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

  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},
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… 

Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

Compared locomotor responses to PCP and MK-801 in rats that were administered 5,7-dihydroxytryptamine into either the dorsal or ventral hippocampus are compared, which has implications for studies utilizing NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

Clozapine-Induced Locomotor Suppression is Mediated by 5-HT2A Receptors in the Forebrain

It is confirmed that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D2, and it is shown that it is the cortical population of 5-HT2A that mediate the locomotor-suppressing effects of clozapine.

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment, suggesting the importance of the constitutive activity of 5- HT2C receptors in NOR.

Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5‐HT2A sites for PCP‐induced locomotion in the rat

PCP‐induced locomotion (PLOC) was potently blocked by the selective serotonin (5‐HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine‐induced Locomotion (ALOC), which is, correspondingly, more potents blocked than ALOC by antipsychotics displaying marked affinity at 5‐HT2A receptors.

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Compounds possessing “balanced” 5- HT1A receptor agonism and D2 antagonism and, in some cases, combined with other beneficial properties, such as 5-HT2A receptor antagonism, are efficacious in a broad range of rodent pharmacological models yet have a lower propensity to elicit EPS or metabolic dysfunction.

Potentiation of excitatory serotonergic responses by MK-801 in the medial prefrontal cortex

5-HT excitatory transmission is selectively impaired at the mPFC level in this pharmacological model of schizophrenia, suggesting that serotonin has a major role in the pathophysiology and treatment of schizophrenia.

Serotonergic modulation of dopamine and GABA inputs to A9 and A10 dopamine neurons and its role in antipsychotic drug efficacy

It is concluded that 5-HT2A receptor antagonism enhanced reversal of amphetamine-induced inhibition by DA D2 antagonism in A10, suggesting thatDA D2 receptor antagonisms combined with 5- HT2A receptors antagonism may play a role in antipsychotic drug atypicality.



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.