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.     

A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice

Summary Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain. When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT). These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain. Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone. The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased. Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems. However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context.     

Regulation of dopamine release and metabolism in rat striatum in vivo: Effects of dopamine receptor antagonists

1. 1. The acute effects of some of typical and atypical antipsychotic drugs on the dopamine release and metabolism in the dorsal striatum of freely moving rats were studied using transcerebral microdialysis technique.

2. 2. Classical neuroleptic drugs haloperidol (0.05, 0.1 and 0.2 mg/kg), thioproperazine (0.1, 0.2 and 0.4 mg/kg) and spiperone (0.02, 0.04 and 0.07 mg/kg) administered i.p. induced pronounced elevation of extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) up to 250–300 % to basal level while producing less increase in that of dopamine (DA) (up to 150–170 %).

3. 3. Atypical neuroleptics clozapine and thioridazine (both 2, 5 and 20 mg/kg) increased striatal DA release and DOPAC level approximately at the same degree (maximally up to 200% and 160%, respectively).

4. 4. Dopamine D3 receptor and autoreceptor preferring antagonists (+)-UH232 and (+)-AJ76 (both 4, 7 and 14 mg/kg) more potently increased DA release in comparison with DOPAC dialysate level ( (+)-AJ76 elevated DA level maximally up to 330 %, DOPAC - up to 250 %).

5. 5. The features of typical and atypical neuroleptics in preferential action on DA release or DOPAC output were observed in all doses of the drugs studied .

6. 6. The ability of the drugs to affect preferentially DA release or DOPAC extracellular level in rat striatum correlates to their relative affinities at D3 and D2 DA receptors.

7. 7. It is concluded that typical and atypical antipsychotic drugs might be clearly distinguished on the basis of their ability to affect preferentially DA synthesis/metabolism or release in rat dorsal striatum in vivo.

     

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA–dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel ¹¹C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean ± SD) in specific ¹¹C-raclopride binding from baseline for ketamine (11.2 ± 8.9) was greater than for saline (1.9 ± 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean ± SD) in specific ¹¹C-raclopride binding caused by amphetamine (15.5 ± 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in ¹¹C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed. Synapse 29:142–147, 1998. Published 1998 Wiley-Liss, Inc.     

MK-801, phencyclidine (PCP), and PCP-like drugs increase burst firing in rat A10 dopamine neurons: Comparison to competitive NMDA antagonists

Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (±)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 19755 and (±) CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists. © 1993 Wiley-Liss, Inc.     

NMDA and dopamine interactions in the nucleus accumbens modulate cortical acetylcholine release

The nucleus accumbens (NAC) plays a key role in directing appropriate motor output following the presentation of behaviorally relevant stimuli. As such, we postulate that accumbens efferents also participate in the modulation of neuronal circuits regulating attentional processes directed toward the identification and selection of these stimuli. In this study, N-methyl-d-aspartate (NMDA) and D1 ligands were perfused into the shell region of the NAC of awake rats. Cortical cholinergic transmission, a mediator of attentional processes, was measured via microdialysis probes inserted into the prefrontal cortex (PFC). NMDA perfusions (150 or 250 microm) into NAC resulted in significant increases in acetylcholine (ACh) efflux in PFC (150-200% above baseline levels). Co-administration of the D1 antagonist SCH-23390 (150 microm) markedly attenuated (by approx. 70%) ACh efflux following perfusions of 150 microm NMDA but not following 250 microm NMDA, suggesting that D1 receptor activity contributes to the ability of the lower but not the higher concentration of NMDA to increase cortical ACh release. Collectively, these data reveal a positive modulation of NMDA receptors by D1 receptors in NAC that is expressed trans-synaptically at the level of cortical transmission. This modulation may underlie the coordinated linking of attentional processes and motor output following exposure to salient and behaviorally relevant stimuli.     

Involvement of corticostriatal glutamatergic terminals in striatal dopamine release elicited by stimulation of delta-opioid receptors

We have previously shown that striatal dopamine release induced locally by a delta-opioid receptor agonist was totally inhibited by a glutamate N-methyl-D-aspartate receptor antagonist, indicating the involvement of glutamatergic receptors in this effect. The aim of the present study was to specify this mechanism. Firstly, we investigated the effect of [D-Pen2,D-Pen5]-enkephalin (DPDPE) on glutamate release in rats by intrastriatal microdialysis. The infusion of DPDPE (10 microm) enhanced the glutamate content in dialysate by approximately 34%, an effect which did not appear to result from inhibition of glutamate uptake. We then considered the consequences of a unilateral thermocoagulation of the frontal cortex on either glutamate or dopamine release induced by stimulation of delta-opioid receptors 2 days later. This lesion, which decreased the glutamate content in ipsilateral striatum by approximately 30%, totally prevented the increase in dialysate levels of glutamate induced by DPDPE. Moreover, whereas DPDPE (10 microm) was found to increase the striatal dopamine release in intact animals by approximately 59%, this effect was also completely suppressed by the cortical lesion. Finally, we studied the effect of the lesion on the [3H]-DPDPE binding to striatal membranes prepared from the whole striatum. In the ipsilateral striatum a significant decrease in this [3H]-DPDPE binding (by approximately 18%) was found 2 days after the lesion. Our results indicate that the increase in striatal dopamine release induced by DPDPE probably depends on glutamate release from corticostriatal glutamatergic afferents in response to the stimulation of delta-opioid receptors located on terminals of these neurons.     

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.     

Differential effects of LY235959, a competitive antagonist of the NMDA receptor on κ-opioid receptor agonist induced responses in mice and rats

The effects of the competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, LY235959, were determined on the analgesic and hypothermic effects as well as on the development of tolerance to these effects of U-50,488H, a κ-opioid receptor agonist in mice and rats. In the mouse, a single injection of LY235959 given 10 min prior to U-50,488H did not modify the analgesic action of the latter. Similarly, chronic administration of LY235959 twice a day for 4 days did not modify U-50,488H-induced analgesia in mice. Repeated pretreatment of mice with LY235959 dose-dependently attenuated the development of tolerance to the analgesic actions of U-50,488H. In the rat, LY235959 by itself produced a significant analgesia and prior treatment of rats with LY235959 enhanced the analgesic action of U-50,488H. Similar effects were seen with the hypothermic action. Pretreatment of rats with LY235959 attenuated the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. These results provide evidence that LY235959 produces differential actions on nociception and thermic responses by itself and when given acutely with U-50,488H in mice and rats. However, when the animals are pretreated with LY235959, similar inhibitory effects are observed on the development of tolerance to the analgesic action of U-50,488H in both the species. These studies demonstrate an involvement of the NMDA receptor in the development of κ-opioid tolerance and suggest that the biochemical consequences of an opioid's interaction with the opioid receptor are not the only factors that contribute to the acute and chronic actions of opioid analgesic drugs.     

Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release,in vivo receptor displacement and behaviour

Summary To establish possible functional differences between the dopamine D2 and D3 receptor we investigated the relation between the ability, for a set of nine mixed dopamine D2 and D3 receptor antagonists, to displace N, N-dipropyl-2-amino-5,6-dihydroxy tetralin (DP-5,6-ADTN) from striatal binding sites and the subsequent behavioural consequences in vivo. Dopamine D2 receptor preferring antagonists are powerful displacers of DP-5,6-ADTN from the striatum. Maximal displacement is followed by strong hypomotility. Displacement of the agonist by the D3 preferring antagonist U99194A is only partial and results in synergistic increases in locomotor activity. Superimposing haloperidol upon GBR12909 leads to a synergistic increase in striatal dialysate dopamine concentrations. This effect is absent when combining GBR12909 with the putative D3 antagonist U99194A. These data give support for the hypothesis that the dopamine D3 receptor is functionally relevant at the postsynaptic level. Here, in contrast to the D2 receptor, it is proposed to exert an inhibitory influence on psychomotor functions.     

The role and mechanism of glutamic NMDA receptor in the mechanical hyperalgesia in diabetic rats

Objectives: Some studies have shown that painful neuropathy is a common and costly complication of both type 1 and type 2 diabetes mellitus, and glutamate is involved in the process although the mechanisms are not clear. The purpose of the present study was to investigate the effect of N-methyl-D-aspartate (NMDA) receptor on mechanical hyperalgesia in diabetic rats and the possible mechanism.

Methods: Diabetic rat model was established by intraperitoneal injection of streptozotocin (STZ, 1%, 70 mg/kg) once, and evaluated by the change in the fasting blood glucose. The mechanical hyperalgesia was estimated by mechanical withdrawal threshold (MWT) using a set of calibrated Von Frey’s filaments. In addition, the expressions of phosphorylated NMDA NR1 and phosphorylated cAMP response element binding protein (pCREB) in L4/L5 dorsal horns of spinal cord were observed.

Results: Behavioral results showed that MK-801, an antagonist of NMDA receptor, could reduce the proportion of mechanical hyperalgesia in diabetic rats from 76.67 to 20.00%. Meanwhile, the mean MWTs in STZ group or saline-treated STZ group decreased significantly at 3–8 week, while, the MWTs in MK-801 treated STZ group were significant higher than those in STZ or saline-treated STZ group. In addition, the expressions of NMDA NR1 and pCREB in L4/5 dorsal horns of spinal cord were significant higher in diabetic rats, and MK-801 down-regulated their expressions partly.

Conclusion: All these results suggested that NMDA receptor and pCREB in the spinal cord were involved in the regulation of mechanical hyperalgesia in diabetic rats.     

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 synergistic effect of fluoxetine on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist

Summary It was found previously that the MK-801 (an uncompetitive NMDA receptor antagonist)-induced locomotor hyperactivity in rats was potently increased by antidepressant drugs. The present paper analysed the locomotor hyperactivity induced by combined treatment with fluoxetine + MK-801 in male Wistar rats. The MK-801 hyperactivity was increased by citalopram (the latter effect was prevented by zacopride and ketanserin), sertraline, p-chloramphetamine, 8-OH-DPAT and TFMPP. The hyperlocomotion caused by fluoxetine + MK-801 was antagonized by tropisetron and zacopride and, to a lesser extent, by ketanserin, ritanserin and NAN-190, but not by WAY 100135, pindolol, metergoline or mianserin. Sulpiride and clozapine were able to inhibit the fluoxetine + MK-801 hyperlocomotion. The hyperlocomotion induced by D-amphetamine or apomorphine was not modified by fluoxetine or citalopram. Fluoxetine increased the release of dopamine (measured by a microdialysis method) in the striatum, induced by MK-801. The obtained results indicate that fluoxetine increases the MK-801-induced locomotor hyperactivity via activation of 5-HT₃ receptors and, to a lesser degree, 5-HT₂ ones.     

Condition-independent sensitization of locomotor stimulation and mesocortical dopamine release following chronic nicotine treatment in the rat

Chronic nicotine (NIC) pretreatment has been shown to enhance NIC-induced locomotor stimulation, an effect that seems critically dependent on activation of brain dopamine (DA) systems. In the present study the effects of chronic, intermittent NIC treatment were examined in the rat to establish whether such behavioral sensitization is associated with specific, regional changes in brain dopaminergic activity. Male rats received daily injections in their home cage with either saline (SAL) or NIC (0.5 mg/kg, s.c.) for 12 days. Twenty-four hours later, the locomotor activity of the animals subjected to NIC challenge as well as the functional responsiveness of the mesolimbocortical dopaminergic system were assessed. To this end, microdialysis experiments were performed in awake animals, measuring extracellular concentrations of DA and its metabolites in the prefrontal cortex (PFC) and the nucleus accumbens (NAC). Extracellular single cell recordings from DA neurons in the ventral tegmental area (VTA) were also performed in anesthetized animals. NIC (0.5 mg/kg, s.c.) increased all measured parameters of locomotor activity, with the exception of rearing, in SAL-pretreated animals; these effects were substantially enhanced after pretreatment with NIC. Nicotine (0.5 mg/kg, s.c.) increased DA release in both the PFC and the NAC in SAL-treated animals. Nicotine pretreatment significantly enhanced this effect in the PFC, whereas it did not affect the response in the NAC. Low doses of intravenously administered NIC dose-dependently increased burst activity, starting at 12 μg/kg in the SAL pretreated animals and at 6 μg/kg in the NIC-pretreated animals, and also dose-dependently increased firing rate in SAL as well as NIC-pretreated animals, although starting at a higher dose level, i.e., 25 μg/kg. These results demonstrate that behavioral sensitization after chronic NIC treatment is accompanied by an enhanced dopamine release specifically within the PFC. This phenomenon may be highly significant for the dependence-producing effects of NIC, particularly in association with major psychiatric disorder, such as schizophrenia. © 1996 Wiley-Liss, Inc.     

Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists

Summary. Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31 mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [³H]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [³H]MK-801 binding in the frontal cortex by 40.3%. The same treatment with amantadine did increase [³H]raclopride binding to dopamine D₂ receptors by 13.5%. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D₂ receptor expression. Received September 18, 1998; accepted November 16, 1998     

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.     

Enhanced expression of dopamine D1 and glutamate NMDA receptors in dopamine D4 receptor knockout mice

Expression of dopamine ([DA] D₁ and D₂) and glutamate ([Glu]), (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D₄ receptor knockout mice and their wild-type controls. Selective radioligand binding to D₄ receptors was virtually absent in D₄ receptor knockout mouse brain in contrast to significant specific D₄ binding in forebrain tissue of wild-type controls. Labeling of D₁ receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D₄-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA₁ (21%) and CA₃ (25%) regions of D₄ knockouts vs wild-type controls. No changes in D₂, AMPA or KA receptors were found. The findings suggest that D₁, D₄, and NMDA receptors might interact functionally and that developmental absence of D₄ receptors might trigger compensatory mechanisms that enhance expression of D₁ receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.     

Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease

Summary Memantine is a 1-amino-adamantane derivative which has been proposed to be useful in the treatment of Parkinson's disease. Its beneficial effect has been related to its novel properties as an NMDA receptor blocker which can neutralize the effect of glutamate at striatal and subthalamic levels. In the present study, conducted in an open-fashion, 14 parkinsonian patients with motor fluctuations taking L-dopa, were given a supplement of memantine 30 mg/day. After one month, 10 patients completed the treatment (4 discontinued it due to abdominal pain, psychomotor agitation, confusion and dizziness). In 5 patients, the main parkinsonian features improved significantly (1 point or more on the Webster scale). In 6 patients, off episodes improved (from daily mean of 273 minutes, to 172 minutes). In summary, memantine addition to parkinsonian features, could form a basis for novel therapeutic strategies directed to neutralize the effects of glutamate at striatal and subthalamic levels.     

Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(±)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(±)-SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with α-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 μg, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms.