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

Abstract

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 (N2O) 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 N2O self-administration paradigm. The initially insensitive rats self-administered significantly more N2O 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 N2O administration, but that insensitive rats generated more heat and thereby remained relatively normothermic. Calorimetry testing conducted after self-administration revealed that whereas N2O’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 N2O-induced hypothermia, subsequently self-administered more N2O, and developed hyperthermic overcompensation during N2O inhalation, consistent with increased abuse potential and an allostatic model of addictive vulnerability.

Concentration-related metabolic rate and behavioral thermoregulatory adaptations to serial administrations of nitrous oxide in rats

“…When first administered at these levels N 2 O increases heat loss and causes hypothermia [ 3 , 5 , 6 , 8 , 9 , 11 , 13 , 16 ]. Following several administrations, core temperature instead remains within the normal ‘homeostatic’ range during administration–the hallmark of hypothermic tolerance–but this tolerance mostly results from an acquired increase of metabolic rate.…”

“…Following several administrations, core temperature instead remains within the normal ‘homeostatic’ range during administration–the hallmark of hypothermic tolerance–but this tolerance mostly results from an acquired increase of metabolic rate. More remarkably, with further administrations the rats exhibit hyperthermia, hypermetabolism and elevated heat loss during N 2 O administration [ 6 , 8 , 9 , 11 , 13 ]. We regard this situation as an instance of allostatic—not homeostatic—regulation involving an energetically inefficient overcorrection of a regulated outcome [ 17 ].…”

“…These data demonstrate that drug administrations that have no effect on core temperature may nonetheless have significant biological effects on the physiological and behavioral determinants of core temperature–a lesson that emphasizes the interpretational challenges associated with using core temperature in toxicology screens [ 24 ]. Similarly, some rats are insensitive to 60% N 2 O’s typical hypothermic effect during initial administration because increased heat loss is offset by a prompt increase of heat production [ 3 , 13 ].…”

“…Importantly, rats that exhibited minimal hypothermia during initial 60% N 2 O administration engaged in significantly more N 2 O self-administration in comparison to hypothermia-sensitive rats, and the minimal hypothermia animals also exhibited elevated metabolic heat production in a final test session in the calorimeter [ 13 ]. These data indicate that a robust (but usually hidden) regulatory phenotype can explain what looks like initial drug insensitivity as defined by the relative stability of core temperature during drug administration (core temperature has long used to define and study drug sensitivity and tolerance in animal models [ 4 , 10 , 25 , 26 ], and has also been used to screen for toxicants [ 24 ]).…”

Brown adipose tissue thermogenesis does not explain the intra-administration hyperthermic sign-reversal induced by serial administrations of 60% nitrous oxide to rats

“…The effects of ≥60% N 2 O to evoke hypothermia upon initial administration to rats, but to evoke hyperthermia in rats adapted to serial N 2 O administrations are well documented by our group (Kaiyala et al, 2007a(Kaiyala et al, , 2007bKaiyala et al, 2012;Kaiyala et al, 2001;Kaiyala et al, 2014;Ramsay et al, 2015;Ramsay et al, 2005;Ramsay, Seaman, & Kaiyala, 2011;Ramsay, Woods, & Kaiyala, 2014a;Ramsay, Woods, et al, 2014b). Moreover, we have documented that the initial hypothermic effect is underlain by a state of negative heat balance caused by a marked increase of whole-body heat loss accompanied by a reduction of or no change in whole-body heat production, while the subsequent acquisition of an intra-administration hyperthermic state is primarily due to a marked increase of heat production (Kaiyala et al, 2007a(Kaiyala et al, , 2007bKaiyala et al, 2012;Kaiyala et al, 2014;Ramsay et al, 2015;Ramsay, Woods, et al, 2014b). However, the mechanisms underlying the alterations of heat loss and heat production have not been identified.…”