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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

Final Calorimetric Assessment during a 60% N2O Administration for Initially Sensitive and Initially Insensitive Rats.A calorimetry retest conducted after the self-administration phase revealed that the IS and II groups both became frankly hyperthermic with the onset of 60% N2O administration but the magnitude was markedly greater and more persistent in the N2O self administration-prone II rats (A) due primarily to a greater HP response (B). The increases in DHL (C) and EHL (D) likely reflect a durable pharmacological effect of N2O in addition to the effect of increased body heat content to promote heat loss. The II and IS groups did not differ during the control gas session (E, F, G, H).
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pone.0124740.g004: Final Calorimetric Assessment during a 60% N2O Administration for Initially Sensitive and Initially Insensitive Rats.A calorimetry retest conducted after the self-administration phase revealed that the IS and II groups both became frankly hyperthermic with the onset of 60% N2O administration but the magnitude was markedly greater and more persistent in the N2O self administration-prone II rats (A) due primarily to a greater HP response (B). The increases in DHL (C) and EHL (D) likely reflect a durable pharmacological effect of N2O in addition to the effect of increased body heat content to promote heat loss. The II and IS groups did not differ during the control gas session (E, F, G, H).

Mentions: Following completion of the self-administration phase, the rats were returned to the colony housing room for 3 d. Then, on each of the next 2 d, the rats were tested individually using combined direct and indirect calorimetry as during the initial N2O exposure. One test session delivered 60% N2O exactly as was done during the initial screening evaluation in Phase 1, and the other was identical except that only control gas was delivered. The order of the two sessions was counterbalanced within and between groups. Comparison of the initial and final N2O exposures effect on Tc (Figs 1A vs. 4A) reveals that the intervening N2O exposures that occurred during the self-administration phase engendered an adapted state in both the IS and II groups with features that depart from the standard definition of chronic tolerance wherein the measured outcome stays at or near baseline during drug administration in drug-adapted individuals.


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)

Final Calorimetric Assessment during a 60% N2O Administration for Initially Sensitive and Initially Insensitive Rats.A calorimetry retest conducted after the self-administration phase revealed that the IS and II groups both became frankly hyperthermic with the onset of 60% N2O administration but the magnitude was markedly greater and more persistent in the N2O self administration-prone II rats (A) due primarily to a greater HP response (B). The increases in DHL (C) and EHL (D) likely reflect a durable pharmacological effect of N2O in addition to the effect of increased body heat content to promote heat loss. The II and IS groups did not differ during the control gas session (E, F, G, H).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124740.g004: Final Calorimetric Assessment during a 60% N2O Administration for Initially Sensitive and Initially Insensitive Rats.A calorimetry retest conducted after the self-administration phase revealed that the IS and II groups both became frankly hyperthermic with the onset of 60% N2O administration but the magnitude was markedly greater and more persistent in the N2O self administration-prone II rats (A) due primarily to a greater HP response (B). The increases in DHL (C) and EHL (D) likely reflect a durable pharmacological effect of N2O in addition to the effect of increased body heat content to promote heat loss. The II and IS groups did not differ during the control gas session (E, F, G, H).
Mentions: Following completion of the self-administration phase, the rats were returned to the colony housing room for 3 d. Then, on each of the next 2 d, the rats were tested individually using combined direct and indirect calorimetry as during the initial N2O exposure. One test session delivered 60% N2O exactly as was done during the initial screening evaluation in Phase 1, and the other was identical except that only control gas was delivered. The order of the two sessions was counterbalanced within and between groups. Comparison of the initial and final N2O exposures effect on Tc (Figs 1A vs. 4A) reveals that the intervening N2O exposures that occurred during the self-administration phase engendered an adapted state in both the IS and II groups with features that depart from the standard definition of chronic tolerance wherein the measured outcome stays at or near baseline during drug administration in drug-adapted individuals.

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