Drug Reinforcement in Animals

Introduction

Early demonstrations that drugs could serve as reinforcers, maintaining operant behavior in laboratory animals, led to the development of a model of human substance use disorder ( Box 6.1 ). The traditional self-administration model was developed within a behavioral analysis conceptual framework that views drugs as reinforcers similar to other “natural” reinforcers such as food. The fundamental principle underlying behavioral analysis is that certain aspects of behavior are controlled by their consequences. A drug is said to be functioning as a reinforcer if responding for it is maintained above responding for saline or other control conditions. The traditional model entails training an animal to self-administer a drug during a short daily session, typically 1–2 h. A low ratio requirement is typically used, such as a fixed ratio 1, where each response produces a drug delivery. Intake is stable under these conditions, which allows for the determination of the effects of pharmacological and environmental manipulations on a stable baseline.

Although the rat is most often used in these studies, this model has been implemented with a variety of species including nonhuman primates, mice, dogs, cats, and baboons. A variety of operant responses have also been used, and typically they depend on the species being studied. For example, a lever press or a nose poke response is typically used for rats and mice, whereas a panel press response is typically used for nonhuman primates. The most common routes of administration are intravenous and oral, but intracerebroventricular, intracranial, inhalation, intragastric, and intramuscular routes have also been used. Generally, these studies use the route of administration that is most similar to the route used in humans for that particular drug. For example, animal studies with alcohol typically use an oral route of administration, whereas an intravenous route is typically used for drugs that have a rapid onset in humans, such as cocaine, methamphetamine, heroin, and nicotine. There is also growing interest in the development and use of inhalation self-administration procedures for the latter type of drugs, since, unlike the intravenous route, this route would not require the use of an indwelling catheter. Such approaches have been used successfully in nonhuman primates, with more recent work demonstrating its feasibility in rats and mice.

Historically, male animals have typically been used in drug self-administration studies. This focus was initially justified by higher rates of drug use and substance use disorder in men versus women. However, gender differences have narrowed over time, and among current adolescent populations, rates of drug use and substance use disorder are often similar between males and females. There are also important differences between men and women with respect to many aspects of substance use disorder, including initiation of use, the development of substance use disorder, and relapse and treatment. In addition, sex differences are observed in animal models of substance use disorder, indicating a biological basis for the gender differences observed in humans. Such differences also further support the need to include both sexes in studies on drugs as reinforcers and substance use disorder, a focus now mandated by the National Institutes of Health.

Results from animal drug self-administration studies have revealed good correspondence between humans and animals; drugs abused by humans generally maintain responding in animals, whereas drugs that do not maintain responding in animals are typically not abused by humans, indicating this paradigm’s utility for determining abuse liability. In addition, similar patterns of drug intake have been reported in humans and animals for ethanol, opioids, nicotine, and cocaine self-administration. These parallel results between the human and animal drug literature validate the animal model of drug self-administration and suggest that its use may lead to a better understanding of human drug-taking behavior and substance use disorder.

In addition to screening drugs for abuse liability, the traditional self-administration procedure has been used to study, through biochemical and pharmacological manipulation, the neurobiological processes underlying the drug reinforcement process. For example, by demonstrating that lesions in some areas of the brain decrease or abolish self-administration behavior, we have developed an understanding of the neuroanatomical substrates for drug reinforcement (e.g., Wise and Bozarth ).

Assessing Reinforcing Efficacy

Despite the advances in our understanding of drug reinforcement in animals, reinforcing efficacy, or a drug’s reinforcing strength, has been difficult to measure. The ability of a drug to support self-administration in laboratory animals under different experimental conditions is a measure of the drug’s strength as a reinforcer. Thus, a highly efficacious drug will be self-administered under a variety of experimental conditions such as low-dose conditions, conditions that require a large work effort, or enriched environmental conditions where other reinforcers are available as choices. In contrast, a weakly efficacious drug will be self-administered only under limited conditions such as food-restricted conditions, moderate- to high-dose conditions, conditions that require a low work effort, or impoverished environmental conditions where there are few or no other reinforcers available as choices. Such effects also depend on the route of drug self-administration. For example, under oral self-administration conditions, enriching the environment with toys or social peers can markedly reduce levels of opioid or psychostimulant drug intake, whereas, under intravenous self-administration conditions, such environmental manipulations are much less effective. Although it is generally believed that the reinforcing strength of a drug is related to its abuse liability, actually measuring reinforcing strength is not straightforward because factors other than the drug’s reinforcing effects can, directly and indirectly, influence responding (i.e., satiating effects, direct effects on responding, and aversive effects). The fixed-ratio schedule is typically used in studies investigating drug reinforcement in animals (e.g., 1–2 h sessions), and under these conditions, an inverted U-shaped relationship has been described between drug dose and rate of responding. That is, as dose increases, responding initially increases (ascending limb) and then decreases (descending limb). At low doses, responding decreases and these doses may not maintain responding. However, doses on the descending limb, which would be presumed to be more efficacious than doses on the ascending limb, maintain quantitatively similar levels or even lower levels of responding than those maintained by doses on the ascending limb. This issue is problematic for the interpretation of changes in reinforcing efficacy in that it is difficult to determine the direction of the change. A number of approaches have been taken to address this issue, including the use of rate-independent approaches such as the progressive-ratio schedule, the threshold procedure, second-order schedules, and choice procedures. Reinforcing efficacy is more readily determined using these approaches, and as such, they have been useful for determining changes as a result of pharmacological or environmental manipulation, or changes over time with the development of substance use disorder.

Progressive-Ratio Schedule

The progressive-ratio schedule is commonly used to evaluate the reinforcing strength of self-administered drugs, particularly psychostimulants. With this schedule, the ratio requirement to obtain a delivery progressively increases within a session, and the final ratio completed, or breakpoint, is believed to be a sensitive measure of motivation to obtain the drug (for a review, see Arnold and Roberts ). In contrast to the fixed-ratio schedule, the dose-effect curve under the progressive-ratio schedule is linear, whereby responding is directly related to reinforcer magnitude: an increase in the unit dose of the self-administered drug corresponds to an increase in breakpoint. This linear relationship allows for a more straightforward determination of the direction of change in reinforcing efficacy than is allowed by more traditional self-administration procedures. Other strengths are that responding for a particular dose of drug can be incredibly stable from day to day within subjects and that there are considerable individual differences in levels of responding between subjects. Sensitivity to pharmacological and environmental manipulations and to individual differences are thus strengths of the progressive-ratio schedule. Sex differences and hormonal influences on drug self-administration behavior are good examples of its sensitivity to individual differences in that under simple fixed-ratio schedules, sex differences and hormonal influences are generally not revealed, whereas, under progressive-ratio schedules, these factors robustly influence breakpoints (for a review, see Perry et al. ). Another advantage of this schedule is that it can be used reliably across different pharmacological classes of drugs including psychostimulants, nicotine, opiates, synthetic cathinones or “bath salts,” and alcohol. It has also been used successfully in several different species including rats, mice, and nonhuman primates with parallel effects observed in laboratory studies in humans with substance use disorder. However, as with the more traditional self-administration paradigms, the satiating and behavioral disruptive effects of drugs can also impact responding under a progressive-ratio schedule, particularly during earlier parts of the sessions, with high doses of the drug, and under low or slowly increasing progressive-ratio schedules.