Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
William A Carlezon, Cécile Béguin, Jennifer A DiNieri, Michael H Baumann, Michele R Richards, Mark S Todtenkopf, Richard B Rothman, Zhongze Ma, David Y-W Lee, Bruce M Cohen
Journal of Pharmacology and Experimental Therapeutics January 2006 DOI: 10.1124/jpet.105.092304 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical behavioral and neurochemical study in rats Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Salvinorin A |
| Dose | 0.125-2.0 mg/kg |
| Measures | Forced swim test (FST), intracranial self-stimulation (ICSS) test, open field locomotor activity, extracellular dopamine and serotonin concentrations in the nucleus accumbens |
| Topics | Salvia divinorum |
| Key points | Salvinorin A dose-dependently increased immobility in the forced swim test and elevated intracranial self-stimulation thresholds in rats, effects the authors describe as depressive-like and opposite to those of standard antidepressants, without altering locomotor activity. At an effective dose it decreased extracellular dopamine in the nucleus accumbens but not serotonin. The authors argue these data support the hypothesis that kappa-opioid receptor stimulation produces depressive-like signs, possibly via reduced accumbens dopamine. |
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.
Comparable studies
Other preclinical and animal studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Mice | 2005 | Experimental study | |
| Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents Male Sprague-Dawley rats and male Albino Swiss mice | 2009 | Experimental study | |
| Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Wistar rats | 2008 | Experimental study | |
| Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Rats | 2010 | Experimental study | |
| The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Rhesus monkeys | 2004 | Experimental study | n = 3 |
Citations in the library
Cited by 76
- Opioid receptors and legal highs:Salvia divinorumand Kratom Clinical Toxicology 2008
- Clinical applications of hallucinogens: A review. Experimental and Clinical Psychopharmacology August 1, 2016
- Models of psychedelic drug action: modulation of cortical-subcortical circuits Brain October 22, 2021
- Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents British Journal of Pharmacology May 5, 2009
- Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology March 1, 2013
and 71 more in the library
Cites 7
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Journal of Pharmacology and Experimental Therapeutics March 1, 2004
- Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Psychopharmacology May 1, 2005
- Use of nonprohibited hallucinogenic plants: increasing relevance for public health? A case report and literature review on the consumption of Salvia divinorum (Diviner's Sage). Pharmacopsychiatry 2005
- New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors. Bioorganic & Medicinal Chemistry October 1, 2005
and 2 more in the library