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M L Carlsson

Publications and source records attributed to M L Carlsson.

18 recordsLinked to original sources
PubMed1997

MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride.

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (-)-[4aR, 10 aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl- benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.

Animals↗
PubMed1997

The glycine antagonist (+)-HA-966 injected into the nucleus accumbens stimulates locomotion in mice. (Rapid communication).

We have previously observed that NMDA antagonists injected into the ventral striatum cause locomotor stimulation in both normal and monoamine-depleted mice. Since glycine receptor activation is claimed to be a prerequisite for NMDA receptor channel opening, also a glycine site antagonist injected into the ventral striatum should cause behavioural activation. The present study was aimed at investigating whether this is the case. The glycine site antagonist (+)-HA-966, as well as its (-)-enantiomer, were injected bilaterally into the nucleus accumbens of normal, habituated mice. (+)-HA-966, but not (-)-HA-966, was found to stimulate locomotion. The stereoselective response suggests that the underlying mechanism involves the NMDA receptor-coupled glycine site. The present results support the notion that a glycine agonist might be of value in the treatment of schizophrenia, whereas a glycine antagonist should be expected to have psychotogenic effects.

Animals↗
PubMed1997

Glycine and D-serine decrease MK-801-induced hyperactivity in mice.

It is well known that the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine can induce a syndrome in humans that mimics both positive and negative symptoms of schizophrenia. In the light of this observation, it has been hypothesised that schizophrenia might be due to a hypofunction of central glutamate systems. A glycine agonist, by strengthening glutamatergic transmission, has been suggested to be useful as treatment. A crucial issue is the uncertainty regarding the degree of saturation of the glycine site associated with the NMDA receptor. The purpose of this study was to investigate if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site. The effects of systemic and intraventricular administration of glycine. D-serine and L-serine on the hyperactivity induced in mice by the uncompetitive NMDA receptor antagonist MK-801 were tested. Systemically administered glycine and D-serine were found to decrease MK-801-induced hyperactivity. Intraventricularly administered D-serine in doses of 50 or 100 micrograms/side was found to decrease MK-801-induced hyperactivity during the second half hour of registration; L-serine given in the same doses did not affect the MK-801-induced hyperactivity during this period. These data may suggest that the NMDA receptor-associated glycine site is not saturated in vivo.

Animals↗
PubMed1997

Neurotransmitter aberrations in schizophrenia: new perspectives and therapeutic implications.

The dopamine hypothesis has dominated schizophrenia research for decades but is now yielding to a more diversified view, where the interaction of several neurotransmitters in complex circuitries is under scrutiny. Especially, glutamatergic and serotonergic mechanisms are attracting attention. However, the role of dopamine also needs further exploration and may still turn out to have novel therapeutic applications. In the present minireview an attempt is made to integrate preclinical and clinical data on neurotransmitter aberrations in schizophrenia and to discuss their therapeutic implications.

Animals↗
PubMed1996

Concurrent locomotor stimulation and decrease in dopamine release in rats and mice after treatment with the competitive NMDA receptor antagonists D-CPPene and CGS 19755.

The present study was aimed at investigating the effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists D-CPPene (3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) on dopamine (DA) transmission and motor activity in mice and rats. As measures of DA release we used mouse brain 3-methoxytyramine (3-MT) levels, and indirect estimate of DA release, and striatal dialysate measures of DA in conscious and freely moving rats by means of microdialysis. To obtain additional information about monoaminergic neurotransmission, brain tissue levels of DA, DOPAC, HVA, 5-HT and 5-HIAA were measured in both mice and rats. The animals were sacrificed at the time when NMDA antagonist-induced locomotor stimulation was maximal. In mice, D-CPPene and CGS 19755 decreased striatal 3-MT levels, whereas, in general, 3-MT levels in the limbic forebrain were not significantly altered. Treatment with CGS 19755 decreased rat striatal dialysate levels of DA but increased 5-HIAA at time points when locomotor activity was increased. D-CPPene and CGS 19755 have been observed to produce psychotic symptoms in man. The present study suggests that these symptoms are not a result of an increase in central dopamine release.

Animals↗
PubMed1995

Crucial role of the accumbens nucleus in the neurotransmitter interactions regulating motor control in mice.

Previous work, based on systemic drug administration, has shown that neurotransmitter interactions between dopaminergic, adrenergic, glutamatergic and cholinergic systems are involved in locomotor control in mice. In an attempt to identify the target sites in the brain of these interactions, we have started a series of experiments, where the drugs are administered intracerebrally in mice. The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA antagonist MK-801 were investigated by means of local application in the accumbens nucleus of monoamine-depleted and monoaminergically intact mice, respectively. The threshold dose of AP-5 was lower in depleted than in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomotor effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were registered in monamine-depleted mice after local application in the accumbens or entopeduncular nucleus (= medial pallidum). Both AP-5 and CNQX stimulated locomotor activity in the accumbens, but had no effects in the entopeduncular nucleus. We have previously shown synergistic interactions with regard to locomotor stimulation in monoamine-depleted mice, between an NMDA antagonist and an alpha 2-adrenoceptor agonist or a dopamine D1 agonist (all drugs given systemically). In the present study the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline was applied intracerebrally in combination with a subthreshold dose of MK-801 given intraperitoneally: Locomotor stimulation was produced after alpha-methyl-noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or thalamus. Likewise, local application of the D1 agonist SKF 38393, in combination with a subthreshold dose of MK-801 given intraperitoneally, point to an important role of the accumbens nucleus in motor control. Previous experiments based on systemic drug administration have also shown a synergistic interaction between a muscarine antagonist and an alpha 2-adrenoceptor agonist in monoamine-depleted mice. Local application of the muscarine antagonist methscopolamine, in combination with the alpha 2-adrenoceptor agonist clonidine given intraperitoneally, showed that the striatum, in this case both the ventral and dorsal parts of the striatum, is an important target for the muscarine antagonist. Unilateral injection of AP-5 into the accumbens nucleus of mice induces rotational behaviour: Previous findings have shown that the rotation is ipsilateral in monoaminergically intact animals, whereas monoamine-depleted animals rotate contralaterally. In addition, these findings have shown that dopamine D2 receptor stimulation seems to determine whether AP-5 will induce ipsilateral or contralateral rotation. In the present study we report further evidence for a crucial role of the D2 receptor in this respect. Finally, the rotational effects of AP-5 injected into the dorsal striatum or hippocampus were investigated: As after AP-5 application into the accumbens nucleus, monoaminergically intact mice rotated ipsilaterally, whereas monoamine-depleted animals rotated contralaterally, following AP-5 application in the dorsal striatum or the hippocampus. The present data show that the accumbens nucleus has an important role in motor control. Both glutamatergic, muscarine cholinergic, dopaminergic and alpha-adrenergic systems are involved in the control of motor functions in the accumbens nucleus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

The muscarine antagonist methscopolamine and the NMDA antagonist AP-5 injected unilaterally into the nucleus accumbens cause mice to rotate in opposite directions.

Previously, we have reported that the NMDA antagonist AP-5, injected unilaterally into the nucleus accumbens of mice, induces ipsilateral rotation in monoaminergically intact mice, but contralateral rotation in monoamine-depleted animals. In this paper we report that the muscarine antagonist methscopolamine, injected unilaterally into the nucleus accumbens, induced predominantly contralateral rotation in monoaminergically intact mice. In monoamine-depleted animals intra-accumbens methscopolamine induced only a weak stimulation of rotational behaviour (not significant), but the direction of the rotation was exclusively contralateral, and the animals showed contralateral body deviation. Moreover, when these animals received additional treatment with the alpha-adrenergic agonist clonidine, which potentiates the motor effects of cholinergic antagonists in monoamine-depleted mice (Carlsson et al., 1991), a clear-cut contralateral rotation was induced. The observed behavioural effects are discussed in relation to the positive and negative feedback circuits, which link the nucleus accumbens with the cerebral cortex and thalamus. In previous papers, we have suggested that the ipsilateral rotation induced by AP-5 is mediated primarily by the positive feedback circuit, whereas the AP-5-induced contralateral rotation is due to interference with primarily the negative feedback circuit. Applying this reasoning to the rotational effects of methscopolamine, it seems that methscopolamine interferes primarily with the negative feedback circuit.

2-Amino-5-phosphonovalerate↗
PubMed1995

The selective 5-HT2A receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic or muscarinic neurotransmission in the mouse--implications for psychosis.

The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the alpha-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2A receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12,909. A putative "permissive" role of the 5-HT2 receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.

Animals↗
PubMed1994

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

We have previously observed that an N-methyl-D-aspartate (NMDA) antagonist in combination with the alpha 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.

Allosteric Site↗
PubMed1994

On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801.

The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.

Animals↗
PubMed1994

Glutamatergic neurons projecting to the nucleus accumbens can affect motor functions in opposite directions depending on the dopaminergic tone.

1. Intracerebral cannulas were implanted stereotactically into the nucleus accumbens, dorsal striatum or nucleus entopeduncularis of male NMRI mice. 2. Monoamine-depleted mice were injected intracerebrally with the competitive NMDA receptor antagonist AP-5, the non-competitive NMDA antagonist MK-801 or the AMPA-kainate receptor antagonist CNQX. A marked locomotor stimulation was produced when AP-5 was injected into the nucleus accumbens, but not when injected into the dorsal striatum. Likewise, CNQX stimulated locomotor activity when injected into the nucleus accumbens. Neither AP-5 nor CNQX produced behavioral stimulation following injection into the nucleus entopeduncularis. 3. The tone in the monoaminergic systems influences the potency of competitive and non-competitive NMDA antagonists differently with regard to stimulation of locomotor activity. In the case of the competitive NMDA antagonist AP-5 the potency was higher in monoamine-depleted than in monoaminergically intact mice. In contrast, the potency of the non-competitive NMDA antagonist MK-801 was higher in monoaminergically intact than in monoamine-depleted animals. 4. A unilateral injection of AP-5 into the nucleus accumbens caused the animals to rotate: The rotation was predominantly ipsilateral in monoaminergically intact animals, whereas monoamine-depleted mice rotated exclusively contralaterally. When AP-5 was given to monoamine-depleted mice treated with the D-2 agonist quinpirole the animals rotated ipsilaterally, whereas monoamine-depleted mice treated with the D-1 agonist SKF 38393 still rotated contralaterally after AP-5 treatment. These data show that glutamatergic neurons projecting to the nucleus accumbens can affect behavior in different directions depending on the degree of dopamine D-2 receptor stimulation.

2-Amino-5-phosphonovalerate↗
PubMed1993

Are the disparate pharmacological profiles of competitive and un-competitive NMDA antagonists due to different baseline activities of distinct glutamatergic pathways? (Hypothesis).

Corticostriatal glutamatergic neurons impinging on the so-called "direct" striato-thalamic pathways appear to act as a driving force with respect to psychomotor functions, whereas corticostriatal glutamatergic neurons projecting to the "indirect" striato-thalamic route appear to mediate inhibition of the thalamus and thus act as a "brake" with respect to psychomotor functions. The GABAergic striatal projection neurons pertaining to the "direct" pathway mediating behavioural stimulation appear to be phasically activated, whereas GABAergic striatal projection neurons pertaining to the "indirect" pathway mediating suppression of behaviour must be assumed to display a high tonic activity. Such an organization could explain some of the behavioural differences between competitive and un-competitive NMDA antagonists, since the binding of competitive NMDA antagonists is inhibited by glutamate, whereas the binding of un-competitive NMDA antagonists is enhanced by the presence of NMDA receptor agonists, a phenomenon called use/agonist dependence.

Animals↗
PubMed1992

Interaction between glutamatergic and dopaminergic tone in the nucleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control.

The rotation induced by a unilateral injection of the competitive NMDA receptor antagonist AP-5 was studied in mice with different tone in the central dopaminergic systems. AP-5 induced contralateral rotation in monoamine-depleted mice and in monoamine-depleted mice treated with a dopamine D-1 receptor agonist. In contrast, AP-5 induced predominantly ipsilateral rotation in monoamine-depleted mice treated with a mixed D-1/D-2 or a D-2 selective dopamine agonist and in mice with intact monoaminergic systems.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

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

Previous studies have shown that administration of NMDA antagonists in combination with the alpha 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 alpha-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 alpha 2-adrenoceptor antagonists yohimbine (10 mg/kg) or idazoxan (10 mg/kg) but not with the selective alpha 1-adrenoceptor antagonist prazosin (1 mg/kg). The present results suggest that ethanol in conjunction with alpha 2-adrenoceptor stimulation induces locomotion in monoamine-depleted mice via a mechanism that may involve interference with glutamate receptor-mediated neurotransmission.

Animals↗
PubMed1992

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

Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilipine (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.

Animals↗
PubMed1992

Injection of the competitive NMDA receptor antagonist AP-5 into the nucleus accumbens of monoamine-depleted mice induces pronounced locomotor stimulation.

Following injection of 5 micrograms of the competitive NMDA receptor antagonist AP-5 into the nucleus accumbens of monoamine-depleted mice a pronounced locomotor stimulation was produced. Additional treatment with an intraperitoneal (i.p.) injection of the alpha-adrenoceptor agonist clonidine markedly increased the locomotor effects of AP-5 administration into the nucleus accumbens. Injection of 5 or 10 micrograms AP-5 into the dorsal striatum was ineffective with regard to locomotor stimulation. However, when AP-5 (10 micrograms) was combined with an i.p. injection of clonidine, a marked locomotor stimulation was produced following application into the dorsal striatum, but not following application into the prefrontal cortex. The present results are in line with the idea that corticostriatal glutamatergic pathways, especially those projecting to the ventral striatum, exert an inhibitory influence on psychomotor functions.

2-Amino-5-phosphonovalerate↗
PubMed1982

Diagnosis of bacteraemia by automated head-space capillary gas chromatography.

Blood cultures from 196 patients with suspected bacteraemia or septicaemia were analysed by automated head-space gas chromatography, using a 25 m fused silica capillary column, when turbidity indicated growth. Gas chromatography correctly identified 105 cultures as positive and 71 correctly as negative. No false-positive results were obtained. Of the 20 false-negative chromatographic results, Staphylococcus spp accounted for 14. Automated head-space gas chromatography is quicker, easier and more efficient than other gas chromatographic techniques for the evaluation of blood cultures.

Chromatography, Gas↗