Compulsive Drug‐Seeking Behavior and Relapse: Neuroadaptation, Stress, and Conditioning Factors
Abstract
The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5-HT transmission in the nucleus accumbens--neurochemical systems that are activated by cocaine and ethanol self-administration and deficient during withdrawal--as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli. The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug-related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior. Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.
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Precipitated opioid withdrawal increases the release of CRF in the CeA.
“Precipitated opioid withdrawal increases the release of CRF in the CeA (Weiss et al., 2001).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Weiss et al., 2001
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- Authors
- WEISS, F., CICCOCIOPPO, R., PARSONS, L. H., KATNER, S., LIU, X., ZORRILLA, E. P., VALDEZ, G. R., BEN‐SHAHAR, O., ANGELETTI, S., & RICHTER, R. R.
- Affiliations
- Scripps Research Institute (US)
- Università di Camerino (IT)
- University of California, Santa Barbara (US)
- Corresponding author
- WEISS, FRIEDBERT
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2001-06
- Volume
- 937
- Issue
- 1
- Pages
- 1-26
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W2167219760
- Cited by
- 430
- References
- 8
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 10 · 2023: 19 · 2022: 9 · 2021: 6 · 2020: 14 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 16 · 2015: 21 · 2014: 17 · 2013: 27 · 2012: 20
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- relapse, drug-seeking behavior, drug addiction, withdrawal, cocaine, ethanol, nucleus accumbens, dopamine, serotonin, central amygdala, corticotropin-releasing factor, cocaine craving, opioid receptors, medial prefrontal cortex, basolateral amygdala, stress, anxiogenic effects
- MeSH terms
- Adaptation, Physiological, Affect, Ethanol, Animals, Central Nervous System Depressants, Cocaine, Conditioning, Psychological, Disease Models, Animal, Humans, Nucleus Accumbens, Receptors, Dopamine, Receptors, Serotonin, Recurrence, Reinforcement, Psychology, Stress, Psychological, Substance Withdrawal Syndrome, Dopamine Uptake Inhibitors, Substance-Related Disorders, Cocaine-Related Disorders
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