A theory of drug tolerance and dependence I: a conceptual analysis

Peper, A.

doi:10.1016/j.jtbi.2004.04.010

Cited by 30 publications

(70 citation statements)

References 34 publications

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“…Adaptation models of drug addiction are popular because they account for central features of the drug addiction process, including tolerance, dependence and withdrawal (Jaffe 1985;Peper 2004). These phenomena are thought to be manifestations of a common underlying adaptive response that develops with repeated drug use.…”

Section: Introductionmentioning

confidence: 99%

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

2005

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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.

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Section: Introductionmentioning

confidence: 99%

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

2005

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“…Cannon translated Bernard's observation into the model of homeostasis, which assumes physiological processes to maintain a steady state through feedback (Cannon 1929). An earlier publication (Peper 2004a) demonstrates that the model of homeostasis is not adequate to describe the effect of repeated disturbances on the functioning of living organisms and argues that, rather than maintaining a steady state as Cannon proposed, living organisms are constantly striving for the best obtainable compromise in their functioning in constantly changing circumstances. In this search for an optimum, the tolerance mechanism plays an important role.…”

Section: A Dynamic Model Of the Dose-response Relationmentioning

confidence: 99%

“…In addition to this dynamic action, a lasting shift in functioning develops. In the mathematical model described previously, these two activities are modelled with a fast and a slow regulator respectively (Peper et al 1987(Peper et al , 1988Peper 2004aPeper , 2004b, illustrating the twofold effect of drugs. A drug not only causes a direct, relatively short lasting effect, but it also fundamentally changes the level of functioning of the processes involved.…”

Section: A Dynamic Model Of the Dose-response Relationmentioning

confidence: 99%

“…In previous publications, a model of drug tolerance and dependence was presented (Peper et al 1987(Peper et al , 1988Peper and Grimbergen 1999;Peper 2004aPeper , 2004b. The two 2004 papers present an advanced mathematical model of intermittent adaptation describing the mechanism of tolerance development and elaborate the theory underlying the model (Peper 2004a(Peper , 2004b.…”

Section: Introductionmentioning

confidence: 99%

“…The two 2004 papers present an advanced mathematical model of intermittent adaptation describing the mechanism of tolerance development and elaborate the theory underlying the model (Peper 2004a(Peper , 2004b. The model is essentially more complex than the generally supported model of homeostasis, which has been demonstrated to fail in describing tolerance development to repeated drug administrations (Peper et al 1987, Peper 2004a. The papers argue that tolerance to a drug is not just tolerance to the properties of a certain drug, but tolerance to a certain dose of that particular drug, and that the magnitude of the compensatory response is not determined by the actual dose of the administered drug but by the dose the organism anticipates.…”

Section: Introductionmentioning

confidence: 99%

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Aspects of the Relationship between Drug Dose and Drug Effect

Peper

2009

Dose-Response

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ᮀ It is generally assumed that there exists a well-defined relationship between drug dose and drug effect and that this can be expressed by a dose-response curve. This paper argues that there is no such clear relation and that the dose-response curve provides only limited information about the drug effect. It is demonstrated that tolerance development during the measurement of the dose-response curve may cause major distortion of the curve and it is argued that the curve may only be used to indicate the response to the first administration of a drug, before tolerance has developed. The precise effect of a drug on an individual depends on the dynamic relation between several variables, particularly the level of tolerance, the dose anticipated by the organism and the actual drug dose. Simulations with a previously published mathematical model of drug tolerance demonstrate that the effect of a dose smaller than the dose the organism has developed tolerance to is difficult to predict and may be opposite to the action of the usual dose.

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Beginning the journey: addiction as choice

West

Brown

2013

Theory of Addiction

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A theory of drug tolerance and dependence I: a conceptual analysis

Cited by 30 publications

References 34 publications

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

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

Aspects of the Relationship between Drug Dose and Drug Effect

Beginning the journey: addiction as choice

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