Muscarinic receptor activation preferentially inhibits rebound in vulnerable dopaminergic neurons.

Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch clamp electrophysiology on ex vivo slices from adult mice of both sexes, we find that muscarinic activation with the non-selective muscarinic agonist Oxotremorine inhibits rebound activity more strongly in vulnerable vs resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current (Ih) in vulnerable SNc neurons, but that Ih activity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that Oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations.

A retrospective chart review of the use of olanzapine for the prevention of delayed emesis in cancer patients.

Chemotherapy-induced delayed emesis (DE) affects approximately 50-70% of patients receiving moderately and highly emetogenic chemotherapy. DE most commonly occurs within the first 24-48 hours of chemotherapy administration and can persist for 2-5 days. Olanzapine, which has been used anecdotally for chronic nausea in advanced cancer patients, might be a useful treatment for the prevention of delayed emesis in chemotherapy patients. We conducted a chart review to explore this hypothesis and to plan potential studies. Using pharmacy records or an electronic medical record, we identified all patients who had received olanzapine in the oncology clinic (n = 98). We reviewed these records and selected all patients (n = 28) who had received olanzapine for the prevention of delayed emesis for structured review. There were 17 women (60.7%) and 11 men (39.3%). Eleven patients (39.3%) had at least one instance of nausea recorded while undergoing olanzapine treatment and seven (25%) had an episode of vomiting recorded. During 95 total cycles of chemotherapy with olanzapine (mean = 3.4 cycles per patient), there were 21 incidents of nausea (22.1%) and 10 instances of vomiting (10.5%). Side effects were rarely noted. These data suggest that olanzapine was well tolerated and may reduce the incidence of delayed emesis in patients receiving moderate to highly emetogenic chemotherapy. A series of prospective trials are underway.