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Considerable data suggest that individuals who appear minimally disrupted during an initial drug administration have elevated risk for abusing the drug later. A better understanding of this association could lead to more effective strategies for preventing and treating drug addiction. To investigate this phenomenon using a rigorous experimental model, we first administered the abused inhalant nitrous oxide (N 2 O) to rats in a total calorimetry and temperature system to identify groups that were sensitive or insensitive to the drug’s hypothermic effect. We then enrolled the two groups in a novel N 2 O self-administration paradigm. The initially insensitive rats self-administered significantly more N 2 O than sensitive rats, an important step in the transition to addiction. Continuous non-invasive measurement of core temperature and its underlying determinants during screening revealed that both groups had similarly increased heat loss during initial N 2 O administration, but that insensitive rats generated more heat and thereby remained relatively normothermic. Calorimetry testing conducted after self-administration revealed that whereas N 2 O’s effect on heat loss persisted comparably for both groups, initially insensitive rats actually over-responded by generating excess heat and becoming hyperthermic. Thus, rats with the greatest initial heat-producing compensatory response(s) appeared initially insensitive to N 2 O-induced hypothermia, subsequently self-administered more N 2 O, and developed hyperthermic overcompensation during N 2 O inhalation, consistent with increased abuse potential and an allostatic model of addictive vulnerability.

Predicting Addictive Vulnerability: Individual Differences in Initial Responding to a Drug’s Pharmacological Effects