Behavioral and neuropharmacological toxicology of the macrocyclic ether 18-crown-6

18-CROWN-6 was assessed for neurologic effects in rats, mice, and rabbits by intravenous (IV) and intraperitoneal (IP) routes of administration. Male rats and mice exhibited no effects with IV doses to 20 mg/kg. Given IP doses of 20 to 160 mg/kg/day, rats and mice exhibited numerous signs, including aggression, tremors, muscle weakness and a degradation of some reflexes. All signs faded after four days when dosage levels were kept constant, but returned when the dose was doubled. All signs disappeared upon discontinuance of exposure. Treatment with PCPA (p-chlorophenylalanine) or dibenzyline caused most signs to disappear. Rabbits given 6.0 mg/kg/day IV displayed tremors, hyperactivity, unsteady gait and stereotypic behavior, with acclimation as in rats and mice. 18-CROWN-6 had no activity in isolated tissue preparations unless it was first incubated with tissues. PCPA and dibenzyline reversibly blocked the actions of incubated 18-CROWN-6 on isolated tissue. 18-CROWN-6 is hypothesized to be metabolized to a serotonergic agonist.