The novel antipsychotic brexpiprazole partly reverses a disruption of thalamocortical function induced by phencyclidine

Abstract

[Background] Brexpiprazole (BREX) is a novel compound with antipsychotic properties [1] recently approved for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder (MDD). Compared to the classical and atypical antipsychotics, which primarily antagonize the dopamine D2 receptor and the serotonin 5-HT2A receptor, respectively, and which especially fail to improve negative and cognitive symptoms of schizophrenia, BREX possesses a different binding profile with superior affinity for 5-HT1A and ¿1B-adrenergic receptors [2]. Non-competitive NMDA receptor antagonists such as phencyclidine (PCP) are widely used as pharmacological models of schizophrenia. Previous work of our group has shown that PCP markedly disrupts thalamocortical activity, increasing excitatory neuron discharge and reducing low frequency oscillations (LFO; 0.15¿4 Hz) in both the prefrontal cortex (PFC) and the centromedial (CM) and mediodorsal (MD) nuclei of the rodent thalamus [3,4]. First and second generation antipsychotic drugs have been shown to reverse these effects [5]. Since the underlying mechanisms of BREX are still largely unknown, we aimed to clarify the neuronal circuits involved in the antipsychotic effects of BREX. For this purpose, we investigated the ability of BREX to reverse a disruption of thalamocortical function induced by PCP.

[Methods] Single neuron and local field potential were recorded in the medial PFC (mPFC) and in the thalamic CM/ MD nuclei of the rat anesthetized with chloral hydrate to investigate the effects of BREX on neuronal firing rate and LFO. Two doses of BREX (0.25 mg/kg i.v. each) were administered after PCP (0.25¿0.5 mg/kg i.v.). Repeated measures one-way ANOVA analyses with post-hoc Newman-Keuls tests were performed to detect significant differences between conditions.

[Results] In the thalamus, BREX reversed the PCP-induced increase in firing rate (0.25 mg/kg: partial reversal; 0.5 mg/kg:complete reversal, n = 13, p < 0.01 vs PCP) without affecting LFO. Conversely, BREX partially reversed the PCP-induced decrease in LFO in the mPFC (0.5 mg/kg, n = 16, p < 0.001 vs PCP) without affecting pyramidal neuron firing rate. Lack of effect on thalamic LFO might be explained by a decrease in LFO induced by BREX itself (0.125¿1.0 mg/kg), while LFO in the mPFC were only reduced after low doses of BREX (up to 0.5 mg/kg), returning to basal after a high dose (1.0 mg/kg). BREX on its own did not affect firing rate of both thalamic and mPFC pyramidal neurons.

[Conclusions] BREX partly antagonizes thalamocortical hyperactivity associated with schizophrenia, with differential effects in the thalamus versus the mPFC. The stronger effects of BREX in the thalamus point to a primary action in this area, which would be in line with the abundant expression of ¿1B-adrenergic receptors in the thalamus. Whether these effects of BREX are mediated via ¿1B-adrenergic receptors as well as the potential involvement of 5-HT1A receptors will be investigated in following experiments.