The neural basis of drug craving: An incentive-sensitization theory of addiction

The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine----each ofwhich also has psychomotor stimulant actions--may activate the docaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration. Attempts at a general theory of addiction are attempts to isr late--from a variety of irrelevant actionsmthose drug actions that are responsible for habitual, compulsive, nonmedical drug self-administration. The common assumption of addiction theorists is that general principles of addiction can be learned from the study of one drug and that these principles will have heuristic value for the study of other drugs. Thus far, attempts at a general theory of addiction have failed to isolate common actions that can account for addiction across the range of major drug classes. A major stumbling block has been the psychomotor stimulants--amph etamine and cocainemwhich do not readily fit models traditionally based on depressant drug classes. The present article offers a new attempt at a general theory of addiction. It differs from earlier theories (e.g., Collier, 1968; Himmelsbach, 1943; Jaffe & Sharpless, 1968; Jellinek, 1960; Kalant, 1977; Lindsmith, 1947; Solomon & Corbit, 1974) in that it is based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on the common denominator of the socalled depressant drugs~opiates, barbiturates, alcohol, and others. We take up two topics before presenting the new theory. First, we briefly discuss the heuristic value of a biological approach and suggest that the biologist's distinction between homology and analogy offers a useful insight. Next we discuss the shortcomings of earlier theories--variants of dependence theory. Then we outline the new theory and review the relevant evidence for its three major assertions: (a) that all addictive drugs have psychomotor stimulant actions, (b) that the stimulant actions of these different drugs have a shared biological mechanism, and (c) that the biological mechanism of these stimulant

A psychomotor stimulant theory of addiction

Drug addiction, dysregulation of reward, and allostasis.

Caffeine is the most widely consumed behaviorally active substance in the world. Almost all caffeine comes from dietary sources (beverages and food), most of it from coffee and tea. Acute and, especially, chronic caffeine intake appear to have only minor negative consequences on health. For this

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

Rhesus monkeys surgically prepared with intravenous catheters were given 23 hr daily access to injection of either cocaine, d-amphetamine, 1-amphetamine, d-methamphetamine or diethylpropion on a fixed ratio 1 schedule of reinforcement for a maximum of 30 days. Responding was maintained by all these drugs but showed both day-to-day and hour-to-hour variability. The two animals self-administering 0.2 mg/kg/infusion cocaine died in less than 5 days. All 6 animals given access to 0.05 mg/kg/infusion d-amphetamine or 0.025 mg/kg/infusion d-methamphetamine also died, but tended to survive more days than animals exposed to cocaine. Three of the 5 animals whose responding was maintained by 0.5 mg/kg/infusion diethylpropion and one of the two animals whose responding was maintained by 0.05 mg/kg/infusion 1-amphetamine survived the entire 30 days despite high rates of intake. Food intake was initially decreased, but often returned to predrug levels and was not related to level of drug intake.

Self-administration of psychomotor stimulant drugs: the effects of unlimited access.

A group of ten normal human volunteers participated in choice experiments comparing d-amphetamine or diazepam with placebo and with each other. Although amphetamine was preferred to placebo by most subjects, 2 mg diazepam and placebo were chosen equally. However, placebo was chosen over higher doses (5 and 10 mg) of diazepam and 5 mg d-amphetamine was preferred to 2 mg diazepam. Subjective effects were assessed using the Profile of Mood States (POMS) before drug was taken and 1, 3, and 6 h later. Compared to placebo, amphetamine produced changes in mood on the POMS including increases in Vigor and Arousal. Doses of 5 and 10 mg diazepam produced decreases in Vigor and Arousal and increases in Fatigue and Confusion. The effects of diazepam were most pronounced 1 h after ingestion and appeared dose-dependent. For one subject who consistently chose diazepam, its subjective effects were similar to placebo and he stated that he could not distinguish them. These results are discussed in terms of the abuse liability of diazepam.

Drug preference and mood in humans: diazepam.

Individual differences in the reinforcing and subjective effects of amphetamine and diazepam

A total of 31 normal human volunteers participated in a nine-session experiment. During the first four sessions, they received alternately 5 mg d-amphetamine or placebo. During the next five sessions, they were given a choice between amphetamine and placebo. Subjective effects were assessed using the Profile of Mood States (POMS) before the drug was taken and 1, 3, and 6 h later. Subjects chose amphetamine a mean of 4.03 times. Compared with placebo, amphetamine produced changes in mood on the POMS including increased Vigor, Elation, Friendliness, Arousal and Positive Mood and decreased Confusion. These differences were greatest 3 h after ingestion. Mood changes produced by d-amphetamine were comparable in all subjects regardless of the actual number of times each chose the drug. These data suggest that that subjective effects do not predict drug choice. The results are discussed in terms of developing methods for predicting the abuse potential of psychotropic drugs.

Drug preference and mood in humans: d-amphetamine.

Long-lasting depletion of dopamine and concomitant loss of dopamine uptake sites follow repeated administration of methylamphetamine to rats We found similar effects after similar treatment with d-amphetamine, but not after treatment with methylphenidate Methylphenidate also failed to produce long-term depletion of regional catecholamine levels in rhesus monkeys These long-lasting alterations of the dopaminergic system suggest that amphetamines or their metabolites have toxic interactions with dopaminergic neurons, which do not occur with methylphenidate

Chris E. Johanson

Papers

Self-administration of psychomotor stimulant drugs: the effects of unlimited access.

Drug preference and mood in humans: diazepam.

Individual differences in the reinforcing and subjective effects of amphetamine and diazepam

Drug preference and mood in humans: d-amphetamine.

Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate.