Diazepam self-administration and resistance to extinction

doi:10.1016/0091-3057(87)90016-5

Pharmacology Biochemistry and Behavior

Volume 28, Issue 1, September 1987, Pages 81-86

https://doi.org/10.1016/0091-3057(87)90016-5 Get rights and content

Abstract

Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.

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Current approaches and issues in non-clinical evaluation of abuse and dependence
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Citation Excerpt :
For example, cocaine is often used as a standard training substance and many classes of drugs have been shown to induce robust self-administration in cocaine-trained animals. It has been demonstrated that animals trained on cocaine will self-administer opiates (Griffiths, Lukas, Bradford, Brady, & Snell, 1981), benzodiazepines (Grant & Johanson, 1987), quinpirole (Collins & Woods, 2007) and, in our own laboratory, ketamine and nicotine (Moser, Coquelin, & Froger-Colléaux, in press). At the same time some divergent findings have been reported, with morphine for example (Mierzejewski, Stefanski, Bienkowski, & Kostowski, 2007), suggesting that specific conditions of cocaine training that maximise such transfer may be needed.
Preclinical assessment of drug abuse and dependence has been the subject of several recent regulatory guidelines. Both the European and US authorities recommend a tiered approach and are generally aligned on the methods which should be used. The first tier simply compares the pharmacology of the novel substance to known drugs of abuse. The second tier aims to identify abuse and dependence liability more directly. The most direct approach to assessing reinforcing properties is the i.v. self-administration procedure. Unfortunately there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties or pharmacokinetics (PK). Indeed, the choice of training substance, species and procedural parameters can radically affect the outcome. Apart from the lower cost of the rat, the primate presents several advantages for self-administration studies (potentially greater similarity to humans in behavioral effects, active doses and PK). Although it does not measure abuse liability directly, drug discrimination is a powerful method for assessing the similarity of a test substance to a known drug of abuse. In this procedure an animal uses the interoceptive effects of the substance as the discriminative stimulus to determine which of two responses to make. For certain classes of substance, such as hallucinogens acting via the 5-HT_2A receptor, discrimination is the only procedure currently able to identify them. Drug dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, many factors (duration and frequency of drug treatment, dose/exposure levels, duration of observation after discontinuation) can complicate interpretation. Telemetry may represent a novel approach which allows continuous observation of somatic and behavioral parameters during drug withdrawal thereby increasing sensitivity. Presently available tools can identify essentially all substances known to cause abuse or dependence with little risk of false positives. It remains unclear how effective these models will be with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models remains very high.
The predictive validity of the rat self-administration model for abuse liability
2011, Neuroscience and Biobehavioral Reviews
The self-administration model is the primary non-clinical approach for assessing the reinforcing properties of novel compounds. Given the now frequent use of rats in self-administration studies, it is important to understand the predictive validity of the rat self-administration model for use in abuse liability assessments. This review of 71 drugs identifies high concordance between findings from rat self-administration studies and two clinical indicators of abuse liability, namely reports of positive subjective-effects and the DEA drug scheduling status. To understand the influence of species on concordance we compare rodent and non-human primate (NHP) self-administration data. In the few instances where discrepancies are observed between rat data and the clinical indicators of abuse liability, rat self-administration data corresponds with NHP data in the majority of these cases. We discuss the influence of genetic factors (sex and strain), food deprivation state and the study design (acquisition or drug substitution) on self-administration study outcomes and highlight opportunities to improve the predictive validity of the self-administration model.
Principles of drug abuse liability assessment in laboratory animals
2003, Drug and Alcohol Dependence
This paper describes the rationale for use of preclinical assessments of abuse liability in laboratory animals, and then discusses ‘cross-cutting’ methodological issues that apply to behavioral evaluations intended to contribute to an abuse liability evaluation package. Issues include use of: (1) positive and negative control conditions; (2) full dose–effect evaluations, (3) multiple dependent measures, (4) pharmacokinetic evaluations to guide choice of dose ranges, (5) a species for which good methodological and comparative data are available to aid interpretation of results, and (6) appropriate methods for the group or single-subject experimental design selected. The remainder of the paper describes basic methodology by which three core pieces of behavioral data required by the Food and Drug Administration for its use in the overall abuse liability analysis can be obtained preclinically. Reinforcing effects are assessed in study of drug self-administration; drug discrimination assesses degree of overlap of interoceptive stimulus effects with relevant comparison drugs; physical dependence potential is determined by assessing whether a withdrawal syndrome occurs after chronic drug administration. Background and methodological issues specific to each procedure are discussed. A key consideration for cross-cutting and specific methodological issues is that choices made enable confident interpretation of both positive and negative results.
Schedule-Induced Drug Self-Administration
1993, Handbook of Behavioral Neuroscience
This chapter describes schedule-induced drug self-administration. The characteristics of schedule-induced behavior bear some similarities to the behavioral features of drug abuse. Both are chronically excessive sorts of behavior with powerful motivational efficacies. They are intrusive activities that can take over the stream of behavior, sometimes to the detriment of alternative, adjustive functions. There are commonalities as to how they are generated and why they persist. To make such a case, it is necessary to show that in drug abuse, as in adjunctive behavior, the role of the environment is not simply permissive, but is an active determinant of the behavior. The chapter reviews the studies on schedule-induced oral and intravenous self-administration of drugs. The feasibility of applying the schedule-induction method for illuminating the problem of drug abuse is presented, as well as the behavioral and pharmacologic consequences of inducing chronic drug overindulgences. The chapter also describes the contribution of schedule-induced drug-taking to a theoretical understanding of how drugs may come to operate as powerful and enduring reinforcers for humans.
The gold-standard in preclinical abuse liability testing: It's all relative
2018, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
Quick and Shahan (2009) have proposed that behavioral momentum theory provides a framework for understanding how stimulus contexts contribute to the relative persistence of operant behavior in this assay. Grant and Johanson (1987) have also suggested that the responding maintained under extinction conditions appear to be directly related to the behavioral and drug history of the animals. The resistance to extinction, then, may provide for a useful comparison of the relative potential similarities or differences between drugs with respect to the relative work effort maintained for their delivery.
All new molecular entities (NMEs) with targeted or indirect effects on the central nervous system (CNS) must be evaluated for their abuse liability as a part of their nonclinical development plan. Inherently key in the drug control review is the term “relative abuse liability”. The basis for determination of drug control is critically dependent on the nonclinical assessment of the reinforcing attributes of the NME in animals (rat is the regulatory preferred species) in a standard operant conditioning paradigm. Pharmaceutical representatives without a background in behavioral analysis or operant conditioning models must weigh through conceptually-intriguing language and constructs that accurately convey and communicate the relative potential for abuse to drug regulatory experts in the field. Effective statutory language in the preclinical assessment of relative abuse liabilities for schedule control status reviews must be 1) specific; 2) concise; 3) familiar to the regulators; 4) unambiguous; 5) constructive; and 6) formalized with respect to both international and national drug control policies. In this review we attempt to define and highlight the importance of the statutory language used to report self-administration study results to both parties engaged in NDA approval process.
From benzodiazepine prescription to dependence: Learning processes involved
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¹: Request for reprints should be addressed to Dr. K.A. Grant, Department pf Psychiatry, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637.

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Pharmacology Biochemistry and Behavior

Abstract

References (28)

A sequential hypothesis of animal learning

Evaluation of a suspension system for intravenous self-administration studies of water-insoluble compounds in the rhesus monkey

Pharmacol Biochem Behav

Inhibitory and disinhibitory effects of nitrazepam, diazepam and flurazepamm hydrochloride on delayed matching behaviour in monkeys (macaca mulatta)

Neuropharmacology

Similarities and differences in discriminative-stimulus effects of chlordiazepoxide, pentobarbital, ethanol and other sedatives

The reinforcing properties of diazepam under several conditions in the rhesus monkey

Psychopharmacology (Berlin)

The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioral responses to anxiogenic stimuli in the rat: Extinction and successive discrimination

Psychopharmacology (Berlin)

Use of DRL in differentiating anxiolytic and neuroleptic properties of CNS drugs

Pharmacol Biochem Behav

Dose-dependent impairment in the performance of a go-no go successive discrimination by chlordiazepoxide

Psychopharmacology (Berlin)

Reinstatement of cocaine-reinforced responding in the rat

Psychopharmacology (Berlin)

Schedules of Reinforcement

Benzodiazepine self-administration in animals and humans: A comprehensive literature review

Self-injection of barbiturates and benzodiazepines in baboons

Psychopharmacology (Berlin)

Reinforcing properties of intravenous diazepam in rhesus monkeys (macaca mulatta) with a history of codeine self-administration

Effects of chlordiazepoxide upon successive red-green discrimination responses in Japanese monkeys, Mucaca Fuscata

Psychopharmacologia

Cited by (17)

Current approaches and issues in non-clinical evaluation of abuse and dependence

The predictive validity of the rat self-administration model for abuse liability

Principles of drug abuse liability assessment in laboratory animals

Schedule-Induced Drug Self-Administration

The gold-standard in preclinical abuse liability testing: It's all relative

From benzodiazepine prescription to dependence: Learning processes involved