TOLERANCE DEVELOPMENT TO THE EFFECTS OF ETHANOL: ROLE OF BEHAVIORAL THERMOREGULATORY RESPONSES

Abstract

The mechanisms which account for the diminished responsiveness (tolerance) of an individual to a drug, as a result of prior exposure to that drug, are not yet fully understood. Recently, it has been suggested that drug tolerance is a learned adaptive response. This possibility was examined by studying the effect of ethanol on body temperature and behavioral thermoregulatory responses of Sprague-Dawley rats. Two major studies were conducted. The first study examined the initial dose-related effects of ethanol (1, 2, or 3 g/kg i.p.); the second study examined the effect of ethanol (2.5 g/kg i.p.) administered on 14 consecutive days. Rats were tested in a thermocline, a hollo plexiglass tube in which a linear temperature gradient (6-36°C) was established through local heating and cooling of opposite ends of the tube. The position of rats in the thermocline was detected by a series of infrared light emitting diodes and photocells. The body temperature of rats in the thermocline was transmitted by a temperature sensitive telemetry capsule surgically placed in the peritoneal cavity. Validation studies demonstrated that rats reliably responded to temperature cues within the thermocline. In the first experiment ethanol produced a dose-related decrease in body temperature. All rats following injection initially selected an ambient temperature cooler than baseline. Rats receiving control treatment or the high dose of ethanol eventually shifted to a warmer ambient temperature. Activity levels were depressed equally by all three doses of ethanol. In the second experiment tolerance developed to the hypothermic effect of ethanol. A diminished response to ethanol was evident by the second test day and was maximal by day 7. Ethanol treated rats selected a cooler ambient temperature than control rats throughout the 14 day period, and activity levels continued to be depressed by ethanol throughout the 14 days. On the fifteenth day all rats were given an injection of saline. Rats which had previously received daily ethanol injections exhibited a hyperthermic response to saline compared to control rats. These results suggest that ethanol altered the central control of thermoregulation by lowering and possibly broadening the thermoregulatory set point. There was evidence for a conditioned hyperthermic response, but not a learned behavioral response, which contributed to the tolerance development.