The effects of centrally administered chlorpromazine on temperature regulation in the hamster

Abstract

THE demonstrated importance of hypothalamic centers in the control of body temperature (1) has stimulated considerable interest in the central component of action of several chemical agents observed to have a disruptive effect on temperature regulation. Chlorpromazine (CPZ), based on its general central depressant activity, has been assumed to produce this disruptive effect by a deppression of hypothalamic neuromechanisms involved in temperature control. However, CPZ has a broad spectrum of peripheral as well as central activity (2) and few attempts have been made to achieve a definitive indication of the relative importance of these components in eliciting alterations in body temperature. The present study was undertaken to investigate the central component of CPZ induced hypothermia in hamsters by means of the direct injection of this agent into the anterior hypothalamus at a low ambient temperature. Because of our interest in the influence of genetic predisposition on the effects of psychotropic drugs (3,4,5) and since the hamster is the most readily available animal whose innate thermoregulatory control mechanisms permit a state of hibernation, it was decided to compare the central effects of CPZ in this species with those reported to occur in a non-hibernator such as the rat. Rewerski and co-workers (6,7) have observed a hyperthermic effect following the intrahypothalamic injection of CPZ in rats subjected to ether anesthesia and stereotaxic restraint at 20°C. However, since it is well known that ambient temperature and degree of stress both influence the effect of CPZ on body temperature (2,8), it was decided to perform the experiments described below in unanesthetized, partially restrained animals at an ambient temperature of 10°C. Finally, on the basis of the demonstrated hypothermia mediated by the central activity of several cholinergic agents (9,10,11) and cholinesterase inhibitors (12), the ability of atropine to prevent this effect and to elicit hyperthermia following central administration (13), and the anticholinesterase activity of CPZ by pretreatment with centrally administered atropine. The injection of 12.5 – 37.5 ug of CPZ into the anterior hypothalamus of hamsters has been shown to elicit an immediate, dose-dependent hypothermia when the experiments are conducted at a low environmental temperature. A 50 ug dose of CPZ sulfoxide produced only a slight fall in rectal temperature comparable to that obtained following the lowest dose of CPZ. The CPZ response was not antagonized by an equimolar dose of atropine and was not accompanied by changes in EMG or skin temperature indicative of interference with the thermoregulatory mechanisms of shivering and peripheral vascular tone. However, undetected vascular changes may have occured. These results are consistent with the possibility that the effect of CPZ on the central control of body temperature in the hamster may be mediated through its influence on non-shivering thermogenesis.