Olanzapine, an atypical antipsychotic, alleviates symptoms of schizophrenia while producing fewer side effects compared to first generation antipsychotics. However, chronic usage remains problematic due to the propensity of olanzapine to induce weight gain and metabolic disturbances. Moreover, the cellular mechanisms underlying the metabolic side effects are poorly understood. The central nervous system (CNS) exerts both hormonal and neuronal control over whole body homeostasis. The dorsal motor nucleus of the vagus (DMV) participates in this regulation through modulation of the parasympathetic outflow to subdiaphragmatic organs. We hypothesized that olanzapine disrupts neurotransmission of the DMV, and thus contributes to the dysregulation of metabolism. We used whole-cell patch-clamp recordings from female C57BL/6J to assess the effect of olanzapine on DMV neurons. First, we investigated the effect of acute olanzapine administration on the activity of DMV neurons. Acute application of 10 µM olanzapine on DMV neurons induced both pre- and postsynaptic effects. Voltage-clamp recordings revealed that, in 5 out of 9 DMV neurons, excitatory inputs to DMV neurons were significantly increased by 71.6 ± 22.1%. In addition, in current-clamp mode, olanzapine induced a robust hyperpolarization from -49.00 ± 0.64 mV to -60.82 ± 2.78 mV. The hyperpolarization suppressed action potential firing. As a next step, we investigated the subchronic effect of olanzapine on the activity of DMV neurons. Daily subcutaneous injections were made for 20 days (5 mg/kg/day of olanzapine and vehicle). We did not find significant differences in body weight, blood glucose, and insulin or leptin levels. Subchronic administration of olanzapine generated presynaptic changes in DMV neurons. In treated animals, additional infusion of 10 µM olanzapine on DMV neurons significantly reduced excitatory neurotransmission by 41.0 ± 3.1% in 10 out of 17 neurons. Our findings indicate that olanzapine directly modulates the neuronal activity in DMV neurons, and could thus contribute to the metabolic disturbances seen in long-term treatments.
