Depressive-Like Effects of the κ-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats
Abstract
Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of kappa-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective kappa-opioid agonist, would produce depressive-like effects in the forced swim test (FST) and intracranial self-stimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressive-like effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain kappa-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.
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Kappa receptor agonists induce anxiogenic and dysphoric effects in humans and depressive-like behavior in animals.
“Kappa receptor agonists induce anxiogenic and dysphoric effects in humans (141-143) and depressive-like behavior in animals (i.e., increased immobility in the forced swim test) (144, 145).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [144]
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- Authors
- Carlezon, W. A., Béguin, C., DiNieri, J. A., Baumann, M. H., Richards, M. R., Todtenkopf, M. S., Rothman, R. B., Ma, Z., Lee, D. Y.-W., & Cohen, B. M.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 316
- Issue
- 1
- Pages
- 440-447
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2004109806
- Cited by
- 390
- References
- 40
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 11 · 2021: 21 · 2020: 15 · 2019: 20 · 2018: 16 · 2017: 15 · 2016: 26 · 2015: 18 · 2014: 24 · 2013: 28 · 2012: 26
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1c06rr011213-01, 5r01mh063266-25)
- National Institute of Mental Health (MH63266)
- National Center for Research Resources (RR11213)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- salvinorin A, kappa opioid receptor, depression, depression-like behavior, forced swim test, intracranial self-stimulation, nucleus accumbens, dopamine, serotonin, dynorphin, Salvia divinorum, locomotor activity, reward systems
- MeSH terms
- Animals, Behavior, Animal, Brain Chemistry, Depression, Chemical, Diterpenes, Dopamine, Extracellular Space, Male, Motor Activity, Psychotropic Drugs, Serotonin, Swimming, Rats, Sprague-Dawley, Receptors, Opioid, kappa, Microdialysis, Diterpenes, Clerodane, Rats
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