The search for a more thorough understanding of the basic commnon processes underlying drug dependence has been thwarted by the lack of a conceptual map of the terrain. Investigators have been in the position of the crew in Lewis Carroll’s The Hunting of the Snark. The Bellman brought a map purporting to show the elusive Snark’s location: once the voyage was underway, however, the crew discovered the map was completely blank. All too often those of us in the field of drug dependence find ourselves floating on an uncharted conceptual sea, zigging and zagging in search of a common causal process.
It would be as naive to suppose that all forms of heart disease have a common cause. Instead, it is more reasonable to suppose that, Just as there are similarities in the symptoms in various forms of heart disease, there are also similarities in the symptoms in various forms of drug dependence. However, in both cases one cannot expect the normal controlling mechanisms to have gone awry in precisely the same ways. It must be assumed that a relatively limited number of variables, whose weightings differ among forms of substance abuse, interact to produce the various states of dependence (see Levison’s discussion, this volume).
A second problem facing the field has been the absence of a unit of analysis and a metric for assessing the control drugs exercise over the behavior of the user. It wasn’t until the mid 1960’s that control over Objectively measurable behavior was suggested as a criterion for assessing dependence-producing properties of drugs. Finally, we have struggled to develop more Objective ways of assessing behavioral consequences of the drugs which are self-administered, and to provide a consistent framework within which to interpret those effects.
Thus, like Janus’s two faces, two oppositefacing problems of drug dependence have oriented investigators in opposite directions. Behavioral pharmacologists have treated drug self-administration and the study of other behavioral effects of drugs as only nominally related. People in the drug treatment community have focused primarily on the adverse conseouences of drug dependence, with little interest in drug self-administration, per se. Now the two have finally come face to face (see chapters by Brady and Lasagna). 1.
Drug dependence involves a cluster of processes in which a state is produced by repeated self-administration of the drug, such that the drug user will engage in substantial amounts of behavior leading specifically to further administration of the drug, whicn will continue even when this requires the sacrifice of other important reinforcers and sources of satisfaction (Kalant et al. 1978). An understanding of drug dependence requires knowledge of the factors responsible for development, maintenance, and elimination of drug self-administration, and of the effects of the self-administered drug on other ongoing biobehavioral processes.
We are interested, therefore, not only in how a drug comes to serve as a potent reward exercising extensive behavioral control, but how the drug influences the subject’s ability to meet environmental demands. The aspects of an animal’s or person’s behavioral functioning which are altered by a drug are the drug’s locus of action. The processes which account for the drug’s behavioral effects are the mechanisms of action. BEHAVIORAL MECHANISMS OF DRUG ACTION In the natural sciences, there is broad agreement concerning what the term “mechanism” means.
For example, the mechanism by which oxygen is transferred from the atmosphere into the blood stream involves the differing gradients of partial pressure of oxygen and carbon dioxide in the alveoli of the lungs and in the bloodstream. The degree to which oxygen and carbon dioxide are exchanged has to do with differential pressure gradients. Therefore, in this case we refer to a general principle of gradients of partial pressure of gases across a membrance in specifying the mechanism. In pharmacology, the concept of mechanism of action is intertwined with that of locus of action.
Claude Bernard (1856) conducted several experiments elucidating these two concepts. In one study, he examined the site of the paralytic action of curare. Using a nerve-muscle preparation, Bernard showed that if a muscle was stimulated directly, the muscle would contract. However, if the nerve itself was stimulated, even though the nerve continued to conduct along its axons, the muscle would not contract. Therefore, Bernard concluded that the site of action of curare must be at the myoneural junction. In a related experiment, Bernard studied the mechanism by which carbon monoxide causes asphyxiation.
He knew it was necessary for oxygen to be carried to the tissues by the bloodstream. Moreover, he knew that when an animal was placed under a bell jar filled with carbon monoxide, the animal was asphyxiated. In a series of elegant experiments, he demonstrated carbon monoxide has a differential and selective affinity for hemoglobin, the active element responsible for distribution of oxygen to the tissues. Bernard’s experiment was critically important for the development of the concept of mechanism of action, because he demonstrated that carbon monoxide altered a normal function of hemoglobin which was responsible for oxygenation of tissues.
Thus, the term “mechanism” in pharmacology. as in other areas of natural sciences. refers to a description-of a phenomenon in terms of a more general set of scientific principles. 2 In pharmacology, most of the mechanisms to which we have customarily referred have been reductionistic. To a degree, this has been a fortuitous historical development which has become entangled with unwarranted tenacity in our theoretical fabric.
In attempting to specify the mechanism responsible for the effects of mescaline on the behavior of certain native Indian tribes who use the drug as part of religious rites, it is not especially helpful to specify the receptor sites in the central nervous system activated by the drug. The mechanisms which account for the drug’s effect have to do with psychological, social, and cultural factors rather than specific neurochemical factors. It becomes evident that the choice of level of analysis is dictated by the system under study and by the degree to which the mechanisms proposed fit into an established set of lawful relationships.
The existence of a substantial knowledge base with a rich network of lawful relationships makes it profitable to explore behavioral mechanisms of drug action. By behavioral mechanism of drug action, we refer to a description of a drug’s effect on a given behavioral system (1ocus) expressed in terms of some more general set of environmental principles regulating behavior. Specifying the behavioral mechanism(s) responsible for an observed effect involves: a) identifying the environmental variables which typically regulate the behavior in question, and b) characterizing the manner in which the influence of those variables iS altered by the drug.
In some Instances, the drug assumes the status of a behavioral variable, per se, rather than modulating an existing environmental variable. The search for environmental controlling variables which can be modulated by drugs is aided by a systematic exploration of antecedent factors, current environmental variables, and response consequence factors which are known to regulate behavior. Thus, the three terms in the statement of a behavioral mechanism are: 1) the drug; 2) the behavioral phenomenon; and 3) a qualitative statement of the relation between the two.
The papers in the present volume are, therefore, organized around these three classes of mechanisms. ANTECEDENT VARIABLES Behavioral mechanisms of drug dependence can involve three classes of antecedent variables regulating behavior. The Subject’s history provides the first class of variables.
Environmental history can modulate the behavioral locus of a drug’s action: for example, whether punished responding is increased or decreased by amphetamine, or whether response rates increase under fixed interval schedules following amphetamine administration. Figure 1 illustrates such a reinforcement history effect (see chapter by Weiner).
Environmental history as well as genetic factors can control the reinforcing efficacy of drugs. Pharmacological history can determine the magnitude of a drug’s effect (e. g. , tolerance) and the disruptive effect of discontinuing administration of certain drugs (withdrawal) (see chapter by Young et al. ). In humans, the confluence of historical and genetic dispositional variables is usually 3.