Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone

@article{Martin1998RodentDA,
  title={Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone},
  author={P. Martin and Nicholas Waters and Christopher J. Schmidt and Arvid Carlsson and Maria Lizzie Carlsson},
  journal={Journal of Neural Transmission},
  year={1998},
  volume={105},
  pages={365-396}
}
Summary. The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907… 

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References

SHOWING 1-10 OF 104 REFERENCES

Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies.

The data indicate that MDL 100,907 has a clozapine-like profile of potential antipsychotic activity with low extrapyramidal sid-effect liability.

Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.

The data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.

Locomotor hyperactivity induced by MK-801 in rats.

The results indicate that the dopamine system is mainly involved in the locomotor hyperactivity induced by MK-801, which was antagonized by haloperidol and, to a lesser degree, by SCH 23390 and sulpiride.

Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice

The present findings support the hypothesis that antagonism at 5-HT2A receptors contributes to the in vivo actions of atypical antipsychotics such as olanzapine and clozapine, and indicate that PCP increases locomotor activity, at least in part, due to actions at5- HT2A, but not 5- HT3 or5-HT1A, receptors.

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

...