Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Abstract

A common in vivo measure of initial drug sensitivity can fail to disclose underlying pharmacological sensitivity owing to regulatory counter-responses. This concept has implications for understanding relationships between phenotypic variation in initial drug sensitivity and subsequent drug-taking phenotypes.

Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats

“…The predictions of this (controversial) model are thus very different from those of the tissue-sensitivity model, which predicts that tolerance is explained by a diminution of the original disturbing pharmacological influence and that no effector response will be evident. In our paradigm, initial administrations of ≥30% N 2 O reliably evokes increased HL, indicating that this is a primary hypothermia-favoring pharmacological effect, whereas the drug's initial impact on HP depends on age and other factors Kaiyala et al 2007). Accordingly, the primary hypothesis evaluated in the current research was that chronic tolerance to N 2 O hypothermia is explained by an acquired increase of HP during drug administration, which counteracts druginduced increases of HL.…”

“…A temperature sensor/transmitter was implanted in the peritoneal cavity of each rat ≥7 days before the first drug exposure as detailed in the companion paper (Kaiyala et al 2007). …”

“…The paradigm described in detail elsewhere Kaiyala et al 2007) was used to quantify HP, HL, and T core during administrations of control gas and N 2 O at 1.16 l min −1 standard temperature and pressure, dry. Briefly, a direct calorimeter quantifies dry HL (DHL) and serves as the exposure chamber.…”

“…It should be appreciated that T core has been used widely by drug researchers to define sensitivity and study tolerance, most notably in the ethanol field (Browman et al 2000;Palmer et al 2002;Lovinger and Crabbe 2005). At concentrations ≥60%, initial administrations of N 2 O typically cause significant hypothermia, but it is important to emphasize that its magnitude exhibits considerable and reliable individual differences (Ramsay et al 1999Kaiyala et al 2001; Kaiyala and Ramsay 2005;Kaiyala et al 2007). The time integral of HP minus HL necessarily determines changes of T core , and the detailed temporal dynamics of the three variables can be rigorously and synchronously quantified via indirect calorimetry, direct gradient layer calorimetry and telemetry, respectively.…”

“…Alternatively, the initial pharmacological effect that promotes the hypothermia might remain intact in the tolerant state, with this state explained by a welldeveloped physiological counter-response. This distinction, pharmacodynamically reduced tissue sensitivity vs dynamic regulatory compensation, is also important to understanding variation in initial sensitivity to druginduced hypothermia (Kaiyala et al 2007) and could have implications for interpreting phenotypes based on hypothermic tolerance, such as mice created by selective breeding to be insensitive (HOT) and sensitive (COLD) to ethanol-induced hypothermia (Browman et al 2000).…”