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Predicting addictive vulnerability: individual differences in initial responding to a drug's pharmacological effects.

Ramsay DS, Al-Noori S, Shao J, Leroux BG, Woods SC, Kaiyala KJ - PLoS ONE (2015)

Bottom Line: 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.We then enrolled the two groups in a novel N2O self-administration paradigm.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Health Sciences, University of Washington, Seattle, WA, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Statistical Comparison of the N2O Preference Ratio for Initially Sensitive and Initially Insensitive Rats.The N2O preference ratio is the ratio of time each rat spent in the N2O chamber versus the control air chamber during each dyad, and was compared between initially insensitive (II, black circles) and initially sensitive (IS, red triangles) rats using linear modeling applied to log-transformed ratios. Points represent geometric means and error bars are pointwise 95% confidence intervals. Ratio comparisons were statistically significant in each of Dyads 5–8. During Dyads 5–8, the II group’s mean N2O preference ratio was 3.68-fold higher than that of IS rats (95% CI: 1.48–9.20; p = 0.003). For Dyads 1–4, the preference ratio was 1.84 times greater than that of the IS group (95% CI: 0.80–4.40), but this difference did not reach statistical significance (p = 0.075). The group-by-dyad interactions were not statistically significant for Dyads 1–4 (p = 0.227) or for Dyads 5–8 (p = 0.343).
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pone.0124740.g003: Statistical Comparison of the N2O Preference Ratio for Initially Sensitive and Initially Insensitive Rats.The N2O preference ratio is the ratio of time each rat spent in the N2O chamber versus the control air chamber during each dyad, and was compared between initially insensitive (II, black circles) and initially sensitive (IS, red triangles) rats using linear modeling applied to log-transformed ratios. Points represent geometric means and error bars are pointwise 95% confidence intervals. Ratio comparisons were statistically significant in each of Dyads 5–8. During Dyads 5–8, the II group’s mean N2O preference ratio was 3.68-fold higher than that of IS rats (95% CI: 1.48–9.20; p = 0.003). For Dyads 1–4, the preference ratio was 1.84 times greater than that of the IS group (95% CI: 0.80–4.40), but this difference did not reach statistical significance (p = 0.075). The group-by-dyad interactions were not statistically significant for Dyads 1–4 (p = 0.227) or for Dyads 5–8 (p = 0.343).

Mentions: The results of the linear models are displayed in Fig 3. On average, the IS group spent less time in the N2O chamber than in the control chamber during all eight dyads, i.e., the mean ratios are all below 1:1. During Dyads 5 through 8, the ratio was significantly higher in II rats than in the IS ones, with II rats spending, on average, more than twice as much time in N2O versus the control chamber during the last two dyads (see Fig 3 legend for more details). The analysis also suggests that the difference between IS and II groups increased over dyads, although the interaction terms were not statistically significant.


Predicting addictive vulnerability: individual differences in initial responding to a drug's pharmacological effects.

Ramsay DS, Al-Noori S, Shao J, Leroux BG, Woods SC, Kaiyala KJ - PLoS ONE (2015)

Statistical Comparison of the N2O Preference Ratio for Initially Sensitive and Initially Insensitive Rats.The N2O preference ratio is the ratio of time each rat spent in the N2O chamber versus the control air chamber during each dyad, and was compared between initially insensitive (II, black circles) and initially sensitive (IS, red triangles) rats using linear modeling applied to log-transformed ratios. Points represent geometric means and error bars are pointwise 95% confidence intervals. Ratio comparisons were statistically significant in each of Dyads 5–8. During Dyads 5–8, the II group’s mean N2O preference ratio was 3.68-fold higher than that of IS rats (95% CI: 1.48–9.20; p = 0.003). For Dyads 1–4, the preference ratio was 1.84 times greater than that of the IS group (95% CI: 0.80–4.40), but this difference did not reach statistical significance (p = 0.075). The group-by-dyad interactions were not statistically significant for Dyads 1–4 (p = 0.227) or for Dyads 5–8 (p = 0.343).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4400068&req=5

pone.0124740.g003: Statistical Comparison of the N2O Preference Ratio for Initially Sensitive and Initially Insensitive Rats.The N2O preference ratio is the ratio of time each rat spent in the N2O chamber versus the control air chamber during each dyad, and was compared between initially insensitive (II, black circles) and initially sensitive (IS, red triangles) rats using linear modeling applied to log-transformed ratios. Points represent geometric means and error bars are pointwise 95% confidence intervals. Ratio comparisons were statistically significant in each of Dyads 5–8. During Dyads 5–8, the II group’s mean N2O preference ratio was 3.68-fold higher than that of IS rats (95% CI: 1.48–9.20; p = 0.003). For Dyads 1–4, the preference ratio was 1.84 times greater than that of the IS group (95% CI: 0.80–4.40), but this difference did not reach statistical significance (p = 0.075). The group-by-dyad interactions were not statistically significant for Dyads 1–4 (p = 0.227) or for Dyads 5–8 (p = 0.343).
Mentions: The results of the linear models are displayed in Fig 3. On average, the IS group spent less time in the N2O chamber than in the control chamber during all eight dyads, i.e., the mean ratios are all below 1:1. During Dyads 5 through 8, the ratio was significantly higher in II rats than in the IS ones, with II rats spending, on average, more than twice as much time in N2O versus the control chamber during the last two dyads (see Fig 3 legend for more details). The analysis also suggests that the difference between IS and II groups increased over dyads, although the interaction terms were not statistically significant.

Bottom Line: 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.We then enrolled the two groups in a novel N2O self-administration paradigm.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Health Sciences, University of Washington, Seattle, WA, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus