1. |
- Carlsson, Maria L., 1959, et al.
(author)
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The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice
- 1999
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In: J Neural Transm. - 0300-9564. ; 106:2, s. 123-9
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Journal article (peer-reviewed)abstract
- The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
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2. |
- Nilsson, Marie, 1968, et al.
(author)
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Glycine and D-serine decrease MK-801-induced hyperactivity in mice
- 1997
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In: J Neural Transm. - 0300-9564. ; 104:11-12, s. 1195-205
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Journal article (peer-reviewed)abstract
- 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.
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3. |
- Nilsson, Marie, 1968, et al.
(author)
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The glycine antagonist (+)-HA-966 injected into the nucleus accumbens stimulates locomotion in mice. (Rapid communication)
- 1997
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In: J Neural Transm. - 0300-9564. ; 104:4-5, s. 419-25
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Journal article (peer-reviewed)abstract
- 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.
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