Olanzapine Reduces Neuronal Activity in the Dorsal Motor Nucleus of the Vagus

Abstract

Olanzapine, a widely prescribed atypical antipsychotic, relieves the symptoms of schizophrenia and bipolar disorder. Despite its positive impact on mental health, patients treated with olanzapine experience side effects related to weight gain and impaired glucose homeostasis. A variety of mechanisms and brain areas underlying the metabolic side effects have been proposed; however, the involvement of the brainstem remained to be elucidated. Parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) set the vagal tone and thus control visceral functions including feeding, digestion, and glucose homeostasis. In this study, whole‐cell patch‐clamp recordings were performed to test the hypothesis that olanzapine modulates neuronal activity in the DMV of mice. Acute application of olanzapine (10 µM) hyperpolarized the majority (~70 %) of DMV neurons in male mice by an average of ‐7.77 ± 1.17 mV (n=20). This effect was concentration‐dependent (EC50 = 16.02 ± 1.78 µM), and was associated with a reduction of input resistance. Similarly, hyperpolarization was observed in female mice (n=9). The hyperpolarization also occurred in the presence of tetrodotoxin, suggesting a postsynaptic mechanism of action. Next, stomach‐ and liver‐projecting DMV neurons were identified with transsynaptic retrograde viral labeling. Acute olanzapine application resulted in hyperpolarization of the majority of both liver‐ and stomach‐related DMV neurons. In summary, our data demonstrate that in slices olanzapine administration hyperpolarizes the majority of DMV neurons via postsynaptic mechanisms. These data suggest that olanzapine has the potential to modulate vagal outflow to subdiaphragmatic organs.Supported by: Pilot Project Grant Tulane University School of Medicine