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W J Schmidt

Publications and source records attributed to W J Schmidt.

At least 19 recordsLinked to original sources
PubMed1992

Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats.

The behavioural and biochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine and memantine, and the competitive NMDA receptor antagonist, CGP 39551, were investigated in rats. Systemic injections of dizocilpine (0.33 mg/kg) increased locomotion and rearing in an open field, whereas memantine (20 mg/kg) increased only locomotor activity. CGP 39551 (10 and 20 mg/kg) did not change open field activity. Dopamine (DA) metabolism--as measured by the ratio of dihydroxyphenylacetic acid/dopamine (DOPAC/DA)--increased in response to dizocilpine in the prefrontal cortex and the nucleus accumbens. Memantine enhanced DOPAC/DA in the prefrontal cortex, the nucleus accumbens and to a lesser degree in the posterior striatum. In contrast to non-competitive NMDA receptor antagonists, CGP 39551 did not increase DA metabolism of subcortical structures and even decreased DOPAC/DA in the prefrontal cortex. These results indicate that competitive and non-competitive NMDA receptor antagonists affect spontaneous locomotion differentially in rats. The biochemical data imply that the stimulant actions non-competitive NMDA receptor antagonists are at least partially due to activation of ascending dopaminergic systems. Potential mechanisms involved in the differential effects of both types of NMDA receptor antagonists are discussed.

2-Amino-5-phosphonovalerate↗
PubMed1992

D-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task.

It is shown that D-cycloserine has cognition-enhancing properties in quinolinic acid hippocampal-lesioned rats. Lesioned rats had a severe impairment of working memory in an allocentric spatial reversal paradigm in the 8-arm maze, and performance could be restored with 12 mg/kg i.p. D-cycloserine, given 30 min before testing. The present findings favour the testing of D-cycloserine for clinical efficacy in patients with Alzheimer's disease with loss of pyramidal neurons and disconnected glycine-NMDA receptor activation.

Analysis of Variance↗
PubMed1992

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior.

The effects of competitive (CGP 37849 and CGP 39551) and non-competitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the non-competitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.

2-Amino-5-phosphonovalerate↗
PubMed1992

Limitations of the in vitro repair synthesis assay for probing the role of DNA repair in platinum resistance.

Several studies have implicated enhanced DNA repair in acquired platinum resistance. To better understand the mechanism of increased repair we have employed an in vitro assay using cell-free extracts from platinum sensitive and resistant murine and human cell lines. Since the platinum resistant murine cell lines used in our previous studies had shown increased repair of diaminocyclohexane(dach)-Pt-DNA adducts while one of the resistant human cell lines did not, we have measured in vitro repair synthesis on DNA damaged by (d,l)-trans-1,2-diaminocyclohexanedichloroplatinum(II) (PtCl2(dach)). The results of this assay were strongly dependent on the method used to calculate repair synthesis activity and appeared to disagree with previous estimates of repair activity in these cell lines. By one method of calculation the in vitro repair synthesis assay underestimated the ratio of repair activities in the resistant versus the sensitive murine cell lines, while by the other method the in vitro assay overestimated the ratio of repair activities in the resistant versus the sensitive human cell lines.

Animals↗
PubMed1992

Behavioural pharmacology of glutamate in the basal ganglia.

In Parkinson's disease the dopaminergic inhibition--mediated by DA2 receptors in the striatum--is reduced. Therefore glutamatergic excitation predominates in the antero-dorsal striatum. In turn the glutamatergic neurons of the subthalamic nucleus become disinhibited. Antagonists of the NMDA-subtype of glutamate receptors injected locally into the glutamatergically innervated nuclei or competitive and non-competitive NMDA-antagonists administered systemically, counteract parkinsonian symptoms in animals.

Animals↗
PubMed1991

Antagonism of AP-5-induced sniffing stereotypy links umespirone to atypical antipsychotics.

Blockade of glutamatergic transmission in the striatum (using the NMDA-antagonist DL-2-amino-5-phosphonovaleric acid AP-5) was recently shown to induce stereotyped sniffing in rats. Comparable stereotyped behaviour is well known to be elicited by stimulation of dopamine activity, which since long was the basis for experimental models to check for possible antipsychotic activity of new compounds. However, whereas dopamine-induced stereotypies are antagonized only by classical neuroleptics, stereotypies induced by blockade of glutamatergic transmission are antagonized by classical as well as by atypical antipsychotics. Umespirone, a novel psychotropic which has been reported to exhibit behavioural effects predictive for antipsychotic as well as anxiolytic potential was evaluated for antagonistic effects against AP-5-induced behaviour. The profile of umespirone was compared with the profile of a non-benzodiazepine anxiolytic buspirone as well as with previously published data of neuroleptics. Umespirone like clozapine specifically antagonized AP-5-induced sniffing, i.e. did not impair spontaneous sniffing but reversed AP-5-induced excessive sniffing. In contrast, buspirone impaired spontaneous and AP-5-induced sniffing to about the same extend. These results are in accordance with the glutamate hypothesis of schizophrenia and again give evidence that umespirone should have antipsychotic potential and a very low liability to exhibit unspecific sedative action.

2-Amino-5-phosphonovalerate↗
PubMed1990

The NMDA antagonist dizocilpine (MK-801) reverses haloperidol-induced movement initiation deficits.

The present study shows that systemic dopamine receptor blockade impaired movement initiation of rats, trained in a simple reaction time task for rapid initiation of locomotion in response to a combined optic/acoustic cue. Reaction time, movement time and the accelerative force were recorded for each initiation of locomotion. Results indicate a dose-related increase of reaction time following systemic administration of haloperidol (0.1, 0.15, 0.3 mg/kg i.p.). Measures derived from resulting force-time patterns showed a haloperidol-induced decrease (0.15 mg/kg i.p.) of the mean rate of force development, indicating a decreased initial acceleration. These effects were reversed by systemic co-administration of dizocilpine (MK-801) (0.08 mg/kg i.p.), a selective non-competitive N-methyl-D-aspartate (NMDA) antagonist. The haloperidol-induced movement initiation deficits in this task are in part comparable to akinesia seen in Parkinson's disease and their reversal by dizocilpine has implications for the treatment of this disease.

Animals↗
PubMed1990

6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze.

The role of mesocortical dopamine neurons in locomotion and acquisition of various delayed and uninterrupted maze tasks was investigated in the rat. Dopaminergic terminals of the medial prefrontal cortex were lesioned by stereotaxically guided injections of the selective neurotoxin 6-hydroxydopamine (6-OHDA), while noradrenergic neurons were protected by systemically administered desipramine. 6-OHDA lesions resulted in a selective depletion of dopamine and its metabolite, dihydroxyphenylacetic acid, in the prefrontal cortex but not in subcortical structures. Prefrontal serotonin was not depleted. 6-OHDA-cloned rats performed uninterrupted alternation tasks (spontaneous and reinforced alternation) in the radial maze in the same manner as controls, whereas performance of delayed alternation in the T-maze and the radial maze was impaired in lesioned rats. In addition, locomotor activity during maze performance was increased in lesioned rats. Based on the hypothesis that increased motor activity and impaired delayed alternation performance are due to increased susceptibility to interfering stimuli, we propose tentatively that prefrontal dopamine may function to suppress interference during the delay period of certain cognitive tasks.

Afferent Pathways↗
PubMed1990

MK-801-induced stereotypy and its antagonism by neuroleptic drugs.

MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclohepten-5,10-imi ne hydrogen maleate], which blocks glutamatergic transmission at the NMDA-receptor-gated ion channel, induced stereotypies which are similar to those found after intrastriatal injections of AP-5, e.g. sniffing and locomotion. Tests in familiar or unfamiliar environment (non-stressful or stressful situation) did not qualitatively change MK-801-induced effects. Haloperidol (0.1 mg/kg, IP) delayed the onset and shortened the duration of MK-801 (0.16; 0.33 mg/kg, IP)-induced stereotypy whereas clozapine (5 mg/kg, SC) potently antagonized it. However, exact quantification of sniffing, measured in an experimental chamber designed for this purpose, revealed an antagonism by both drugs, haloperidol as well as clozapine. Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.

Animals↗
PubMed1989

Effects of intrastriatal blockade of glutamatergic transmission on the acquisition of T-maze and radial maze tasks.

Prefrontal cortex and neostriatum constituting the prefrontal system are connected by glutamatergic neurones. The involvement of this corticostriatal projection in control of maze performance of rats was investigated. Glutamatergic transmission mediated by N-methyl-D-aspartate (NMDA) receptors was blocked by intrastriatal injections of dl-2-amino-5-phosphonovaleric acid (AP-5) (50 nmole in 0.5 microliters). In experiment 1, intrastriatal AP-5 was found to increase the number of errors during acquisition of a delayed alternation task in a T-maze. In experiment 2, the effect of intrastriatal AP-5 on acquisition of different 8 arm maze tasks was investigated. AP-5 did not affect the number of reentries on spontaneous and reinforced alternation; pre- and postdelay errors on delayed alternation were not altered. Therefore, intrastriatal NMDA receptor blockade impairs acquisition of a delayed alternation in a T-maze, while intrastriatal blockade of NMDA receptors does not affect acquisition of different 8 arm maze tasks. The impairment in the T-maze task appears not to be due to deficient acquisition of spatial information per se, since 8 arm maze performance is intact. Instead, repeated delays in the T-maze task seem to be the critical component that gives difficulties in acquisition. These difficulties in bridging successive temporal discontiguities were attributed to an increased susceptibility to external and internal interfering stimuli during delays. Thus, striatal NMDA receptors within the prefrontal system may be involved in correct response retention over the duration of delays.

2-Amino-5-phosphonovalerate↗
PubMed1989

Anticataleptic effects of the N-methyl-D-aspartate antagonist MK-801 in rats.

The N-methyl-D-aspartate (NMDA) antagonist MK-801 was administered to rats in three doses (0.08, 0.16, 0.33 mg/kg) in order to examine its effects on catalepsy that was induced by haloperidol (0.5 mg/kg). The degree of catalepsy was assessed 30 and 60 min after application of drugs by placing the rat on a horizontal bar, on a podium and on a vertical grid. Animals having received saline and haloperidol showed a higher degree of catalepsy than animals having received MK-801 and haloperidol (except for the lowest dose of MK-801). These findings may suggest a therapeutic potential of MK-801 and possibly of other NMDA antagonists in the treatment of Parkinson's disease.

Animals↗
PubMed1988

Haloperidol- and apomorphine-induced changes in pup searching behaviour of house mice.

Maternal pup searching behaviour of lactating house mice treated with apomorphine, haloperidol or saline was examined on a running board with a central depression as a nest. Pup searching was elicited by artificial ultrasonic stimuli: a female moved out from the nest either towards a 50 kHz tone (key stimulus) which is adequate to activate species specific pup searching behaviour or towards a 20 kHz tone (neutral stimulus), thus showing her preference for one of these stimuli. Under apomorphine (0.00625; 0.0125; 0.025 mg/kg) the females preferred the key stimulus. Nevertheless apomorphine (0.00625-0.025 mg/kg) prolonged response latencies and shortened the duration of pup searching. At the highest dose (0.05 mg/kg), apomorphine induced stereotyped sniffing. Haloperidol (0.025; 0.05; 0.1 mg/kg) had opposite effects to apomorphine: it lowered the threshold for elicitation, shortened response latencies and prolonged the duration of pup searching. Females treated with haloperidol (0.025-0.1 mg/kg) did not prefer the key stimulus. Changes in response elicitation and in the performance of pup searching induced by apomorphine and haloperidol, respectively, were assumed to be due to i) a reduced and an increased responsiveness to external stimuli respectively, ii) an enhanced and a reduced tendency for response switching respectively, and iii) a preference for spontaneous behaviour in apomorphine-treated females, with an increased dependence on exteroceptive stimuli following haloperidol.

Acoustic Stimulation↗
PubMed1988

Behavioural effects of N-methyl-D-aspartate in the anterodorsal striatum of the rat.

N-methyl-D-aspartate (NMDA) (0.5 and 1 microgram/0.5 microliter) bilaterally injected into the anterodorsal striatum of rats reduced locomotion, sniffing, rearing and feeding upon presentation of palatable food. Consequently, the number of all behavioural bouts exhibited was reduced and the duration of akinetic phases was prolonged. These results are discussed in connection with previous findings showing that the NMDA receptor blocker DL-2-amino-5-phosphonovaleric acid (AP-5) injected at the same site - produced opposite effects: AP-5 enhanced locomotion, rearing, sniffing as well as the total number of behavioural bouts exhibited.

Animals↗
PubMed1987

Antagonism of AP-5- and amphetamine-induced behaviour by timelotem as compared with clozapine and haloperidol.

Bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5), that blocks glutamatergic transmission at the N-methyl-d-aspartate preferring receptor, induces sniffing and body turns and reduces grooming in rats. Timelotem, a representative of the newly developed chemical class of anellated benzodiazepines antagonized specifically AP-5-induced sniffing and body turns. Classical (haloperidol) as well as atypical (clozapine) neuroleptics had recently been shown to antagonize AP-5-induced sniffing; clozapine, like timelotem, but not haloperidol, additionally antagonized AP-5-induced body turns. Further, timelotem antagonized amphetamine-induced stereotyped behaviour in rats, but was found less active than haloperidol in this test. Comparing the activity of drugs in both paradigms revealed that haloperidol inhibited AP-5-induced sniffing and amphetamine-induced stereotypies within the same dose range, but timelotem and clozapine were found more potent in the AP-5 test than in the amphetamine test. Thus, detailed drug profiles discriminate timelotem and clozapine from haloperidol, linking timelotem again to atypical antipsychotic compounds.

2-Amino-5-phosphonovalerate↗
PubMed1986

Oestrogen modulates dopamine-controlled behaviours in the male ferret.

Oestradiol (100 micrograms/kg) was administered to male ferrets on three successive days. Two and three days after the last oestradiol injection the effects of apomorphine (0.5 mg/kg) on stereotyped, predatory and scent marking behaviour were intensified. Thus, three days of oestradiol administration produced a supersensitive dopaminergic system two days after the last oestradiol injection. However, no initial antidopaminergic effect of oestradiol could be demonstrated one day after the last oestradiol injection.

Animals↗