Stress as a Risk Factor for Substance Use Disorders: A Mini-Review of Molecular Mediators
Open accessAbstract
the mesolimbic pathway remain elusive. In this mini-review article, we highlight three mechanisms by which glucocorticoids (GCs) and the dopaminergic system interact. First, GCs upregulate tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine (DA) synthesis. Second, GCs downregulate monoamine-oxidase (MAO), an enzyme responsible for DA removal. Lastly, GCs are hypothesized to decrease DA reuptake, subsequently increasing synaptic DA. Based on these interactions, we review preclinical literature highlighting how stress modulates the mesolimbic pathway, including the ventral tegmental area (VTA) and nucleus accumbens (NAcs), to alter cocaine abuse-related effects. Taken together, stress enhances cocaine's abuse-related effects at multiple points along the VTA mesolimbic projection, and uniquely in the NAcs through a positive feedback type mechanism. Furthermore, we highlight future directions to elucidate the interaction between the prefrontal cortex (PFC) and key intermediaries including ΔFosB, cAMP response element binding protein (CREB) and cyclin-dependent kinase 5 (CDK5) to highlight possible mechanisms that underlie stress-induced acceleration of the progression to a cocaine use disorder diagnosis.
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GCs upregulate tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis.
“A recent review of preclinical data suggests three mechanisms by which DA and GCs interact: (1) GCs upregulate tyrosine hydroxylase (rate-limiting enzyme in DA synthesis) (2) GCs down-regulate monoamine oxidase (enzyme responsible for DA removal) and (3) GCs are hypothesized to decrease DA uptake subsequently increasing synaptic DA [189].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [189]
GCs are hypothesized to decrease DA uptake subsequently increasing synaptic DA.
“A recent review of preclinical data suggests three mechanisms by which DA and GCs interact: (1) GCs upregulate tyrosine hydroxylase (rate-limiting enzyme in DA synthesis) (2) GCs down-regulate monoamine oxidase (enzyme responsible for DA removal) and (3) GCs are hypothesized to decrease DA uptake subsequently increasing synaptic DA [189].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [189]
GCs down-regulate monoamine oxidase, the enzyme responsible for DA removal.
“A recent review of preclinical data suggests three mechanisms by which DA and GCs interact: (1) GCs upregulate tyrosine hydroxylase (rate-limiting enzyme in DA synthesis) (2) GCs down-regulate monoamine oxidase (enzyme responsible for DA removal) and (3) GCs are hypothesized to decrease DA uptake subsequently increasing synaptic DA [189].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [189]
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Self-citationLu, Q., Mouri, A., Yang, Y., Kunisawa, K., Teshigawara, T., Hirakawa, M., Mori, Y., Yamamoto, Y., Libo, Z., Nabeshima, T., et al. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112053 · Cited by 94 · see citing works
Wiss, D. A., Avena, N., & Gold, M. (2020) · Nutrients · doi:10.3390/nu12113521 · Cited by 66 · see citing works
Depression and substance use disorders: Clinical comorbidity and shared neurobiology
Calarco, C. A., & Lobo, M. K. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.09.004 · Cited by 69 · see citing works
Hyer, M. M., Shaw, G. A., Goswamee, P., Dyer, S. K., Burns, C. M., Soriano, E., Sanchez, C. S., Rowson, S. A., McQuiston, A. R., & Neigh, G. N. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100303 · Cited by 51 · see citing works
Self-citationHylander, B. L., Repasky, E. A., & Sexton, S. (2022) · Animals · doi:10.3390/ani12030371 · Cited by 28 · see citing works
Stadtler, H., Shaw, G. A., & Neigh, G. N. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135698 · Cited by 24 · see citing works
Self-citationGawliński, D., Gawlińska, K., Frankowska, M., & Filip, M. (2020) · Nutrients · doi:10.3390/nu12051462 · Cited by 20 · see citing works
Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine
Wydra, K., Gawliński, D., Gawlińska, K., Frankowska, M., Borroto‐Escuela, D. O., Fuxé, K., & Filip, M. (2020) · Cells · doi:10.3390/cells9061372 · Cited by 20 · see citing works
Convergent actions of stress and stimulants via epigenetic regulation of neural circuitry
Murphy, M. D., & Heller, E. A. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.10.001 · Cited by 18 · see citing works
Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation
Mack, S. M., Gomes, I., & Devi, L. A. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00559 · Cited by 18 · see citing works
Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner
Bertagna, N. B., Favoretto, C. A., Rodolpho, B. T., Palombo, P., Yokoyama, T. S., Righi, T., Loss, C. M., Leão, R. M., Miguel, T. T., & Cruz, F. C. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.775404 · Cited by 17 · see citing works
A proposed role for glucocorticoids in mediating dopamine-dependent cue-reward learning
Lopez, S. A., & Flagel, S. B. (2020) · Stress · doi:10.1080/10253890.2020.1768240 · Cited by 14 · see citing works
Curley, D. E., Webb, A. E., Sheffler, D. J., & Haass‐Koffler, C. L. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.786855 · Cited by 13 · see citing works
An Analysis on Youth Drug Abuse: Protective and Risk Factors in High-Risk Area
Shafie, A. A. H., Othman, K. B., Baharudin, D. F., Yasin, N. M., Amat, S., Jaladin, R. A. M., Rahimi, M. K. A., Mokhtar, A. N., Wahab, S. B., & Anuwar, N. H. K. (2023) · Pertanika journal of social science & humanities · doi:10.47836/pjssh.31.2.07 · Cited by 8 · see citing works
Neurobiological intersections of stress and substance use disorders
Juliano, V. A. L., Albernaz-Mariano, K. A., Covre, L. H. H., Jucá, P. M., Pereira, R. M., Shigeo-de-Almeida, A., Sampaio, L. L., Duque, É. D. A., & Munhoz, C. D. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1548372 · Cited by 7 · see citing works
Exposure to state violence and substance use
Blackman, A. D., Kammourh, S., & Nugent, E. R. (2022) · Research & Politics · doi:10.1177/20531680221136088 · Cited by 3 · see citing works
Kanhere, H. S., Kokare, D. M., Jogdand, Y. R., Dudhabhate, B. B., & Subhedar, N. K. (2026) · Neurochemical Research · doi:10.1007/s11064-025-04655-w · Cited by 2 · see citing works
López, S., & Luís, J. (2019) · Cited by 1 · see citing works
Causes of Stress and Substance Use Among Adolescents in South Korea a Cross-Sectional StudyPreprint
Nerobkova, N., Jung, Y. H., Park, E., & Jang, S. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4045926 · Cited by 1 · see citing works
Olsavsky, A. K., Chirico, I. S., Ali, D. A., Christensen, H., Boggs, B., Svete, L. J., Ketcham, K., Hutchison, K. E., Zeanah, C. H., Tottenham, N., et al. (2023) · Substance Abuse Research and Treatment · doi:10.1177/11782218231186371 · Cited by 1 · see citing works
Solano, J. L., Novoa, C., Lamprea, M. R., & Ortega, L. A. (2023) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2023.107831
Yeh, Y., Zheng, M. H., Tegge, A. N., Athamneh, L. N., Lemos, R. F., Dwyer, C. L., & Bickel, W. K. (2024) · Quality of Life Research · doi:10.1007/s11136-024-03625-z
Rodolpho, B. T., Bertagna, N. B., Favoretto, C. A., Moretti, N. S., & Cruz, F. C. (2024) · Physiology & Behavior · doi:10.1016/j.physbeh.2024.114786
Stress factors in psycho-neurological disorders’ pathogenesis in HIV-infection
Улюкин, И. М., Рассохин, В. В., Orlova, E. S., & Сечин, А. А. (2023) · Marine Medicine · doi:10.22328/2413-5747-2023-9-2-32-48
- Authors
- Mukhara, D., Banks, M. L., & Neigh, G. N.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Neigh, Gretchen N.
- Venue
- Frontiers in Behavioral Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2018-12-21
- Volume
- 12
- Pages
- 309-309
- ISSN
- 1662-5153 (ISSN-L)
- PMC
- PMC6308626
- OpenAlex
- W2906426747
- Cited by
- 26
- References
- 92
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 3
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute of Nursing Research (NR014886, R01NR014886)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- stress, substance use disorders, cocaine dependence, mesolimbic system, glucocorticoids, dopamine, tyrosine hydroxylase, monoamine oxidase, dopamine reuptake, ventral tegmental area, nucleus accumbens, prefrontal cortex, ΔFosB, CREB, cyclin-dependent kinase 5, positive feedback
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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