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Biomedical subjects

W J Schmidt

Publications and source records attributed to W J Schmidt.

At least 91 records · Page 5Linked to original sources
PubMed1994

Glycine site antagonists abolish dopamine D2 but not D1 receptor mediated catalepsy in rats.

Catalepsy--a state of postural immobility (akinesia) with muscular rigidity (rigor)--and reduced locomotion in animals are behavioral deficits showing similarities with symptoms of Parkinson's disease (PD). The effects of the glycine site antagonists 7-chlorokynurenate and (R)-HA-966 on haloperidol-(D 2 antagonist) and SCH 23390- (D 1 antagonist) induced catalepsy and reduced locomotion are investigated in rats. Both antagonists dose-dependently counteract dopamine D 2 receptor mediated catalepsy but they have no influence on locomotion. Neither 7-chlorokynurenate nor (R)-HA-966 has any effect on dopamine D 1 receptor mediated catalepsy. This finding is surprising, since NMDA receptor antagonists counteract both, dopamine D 1 and D 2 receptor mediated catalepsy. D 1 and D 2 receptors are located on different populations of neurons. Thus, the present findings suggest that these different neuronal populations have different sensitivity for ligands binding at the glycine binding site of the NMDA receptor.

Animals↗
PubMed1994

Pediatric renal transplantation at the University of Minnesota: the cyclosporine years.

Overall mortality was low (3.5%) in 199 children who received 217 transplants and quadruple immunosuppression. Graft survival was better in patients on quadruple immunosuppression, compared with historical patients on standard immunosuppression. When censored for deaths with a functioning graft, cumulative graft survival beyond one year was significantly better in patients on quadruple immunosuppression. Acute rejection was more common in CAD recipients and in retransplant recipients. Acute rejection was also more common in patients with FSGS, compared with other causes of ESRD. Preemptive transplants were not associated with a higher incidence of acute rejection. Late acute rejection episodes tended to be associated with a CsA dose < 5 mg/kg/day at one-year posttransplant. Chronic rejection was the major cause of graft loss. Risk factors for graft loss within the first posttransplant year were acute tubular necrosis and an initial CsA dose of < 5 mg/kg/day. Risk factors for graft loss after the first posttransplant year were late onset of the first acute rejection episode and a panel reactivity of > 25% at the time of transplant.

Actuarial Analysis↗
PubMed1994

Behavioural effects of NMDA-receptor antagonists.

NMDA receptor-antagonists were tested in dose ranges that have previously been found to produce anticonvulsant and anticataleptic (antiparkinsonian) effects in rats. Non-competitive NMDA receptor-antagonists had strong psychomotor stimulating effects, the competitive ones were weaker in this respect when given systemically. However, when locally injected into the striatum or into the nucleus accumbens, also the competitive NMDA-antagonists induced psychomotor stimulation. If at all, NMDA receptor-antagonists have rewarding effects, then they seem to be elicited only by the non-competitive NMDA receptor-antagonists. In maze tests, sensitive for hippocampally mediated learning, NMDA receptor-antagonists impaired learning. While non-competitive NMDA-antagonists produced learning deficits over the whole dose range tested, competitive ones were only effective at higher dose levels.

Animals↗
PubMed1993

The sigma receptor ligand 1,3-di-(2-tolyl)guanidine in animal models of schizophrenia.

The behavioral effects of the selective sigma ligand 1,3-di(2-tolyl)guanidine (DTG) were studied in rats. In the radial 8-arm maze, DTG (2, 4 and 8 mg/kg i.p.) reduced the number of arm entries in the spontaneous alternation task. In animals receiving 4 mg/kg DTG, the percentage of 135 degrees angles between consecutive arm entries decreased. In the open field, equipped with a holeboard, DTG (8 mg/kg) reduced the number of line crossings, rearings and head dips. Sniffing, measured in an experimental chamber, was also reduced. DTG prolonged the time that the animals were inactive. In combination with DL-amphetamine (4 mg/kg) or dizocilpine (0.16 mg/kg), DTG (8 mg/kg) decreased--but did not antagonize--the induced enhancement of locomotion and sniffing. These results demonstrate motor depressant effects of DTG on locomotion, rearing and sniffing. Since antagonists of sigma binding sites are known to produce opposite effects, we conclude that DTG--in behavioral terms--acts like an antagonist at sigma binding sites.

Amphetamine↗
PubMed1993

Tetrahydroaminoacridine attenuates dizocilpine-induced behavioural changes.

The acetylcholinesterase inhibitor tetrahydroaminoacridine (THA) is known to interact with neurotransmitter systems other than the cholinergic, e.g. several studies have shown interaction of THA with the N-methyl-D-aspartate (NMDA) receptor subtype of the glutamatergic system. We therefore investigated whether behavioral changes in rats, caused by the non-competitive NMDA-antagonist dizocilpine, were altered by THA. Spontaneous locomotion was measured in an open field and learning behaviour was evaluated in a spatial learning task in the 8-arm radial maze. Hyperactivity in the open field caused by 0.08 mg/kg i.p. dizocilpine was reversed by 5 mg/kg i.p. THA. Hyperactivity caused by 0.16 mg/kg i.p. dizocilpine was reversed by two THA doses (2.5 mg/kg, 5 mg/kg i.p.). A dizocilpine-induced acquisition deficit in the 8-arm radial maze was attenuated by THA (2.5 mg/kg) on the 6th and 7th day of testing. The effects of THA are discussed with reference to a possible functional glutamate agonism.

Animals↗
PubMed1993

Discrete quinolinic acid lesions of the lateral but not of the medial caudate-putamen reversed haloperidol-induced catalepsy in rats.

Discrete lesions in the medial or lateral subregion of the rostral caudate-putamen (CP) were induced by bilateral intracerebral injections of a low dose of quinolinic acid (30 nmol in 1 microliter/per side) in rats. Quinolinic acid lesions in the lateral CP potently reversed haloperidol-induced catalepsy (0.5 mg/kg,i.p.), while lesions in the medial CP were not effective. Spontaneous locomotor activity was not altered significantly after quinolinic acid lesions of either the medial or lateral CP. These results show that the lateral CP seems to be important for the expression of neuroleptic-induced catalepsy and thus further corroborate the concept of a functional heterogeneity of the striatum.

Animals↗
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↗