Targeting beta-2 adrenergic receptor attenuates schizophrenia-like behavioral effects induced by ketamine in mice: cAMP/PKA/BDNF-PEA-3 and RIM-1α signaling pathways involvement

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The interplay between cAMP/PKA and neuroplasticity involves intricate signaling pathways that are crucial for brain function and are frequently disrupted in schizophrenia. This study sought to examine the potential neuroprotective effects of formoterol on ketamine-induced schizophrenia-like behaviors with emphasis on several PKA downstream crucial targets for schizophrenia management. Male mice were injected with ketamine (20 mg/kg/day, i.p) for 14 days. From day 8, animals were treated with formoterol (100 μg/kg) with or without, the PKA inhibitor, H89 (0.05 mg/kg). Behavioral endpoints were assessed with n = 15 per group, and following sacrifice animals were stratified into subsets for downstream analyses: histopathology (n = 3), biochemical/neurochemical assays (n = 6), and molecular profiling including western blotting (n = 3) and qRT‑PCR (n = 6). Formoterol improved ketamine- induced anxiety, impaired social interaction and anhedonic behavior. It also restored neurochemical balance and enhanced learning and memory functions. Formoterol attenuated neuro-inflammation and oxidative stress, and modulated synaptic plasticity. Formoterol-induced neuroprotection could be attributed to its boosting action on cAMP/PKA/BDNF signaling to promote RIM-1α and PEA-3 gene expression. Consequently, it upregulated glutamate NMDA receptor subunits namely; GluN2A, and GluN2B and augmented expression of vital synaptic plasticity regulators; kalirin-7, PSD-95, synaptophysin and synapsin-2. Accordingly, formoterol is a promising candidate against schizophrenia-associated synaptic dysfunction and neurotransmitters imbalance. Formoterol neuroprotective effects were abolished upon administration of PKA inhibitor confirming that the cAMP/PKA cascade is a vital key-player in the drug favorable effects.

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