Clozapine and olanzapine, but not haloperidol, reverse cold-induced and lipopolysaccharide-induced cutaneous vasoconstriction.

Abstract

Reduction of body temperature is used as predictor of psychotropic drug action. The cutaneous circulation functions as a heat-loss component of temperature regulation. Clozapine and olanzapine reverse hyperthermia and sympathetically-mediated cutaneous vasoconstriction induced by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), suggesting that these drugs might reverse other forms of sympathetically mediated cutaneous vasoconstriction. Clozapine and olanzapine were compared with haloperidol with respect to their ability to reverse cold-induced and LPS (lipopolysaccharide)-induced cutaneous vasoconstriction in rabbits. Cutaneous blood flow was measured in conscious rabbits by Doppler ultrasonic flow probe implanted around the central ear artery, and body temperature was measured telemetrically. After control observations, animals were transferred from 26 to 10 degrees C, or LPS (0.5 microLg/kg IV) was administered. After 30 min, clozapine, olanzapine or haloperidol was administered and ear pinna blood flow and body temperature were measured for another 30 min. Clozapine, in a dose responsive manner (1, 2.5 and 5 mg/kg IV), substantially reversed cold-induced ear pinna vasoconstriction and reduced body temperature. Clozapine (1 mg/kg IV) reversed LPS-induced cutaneous vasoconstriction and reduced the LPS-induced rise in body temperature. Olanzapine had generally similar effects. Haloperidol (1 mg/kg IV in cold experiments and 0.2 mg/kg IV in LPS experiments) did not reverse ear pinna vasoconstriction, or affect body temperature. Both clozapine and olanzapine, but not haloperidol, reverse physiologically induced cutaneous sympathetic vasomotor discharge. Because of the close link between psychological function and sympathetic regulation of cutaneous blood flow, similar neuropharmacological mechanisms might underly the cutaneous vasodilating action and the psychotropic actions of atypical antipsychotic drugs.