Roy A. Wise

A psychomotor stimulant 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 biologists 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

Neuroleptics and operant behavior: The anhedonia hypothesis.

Neuroleptic drugs disrupt the learning and performance of operant habits motivated by a variety of positive reinforcers, including food, water, brain stimulation, intravenous opiates, stimulants, and barbiturates. This disruption has been demonstrated in several kinds of experiments with doses that do not significantly limit normal response capacity. With continuous reinforcement neuroleptics gradually cause responding to cease, as in extinction or satiation. This pattern is not due to satiation, however, because it also occurs with nonsatiating reinforcement (such as saccharin or brain stimulation). Repeated tests with neuroleptics result in earlier and earlier response cessation reminiscent of the kind of decreased resistance to extinction caused by repeated tests without the expected reward. Indeed, withholding reward can have the same effect on responding under later neuroleptic treatment as prior experience with neuroleptics themselves; this suggests that there is a transfer of learning (really unlearning) from nonreward to neuroleptic conditions. These tests under continuous reinforcement schedules suggest that neuroleptics blunt the ability of reinforcers to sustain responding at doses which largely spare the ability of the animal to initiate responding. Animals trained under partial reinforcement, however, do not respond as well during neuroleptic testing as animals trained under continuous reinforcement. Thus, neuroleptics can also impair responding (though not response capacity) that is normally sustained by environmental stimuli (and associated expectancies) in the absence of the primary reinforcer. Neuroleptics also blunt the euphoric impact of amphetamine in humans. These data suggest that the most subtle and interesting effect of neuroleptics is a selective attenuation of motivational arousal which is (a) critical for goal-directed behavior, (b) normally induced by reinforcers and associated environmental stimuli, and (c) normally accompanied by the subjective experience of pleasure. Because these drugs are used to treat schizophrenia and because they cause parkinsonian-like side effects, this action has implications for a better understanding of human pathology as well as normal motivational processes.

How can drug addiction help us understand obesity

To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry.

Brain reward circuitry: insights from unsensed incentives.

The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.

Neuroadaptation: Incubation of cocaine craving after withdrawal

Relapse to cocaine addiction is frequently associated with subjective reports of craving, a poorly understood state that precedes and accompanies cocaine-seeking behaviours. It has been suggested that over the first few weeks of withdrawal from cocaine, human addicts become sensitized to drug-associated environmental cues that act as external stimuli for craving, although the evidence for this is inconsistent. Here we provide behavioural evidence from laboratory animals suggesting that the onset of craving is delayed and that craving does not decay, but rather increases progressively, over a two-month withdrawal period.

Drug-activation of brain reward pathways.

A wide variety of biologically important stimuli can serve as rewards and establish adaptive behavior patterns in higher animals. Such stimuli act through brain mechanisms that evolved long before the human invention of the hypodermic syringe, the human harnessing of fire, or the human development of methods for refining and concentrating psychoactive substances that occur in nature. These brain mechanisms utilize endogenous neurotransmitters that are blocked or mimicked by a variety of addictive exogenous substances. The brain mechanisms for feeding, for example, have depended on endogenous opioid peptide neurotransmitters from the earliest stages Ž of our evolutionary history Josefsson and Johansson, . 1979; Kavaliers and Hirst, 1987 . A complete understanding of the brain mechanisms of addiction will require an understanding of the anatomy and normal functions of brain pathways that evolved because they served basic adaptive functions. Our current understanding of the brain circuitry through which various rewards gain control over behavior has developed from studies of brain stimulaŽ . tion reward Olds and Milner, 1954 . Rewarding brain stimulation is useful in anatomical localization of reward-relevant circuit elements because focal electrical stimulation of the brain only activates nerve fibers passing within a fraction of a millimetre of the elecŽ . trode tip Fouriezos and Wise, 1984 . However, while stimulation differentially activates fibers of different sizes, the stimulation is indiscriminate with respect to the neurotransmitter a given set of fibers carry. Thus our knowledge of the neurochemical subtypes of reward-relevant neurons derives primarily from pharmacological studies; the rewarding effects of brain stimulation can be attenuated or augmented by drugs that are selective for various neurotransmitter sysŽ . tems Wise and Rompre, 1989 , and neurochemically selective drugs can be rewarding in their own right Ž . Wise, 1978 . Moreover, laboratory animals can be trained to self-administer drugs injected directly into Ž . the brain Bozarth and Wise, 1981 ; such injections are, to a significant degree, both anatomically and neurochemically selective.

Intracranial self-administration of morphine into the ventral tegmental area in rats

Abstract The rewarding properties of morphine injected directly into the ventral tegmental area were investigated using a self-administration procedure. Experimentally naive rats demonstrated rapid acquisition of a lever-pressing response which produced a 100 ng infusion of morphine sulfate solution. Response rates were relatively stable and markedly exceeded lever-press rates of rats passively receiving the same pattern of infusions (i.e., yoked control procedure). Intracranial self-administration was effectively blocked by naloxone suggesting that this behavior is mediated through opiate receptors and is not the consequence of mechanical trauma, or changes in osmolarity or pH.

Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats

Norepinephrine (NE) and dopamine (DA) receptor blockade differentially affected amphetamine self-administration. DA blockade (pimozide, 0.0625 to 0.5 mg/kg, or (+)-butaclamol, 0.0125 to 0.1 mg/kg) caused periods of increased rate of responding for amphetamine which were followed, in the case of higher doses, by response cessation. The response cessation produced by 0.5 mg/kg pimozide was not reversed by non-contingent amphetamine injections until well after the peak effect of the pimozide was over. When access to amphetamine injections was delayed until 4 h after animals received 0.5 mg/kg pimozide, rate of responding was elevated. Thus DA seems to be critically involved in mediation of the reinforcing effects of amphetamine. Alpha-NE blockade with phentolamine (2.5–10 mg/kg) produced dose-related decreases in responding; blockade with phenoxybenzamine (1.25–10 mg/kg) had no effect. Beta-NE blockade with l-propranolol (2.5–10 mg/kg) decreased responding, although probably not through a beta-blocking action. The effects of phentolamine and propranolol do not appear to result from attenuation of the reinforcing effects of amphetamine.

Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats.

Fluctuations in extracellular dopamine and DOPAC levels in nucleus accumbens septi (NAS) were monitored in 1-min microdialysis samples taken from rats engaged in intravenous cocaine self-administration. For four rats the dose per injection was fixed at 2.0 mg/kg; for four others the dose per injection was varied irregularly, from one response to the next, between three levels (0.5, 1.0 and 2.0 mg/kg). Regardless of the dosing regimen, extracellular dopamine levels were tonically elevated by 200–800% within the cocaine self-administration periods, fluctuating phasically within this range between responses. In the fixed dose condition, the phasic increases following each injection (and the phasic decreases preceding them) averaged approximately 50% of the mean tonic elevation. Phasic fluctuations in dopamine levels remained time-locked to lever-presses even when response rate was irregular, because of the variable dose condition. In the variable dose condition greater increases in dopamine and longer inter-response times followed injections of the higher doses; dopamine fluctuations were consistent with the multiple-infusion pharmacokinetics of cocaine. DOPAC levels showed a slow tonic depression during cocaine self-administration, but individual injections were not associated with discernible phasic fluctuations of DOPAC. These data are consistent with the hypothesis that falling dopamine levels trigger successive responses in the intravenous cocaine self-administration paradigm, but inconsistent with the notion that extracellular dopamine levels are depleted at the times within sessions when the animal initiates drug-seeking responses.

Dopamine and reward: The anhedonia hypothesis 30 years on

The anhedonia hypothesis — that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards — was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.