Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

Abstract

Rationale: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations.

Objectives: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops.

Methods: During an initial 3-h administration of 60% nitrous oxide (N(2)O), male Long-Evans rats were screened for N(2)O's hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N(2)O or placebo gas. Core temperature was measured telemetrically.

Results: Rats that exhibited a comparable degree of hypothermia during an initial N(2)O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N(2)O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N(2)O exposure, the II group breathing N(2)O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N(2)O exposures.

Conclusions: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent-adaptive responses may mediate this relationship.

Figure 1.

Core temperature data (dashed line) from a single rat are smoothed (solid line) and calculations of baseline temperature, minimum temperature after drug onset, and the final temperature are made using the smoothed data. The drug effect equals 1.07°C (i.e., 37.24 minus 36.17), the drug effect regression residual equals 0.01637, and the drug effect Z-score equals 0.0308. Acute tolerance equals 0.73°C (i.e., 36.90 minus 36.17), the acute tolerance regression residual equals -0.01099, and the acute tolerance Z-score equals -0.0399. This rat is depicted in the scatterplot of Figure 2a as the most average rat.

Figure 2a, b.

The scatterplot in the left panel (a) illustrates how individual rats were categorized as belonging to one of the three individual difference groups: initially insensitive (II), sensitive with acute tolerance (AT), and sensitive with no recovery (NR). Rats in each individual difference group were assigned randomly to a placebo control condition or a 60% N₂O condition for the subsequent six test sessions. This assignment is indicated in the scatterplot where open circles indicate rats assigned to receive subsequent placebo exposures, open triangles indicate rats assigned to receive subsequent N₂O exposures, and the small dots indicate rats that exited the study because they were not categorized into an individual difference group. Because Z-scores of regression residuals are difficult to visualize in terms of core temperature profiles, the right panel (b) illustrates the average initial temperature effect of a 3-h steady-state administration of 60% N₂O for rats in the II, AT and NR groups that were selected on the basis of the Z-scores shown in the left panel (a). [Of the 400 rats screened, 387 had usable data and 96 (25%) were categorized into one of the individual difference groups as follows: II = 34 (placebo = 17, N₂O = 17), AT = 37 (placebo = 18, N₂O = 19), NR = 25 (placebo = 14, N₂O = 11).

Figure 3.

Mean (± SEM) change of temperature from baseline is depicted for II, AT and NR rats receiving a 90-min steady-state administration of 60% N₂O or placebo on the six exposures (i.e., Sessions 2-7) following the initial screening. The three columns represent the individual difference groups and the rows represent data from Sessions 2-7.

Figure 4.

Mean (± 95% Confidence Intervals) of the difference scores between the N₂O and placebo groups for each of the individual difference groups (i.e., II - Initially Insensitive, AT - Acute Tolerance, and NR - No Recovery). For purposes of statistical analysis, the continuous data presented in Figure 3 are converted to a mean difference score for three 30-minute intervals during Sessions 2-7. Full or complete tolerance development would be indicated by there being no difference (i.e., a zero change score) between the N₂O and placebo groups.