Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors.
Maurizio S Riga, Verónica Paz, Michael Didriksen, Pau Celada, Francesc Artigas
European Journal of Pharmacology August 15, 2023 DOI: 10.1016/j.ejphar.2023.175802 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Awake rats |
| Interventions | Lu AF35700 Phencyclidine Haloperidol SCH-23390 Clozapine |
| Keywords | D1 receptor D2 receptor Phencyclidine Thalamo-cortical activity Cfos |
| Key findings | Lu AF35700 reversed phencyclidine-induced alterations in thalamo-cortical neuronal discharge and low-frequency oscillations and prevented phencyclidine-induced c-fos mRNA increases in thalamo-cortical regions. Sub-effective doses of haloperidol plus SCH-23390 fully reversed the phencyclidine-induced fall in oscillations, and SCH-23390 potentiated low doses of clozapine and Lu AF35700 to differing degrees. The authors argue these data support a synergistic interaction between D1 and D2 receptors, possibly through simultaneous blockade in direct and indirect basal ganglia pathways. |
Abstract
Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-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 D1-R>D2-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 D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-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 D1-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.