Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats
Open accessAbstract
Background Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance.Methods We examined the effects of two drugs that cause disruptions in perception and cognition in humans-the kappa-opioid receptor (KOR) agonist salvinorin A (salvA; 0.125-4.0 mg/kg) and the non-competitive NMDA receptor antagonist ketamine (0.63-20 mg/kg)-on behavior in rats using the 5-choice serial reaction time task (5CSRTT), a food-motivated test that quantifies attention. We also compared the binding profiles of salvA and ketamine at KORs and NMDA receptors.Results SalvA and ketamine produced the same pattern of disruptive effects in the 5CSRTT, characterized by increases in signs often associated with reduced motivation (omission errors) and deficits in processing (elevated latencies to respond correctly). Sessions in which rats were fed before testing suggest that reduced motivation produces a subtly different pattern of behavior. Pretreatment with the KOR antagonist JDTic (10 mg/kg) blocked all salvA effects and some ketamine effects. Binding and function studies revealed that ketamine is a full agonist at KORs, although not as potent or selective as salvA.Conclusions SalvA and ketamine have previously under-appreciated similarities in their behavioral effects and pharmacological profiles. By implication, KORs might be involved in some of the cognitive abnormalities observed in psychiatric disorders such as schizophrenia.
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The Joseph et al. conclusions depend on computational predictions, and their reported affinities and G protein recruitment values conflict with earlier work.
“However, this study’s main findings rely on computational analysis and the predicted affinity and G protein recruitment values it reports are not consistent with several prior publications (Bonaventura et al., 2021; Hirota et al., 1999; Nemeth et al., 2010).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Nemeth et al., 2010
The Methods and Results sections (“In vitro binding studies”; page unavailable) report measured KOR binding affinity and G-protein activity for ketamine and salvinorin A, so Nemeth et al. provides earlier experimental findings relevant to the comparison. This paper does not address Joseph et al.’s computational analysis or report its predicted values, so our copy cannot establish the claimed inconsistency. (LLM, conf=0.82)
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References 57 · Cited by 104
- Authors
- Nemeth, C. L., Paine, T. A., Rittiner, J. E., Béguin, C., Carroll, F. I., Roth, B. L., Cohen, B. M., & Carlezon, W. A.
- Affiliations
- Harvard University (US)
- University of North Carolina at Chapel Hill (US)
- RTI International (US)
- Corresponding author
- Carlezon, William A.
- ORCID
- Venue
- Psychopharmacology
- Published
- 2010-04-01
- Volume
- 210
- Issue
- 2
- Pages
- 263-274
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC2869248
- OpenAlex
- W2025333158
- Cited by
- 104
- References
- 57
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 13 · 2019: 7 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 9 · 2012: 5
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01mh063266-25)
- National Institute of Mental Health (MH063266, R01-MH063266)
- National Institute on Drug Abuse (R01DA009045, R01DA017204)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- kappa opioid receptor, salvinorin A, ketamine, attention, 5-choice serial reaction time task, NMDA receptor antagonism, JDTic, motivation, visual perception, schizophrenia, receptor agonism
- MeSH terms
- Animals, Attention, Dose-Response Relationship, Drug, Ketamine, Male, Reaction Time, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, Opioid, kappa, Diterpenes, Clerodane, Rats
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