Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D 1 and D 2 receptors

Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D receptor (D -R) vs. D receptor (D -R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examin...

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Bibliographic Details
Published in:European journal of pharmacology 2023-08, Vol.953, p.175802
Main Authors: Riga, Maurizio S, Paz, Veronica, Didriksen, Michael, Celada, Pau, Artigas, Francesc
Format: Article
Language:English
Subjects:
Animals
Antipsychotic Agents - pharmacology
Clozapine - pharmacology
Dopamine
Dopamine Antagonists - pharmacology
Haloperidol - pharmacology
Phencyclidine - pharmacology
Rats
Receptors, Dopamine D1
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Summary:Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D receptor (D -R) vs. D receptor (D -R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D -R>D -R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D -R and D -R to the antipsychotic reversal of PCP effects. The D -R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D -R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.
ISSN:1879-0712