Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction

Abstract

Initial administration of 60% nitrous oxide (N ₂O) at 21°C ambient temperature reduces core temperature (Tc) in rats, but tolerance develops to this hypothermic effect over several administrations. After additional N ₂O administrations, a hyperthermic overcompensation (sign-reversal) develops such that Tc exceeds control levels during N ₂O inhalation. This study investigated whether rats would employ behavioral thermoregulation to facilitate, or oppose, a previously acquired hyperthermic overcompensation during N ₂O administration. To establish a hyperthermic sign-reversal, male Long-Evans rats (N = 12) received 10 3-h administrations of 60% N ₂O while housed in a gas-tight, live-in, “inactive” thermal gradient (∼21°C). Following the tenth N ₂O exposure, the thermal gradient was activated (range of 10–37°C), and rats received both a control gas session and a 60% N ₂O test session in counterbalanced order. Mean Tc during N ₂O inhalation in the inactive gradient was reliably hypothermic during the first exposure but was reliably hyperthermic by the tenth exposure. When subsequently exposed to 60% N ₂O in the active gradient, rats selected a cooler Ta, which blunted the hyperthermic sign-reversal and lowered Tc throughout the remainder of the N ₂O exposure. Thus, autonomic heat production effectors mediating the hyperthermia were opposed by a behavioral effector that promoted increased heat loss via selection of a cooler ambient temperature. These data are compatible with an allostatic model of drug addiction that suggests that dysregulatory overcompensation in the drugged-state may motivate behaviors (e.g., drug taking) that oppose the overcompensation, thereby creating a vicious cycle of escalating drug consumption and recurring dysregulation.