Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization
Open accessAbstract
Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM(4)D), we found that activation of hM(4)D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM(4)D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.
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Inhibition of striatal D2R or activation of D1R-expressing striatal neurons enhances sensitivity to the rewarding effects of drugs.
“inhibition of striatal D2R or activation of D1R-expressing striatal neurons (which mediate signalling in the striatal direct pathway) enhance the sensitivity to the rewarding effects of drugs (71–73).”
From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [71]
In the striatum, D2Rs mediate indirect pathway signalling to frontal cortical regions; their down-regulation enhances sensitization to drugs, whereas up-regulation interferes with drug consumption.
“In the striatum, D2Rs mediate signalling in the striatal indirect pathway that modulates frontal cortical regions; and their down-regulation enhances sensitization to the effects of drugs in animal models (68), whereas their up-regulation interferes with drug consumption (69,70).”
From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [68]
Inhibition of striatal D2R or activation of D1 receptor-expressing striatal neurons enhances sensitivity to drug rewards.
“Moreover, inhibition of striatal D2R or activation of D1 receptor-expressing striatal neurons (mediate signaling in the striatal direct pathway) enhances the sensitivity to drug rewards (74).”
From The Addictive Dimensionality of Obesity (2013) · cites this paper as [74]
In striatum, D2 receptors mediate indirect pathway signaling to frontocortical regions; down-regulation enhances drug sensitization, while upregulation interferes with drug consumption.
“In the striatum, D2 receptors mediate signaling through the indirect pathway that modulates frontocortical regions, and its down-regulation enhances drug sensitization in animal models (74), whereas its upregulation interferes with drug consumption (75).”
From The Addictive Dimensionality of Obesity (2013) · cites this paper as [74]
In the striatum, D2Rs mediate signaling from the striatal indirect pathway that modulates prefrontal regions, and downregulation of D2Rs in animal models has been shown to enhance sensitization to the effects of drugs.
“In the striatum D2Rs mediate signaling from the striatal indirect pathway that modulates prefrontal regions, and its downregulation in animal models has been shown to enhance sensitization to the effects of drugs (Ferguson et al 2011).”
From Food and Drug Reward: Overlapping Circuits in Human Obesity and Addiction (2011) · cites this paper as Ferguson et al 2011
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- Authors
- Ferguson, S. M., Eskenazi, D., Ishikawa, M., Wanat, M. J., Phillips, P. E. M., Dong, Y., Roth, B. L., & Neumaier, J. F.
- Affiliations
- University of Washington (US)
- Washington State University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Neumaier, John F
- Venue
- Nature Neuroscience
- Published
- 2010-12-05
- Volume
- 14
- Issue
- 1
- Pages
- 22-24
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3058296
- OpenAlex
- W2020764051
- Cited by
- 418
- References
- 16
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 12 · 2023: 14 · 2022: 16 · 2021: 23 · 2020: 23 · 2019: 38 · 2018: 31 · 2017: 32 · 2016: 42 · 2015: 37 · 2014: 44 · 2013: 43 · 2012: 21
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (5t32gm007108-40, GM07108, U19MH82441, DA023206, T32 GM07108)
- National Institute on Alcohol Abuse and Alcoholism (T32AA009455)
- National Institute of Mental Health (U19MH082441, U19-MH82441, U91MH82441)
- National Institute on Drug Abuse (R01DA023206, R21DA021273, K99DA024762, R21DA021793, R01DA017204, F32DA026273, R37DA023206)
- National Institute of General Medical Sciences (T32GM-007108, T32GM007266, T32GM07266, T-32 GM07108)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- striatopallidal neurons, striatonigral neurons, indirect pathway, direct pathway, behavioral sensitization, dorsal striatum, clozapine-N-oxide, neuronal excitability, drug addiction, behavioral plasticity, repeated drug exposure
- MeSH terms
- Amphetamine, Animals, Cell Line, Transformed, Clozapine, Corpus Striatum, Dopamine, Genetic Vectors, Herpes Simplex, Humans, Male, Membrane Potentials, Motor Activity, Neural Inhibition, Neural Pathways, Reward, Rats, Sprague-Dawley, Ventral Tegmental Area, Receptor, Muscarinic M4, Rats
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