hypolocomotion in mice with more brain D2 dopamine receptors

The relationship between brain D₂ dopamine receptors and locomotor response to amphetamine was investigated in eight strains of mice. The D₂ receptor is defined as that dopaminergic site with high affinity (nanomolar) for neuroleptics and low affinity (micromolar) for agonists. D₂ receptors were measured in the striatum and olfactory tubercle using [³H]spiperone and 10 μM sulpiride to define specific binding. Four inbred strains of mice (CBA/J; C57BL/6J; DBA/2J; SEC/1ReJ) had low receptor densities of about 380 and 160 fmoles/mg protein in the striatum and olfactory tubercle, respectively; all these mice were essentially nonresponsive (i.e., locomotion) to low doses of amphetamine (0.5 and 1.0 mg/kg i.p.) or showed hyperlocomotion to high doses (5 mg/kg). Three other mouse strains (BALB/cJ; A/J; C3H/HeJ) had higher densities of about 600 and 230 fmoles/mg protein in the striatum and olfactory tubercle, respectively, and these mice all responded with hypolocomotion to the low doses and hyperlocomotion to the high dose of amphetamine. The two genetically different populations, one of which responded to amphetamine with hypolocomotion while the other did not, are analogous to hyperactive children, only 70% of whom respond to amphetamine-like drugs. Thus, the mice with high receptor density may serve as a model for studying the hyperactivity syndrome which may be associated with dopaminergic dysfunction.     

GFP标记的TH基因在帕金森病大鼠脑内的表达

目的:探讨HTH_1基因治疗帕金森病的可能性。方法:以绿色荧光蛋白(GFP)作为标记,观察HTH_1基因在体外和脑内的表达。结果:构建同时表达GFP和HTH_1双基因的多基因表达载体GC-GFP-P-HTH_1-SN,并转染L-6TG细胞,移植入帕金森病模型大鼠纹状体内,用荧光显微镜、流式细胞仪、免疫组化、Western blotting等方法检测GFP、THT_1在体外和脑内均有表达。结论:本实验为外源基因表达产物的检测提供一个新方法。     

Beneficial effects of a ketamine/atropine combination in soman-poisoned rats under a neutral thermal environment

Exposure to organophosphorus (OP) compounds, such as pesticides and the chemical warfare agents (soman and sarin), respectively represents a major health problem and a threat for civilian and military communities. OP poisoning may induce seizures, status epilepticus and even brain lesions if untreated. We recently proved that a combination of atropine sulfate and ketamine, a glutamatergic antagonist, was effective as an anticonvulsant and neuroprotectant in mice and guinea-pigs exposed to soman. Since OP exposure may also occur in conditions of heat strain due to climate, wearing of protective gears or physical exercise, we previously demonstrated that ketamine/atropine association may be used in a hot environment without detrimental effects. In the present study, we assess soman toxicity and evaluate the effects of the ketamine/atropine combination on soman toxicity in a warm thermoneutral environment. Male Wistar rats, exposed to 31 °C (easily reached under protective equipments), were intoxicated by soman and treated with an anesthetic dose of ketamine combined with atropine sulfate. Body core temperature and spontaneous locomotor activity were continuously monitored using telemetry. At the end of the warm exposure, blood chemistry and brain mRNA expression of some specific genes were measured. In soman-intoxicated animals, metabolic and genic modifications were related to convulsions rather than to soman intoxication by itself. In the warm environment, ketamine/atropine combination did not produce any side-effect on the assessed variables. Furthermore, the ketamine/atropine combination exhibited beneficial therapeutic effects on soman-intoxicated rats such as a limitation of convulsion-induced hyperthermia and of the increase in some blood chemistry markers.     

Improvement in quality of life in patients with advanced Parkinson''s disease following bilateral deep-brain stimulation in subthalamic nucleus

In this article we investigate the changes observed in the scales that quantify the quality of life (PDQ-39) in patients that have already completed 1 and 2 years of bilateral subthalamic stimulation (DBS-STN). Fourteen patients were evaluated 1 year after DBS-STN; the evaluation was repeated on 11 of them, 2 years after surgery. All of them suffered from Parkinson's disease with a 14.3 (+/-5.7) years history of motor complications. Patients were selected according to CAPSIT criteria. All of them were implanted bilateral electrodes in the subthalamic nucleus. The parameters applied were UPDRS II, UPDRS III, PDQ-39, and the scale of quality of life for caregivers (SQLC). Scorings in motor scales (UPDRS III) improved 45% in relation to the first year, and 48% in relation to the second year (P < 0.001). Patient's quality of life (PDQ-39 summary index) improvement was 62% 2 years after surgery (P < 0.001), and caregivers' quality of life improvement was 68% (P = 0.002) by the same time. DBS-STN is a therapy that efficiently improves the quality of life of selected patients with Parkinson's disease. This improvement is still present 2 years after surgery and has a positive impact on caregivers quality of life.     

Differential response in choice reaction time following apomorphine based on prior dopaminergic treatment

Choice reaction time (CRT) paradigms demonstrated deficits in the preparation and execution of movements in patients with Parkinson's Disease (PD). Predominantly these trials did not consider an influence of acute and long-term dopaminergic substitution. Objective was to determine the acute effect of apomorphine on the response to a repeatedly performed CRT task. We repeatedly executed the CRT paradigm before and after subcutaneous apomorphine injection in previously treated, untreated and long-term dopamine substituted PD patients, who took placebo. No significant change of CRT and movement time (MT) appeared in PD patients with chronic dopaminergic drug intake after apomorphine injection. CRT and MT both significantly worsened in untreated PD patients. Placebo application induced no significant alteration. Binding of apomorphine to presynaptic autoreceptors with subsequent sedation or inhibition of locomotor activity hypothetically explain our results in before untreated PD patients. Previous long-term dopaminergic substitution may cause a certain tolerance to this phenomenon.