title: Actions of antipsychotic drugs on pancreatic beta-cell function: contrasting effects of clozapine and haloperidol.
abstract: The use of antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function, although the underlying mechanisms are unknown. We have studied the effects of the atypical antipsychotic clozapine and of the conventional drug haloperidol on electrical and secretory activity in rat pancreatic beta-cells. At a low glucose concentration (4mM), clozapine (5microM) had little or no effect on membrane potential. However, at a stimulatory glucose concentration (16mM), clozapine was found to hyperpolarize the cell membrane potential, resulting in a complete inhibition of electrical activity. In contrast, haloperidol (5microM) was found to cause a marked depolarization of the membrane potential in the presence of both low and high concentrations of glucose. Clozapine and haloperidol were found, respectively, to increase and decrease-cell input conductance, an index of K(+) permeability. Single channel recordings indicated that changes in K(ATP) channel activity contributed towards these effects. Neither clozapine nor haloperidol affected basal insulin release, although clozapine inhibited glucose-induced insulin release. It is concluded that clozapine and haloperidol exert contrasting actions on electrical activity in rat pancreatic -cells as a result of opposing effects on K(+) permeability. These findings may relate to the increased incidence of diabetes associated with clozapine treatment.
authors.affiliation: Department of Medicine, University of Manchester, Oxford Road, Manchester M13 9WL, UK. Len.Best@cmmc.nhs.uk
authors.forename: Leonard
authors.initials: L
authors.lastname: Best
authors.forename: Allen P
authors.initials: AP
authors.lastname: Yates
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D003024:Clozapine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012636:Secretory Rate / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D007328:Insulin; D015221:Potassium Channels; D003024:Clozapine; D006220:Haloperidol