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Compulsive Drug Use and Brain Reward Systems

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Drug Abuse and Addiction in Medical Illness

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Abstract

Compulsive drug intake is a hallmark of addiction, yet the neurobiological mechanisms that contribute to the loss of control over drug consumption remain unclear. A better understanding of the mechanisms that drive compulsive drug taking may reveal targets for the development of novel therapeutics to alleviate this maladaptive behavioral state. Drug use is initiated primarily to obtain the stimulatory effects of addictive drugs on brain reward systems, an action that can be measured as drug-induced lowering of intracranial self-­stimulation (ICSS) thresholds in rats and mice. Paradoxically, excessive drug intake can result in decreased activity of reward systems, reflected in elevated ICSS. Such drug-induced deficits in brain reward function likely reflect the engagement of compensatory mechanisms to counter drug effects. Recent evidence suggests that compulsive drug intake may develop in response to such adaptive decreases in brain reward systems. Further, environmental stimuli repeated paired with the actions of addictive drugs can attain “hedonic” salience to negatively regulate brain reward systems, and may thereby serve as a novel source of drug craving. The aim of this chapter is to review the impact of excessive drug consumption and drug-paired environmental stimuli on brain reward function, discuss the role for reward pathways in driving compulsive drug taking, and present potential neurobiological mechanisms that may underlie these processes.

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Acknowledgements

J.A.H. was supported by a postdoctoral fellowship from the National Institute on Drug Abuse (NIDA) (DA 024932). P.J.K. was supported by grants from NIDA (DA020686; DA023915; DA025983).

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Authors and Affiliations

  1. Laboratory for Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute—Florida, Jupiter, FL, 33458, USA

    Jonathan A. Hollander & Paul J. Kenny

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  1. Jonathan A. Hollander
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  2. Paul J. Kenny
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Correspondence to Jonathan A. Hollander .

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Editors and Affiliations

  1. Inst. Pharmaceutical Sciences, Department of Psychopharmacology, Utrecht University, Universiteitsweg 99, Utrecht, 3584CG, Netherlands

    Joris C. Verster

  2. Dept. Psychiatry, Medical University of South Carolina, President St. 67, Charleston, 29425, South Carolina, USA

    Kathleen Brady

  3. School of Medicine, Div. Alcoholism & Drug Abuse, New York University, First Ave. 550, New York, 10016, New York, USA

    Marc Galanter

  4. Institute of Psychiatry, King's College London, National Addiction Centre, Windsor Walk 4, London, SE5 8AF, United Kingdom

    Patricia Conrod

Glossary

Reinforcer

Reinforcer is an object or event that is obtained or that occurs in response to a particular behavior, is contiguous with that behavioral response in a temporal and spatial manner, and is associated with an increased probability that the behavior response will occur again. Put simply, a reinforcer is anything that increases the likelihood that a given response will be repeated.

Classical conditioning

Classical conditioning was originally characterized by the Russian physiologist Ivan ­Pavlov, and involves the learning process in which a previously neutral environmental cue (conditioned stimulus; CS) can attain motivational salience and elicit a conditioned response (CR) after being repeatedly associated with an intrinsically salient stimulus (unconditioned stimulus; US) that induces an automatic response (unconditioned response; UR). In our experiments, a CS (previously neutral flashing light and tone) is repeatedly paired with a US, usually a drug of abuse or a receptor antagonist that precipitates withdrawal in drug-dependent animals (see below), during daily conditioning sessions. The CS can eventually elicit responses similar to those induced by the US.

Intracranial self-stimulation (ICSS)

Intracranial self-­stimulation (ICSS) is a behavioral procedure that ­provides a sensitive measure of the effects of addictive drugs on brain reward systems. Rats turn a response wheel to receive electrical pulses directly into their brain via indwelling stimulating electrodes located within components of the brain’s reward system. In our experiments, the stimulating electrode is located within the posterior lateral hypothalamus, targeting the medial forebrain bundle. The intensity of the electrical pulse is varied (according to the method of limits) such that the minimal electrical intensity (termed the “reward threshold”) for which the animal is prepared to respond can be identified for each rat. Acute administration of major drugs of abuse lowers the reward threshold, whereas withdrawal from addictive drugs after chronic administration usually elevates the reward threshold.

Action-outcome (goal-directed) responding

Action-outcome (goal-directed) responding is behavior directed toward achieving a goal, and is under voluntary control (i.e., sensitive to the relative value of the goal). Action-outcome responding is dependent upon the animal learning the causal relationship between its actions and the likelihood of achieving the goal.

Stimulus–response (habit) responding

Stimulus–response (habit) responding usually emerges after goal-directed ­responding has been repeated on many occasions until such responding becomes more habitual and sensitive to goal-associated conditioned stimuli, and less under voluntary control (i.e., insensitive to the relative value of the goal).

Precipitated withdrawal

Precipitated withdrawal is the process by which withdrawal may be transiently “precipitated” in drug-dependent animals (or humans) by ­administration of a compound that antagonizes the actions of that particular drug. For example, withdrawal may be precipitated in opiate dependent rats by administration of the opioid receptor antagonist naloxone.

Escalation of drug intake

Escalation of drug intake in rats is the process by which extended daily access to a drug results in the gradual increase of drug intake over time, a process reminiscent of the loss of control over intake usually observed in human drug addicts.

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Hollander, J.A., Kenny, P.J. (2012). Compulsive Drug Use and Brain Reward Systems. In: Verster, J., Brady, K., Galanter, M., Conrod, P. (eds) Drug Abuse and Addiction in Medical Illness. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3375-0_5

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