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The effects of the dibenzodiazepine derivative, clozapine, on the salivary responses induced by autonomic stimulating drugs, and also on the levels of monoamines and ACh in the salivary glands and brains in mice were examined. The salivary responses induced by pilocarpine (0.8mg/kg, s. c.), phenylephrine (5mg/kg, s. c.), isoproterenol (0.4mg/kg, s. c.) and dopamine (10mg/kg, s. c.) reached a maximum level 20min after administration, but decraesed thereafter and disappeared after 90min. Although clozapine (3, 10 and 30mg/kg) alone had no influence on salivary secretion in anaesthetized and non-anaesthetized mice, clozapine inhibited the pilocarpine-and dopamine-induced salivary responses in a dose-dependent manner. The phenylphrine-induced salivary response was increased with clozapine at 3mg/kg, and decreased at doses of 10 and 30mg/kg. However, clozapine had no influence on the isoproterenol-induced salivary response. The salivary responses induced by autonomic stimulating drugs showed the lowest level when clozapine (10mg/kg) was given 1 or 2 hours before the administrations. In mice treated with clozapine (10mg/kg), the ACh and DA levels decreased in the salivary glands, whereas the levels of monoamine related substances increased in the brain. These results suggest that the biphasic action of clozapine on the α-adrenergic agonist-induced salivary response is related to the paradoxical symptoms of hypo-and hyper-salivation often observed in patients receiving clozapine.

The paradoxical effects of the dibenzodiazepine derivative, clozapine, on autonomic stimulating drug-induced salivary responses in mice.