Repeated exposure to the κ-opioid receptor agonist salvinorin A modulates extracellular signal-regulated kinase and reward sensitivity.
David Potter, Diane Damez-Werno, William A Carlezon, Bruce M Cohen, Elena H Chartoff
Biological Psychiatry October 15, 2011 DOI: 10.1016/j.biopsych.2011.05.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Salvinorin A Cocaine Nor-binaltorphimine |
| Dose | 2 mg/kg salvinorin A, 5.0 mg/kg cocaine, 20 mg/kg nor-binaltorphimine |
| Measures | Intracranial self-stimulation (ICSS), phosphorylated ERK, c-Fos, phosphorylated cAMP response element binding protein |
| Topics | Salvia divinorum |
| Key findings | Salvinorin A produced biphasic effects on intracranial self-stimulation reward, first decreasing and then increasing reward sensitivity, and repeated administration reduced cocaine's reward-potentiating effects. The authors propose that repeated KOR activation may trigger opponent processes in which withdrawal from dysphoria is rewarding and decreases cocaine's net rewarding valence. |
Abstract
Repeated exposure to drugs of abuse and stress increase dynorphin, a κ opioid receptor (KOR) ligand, in the nucleus accumbens (NAc). Acute KOR activation produces dysphoria that might contribute to addictive behavior. How repeated KOR activation modulates reward circuitry is not understood. We used intracranial self-stimulation (ICSS), a method that provides a behavioral index of reward sensitivity, to measure the effects of repeated administration of the KOR agonist salvinorin A (salvA) (2 mg/kg) on the reward-potentiating effects of cocaine (5.0 mg/kg). In separate rats, we measured the effects of salvA on activation of extracellular signal regulated kinase (ERK), cyclic adenosine monophosphate (cAMP) response element binding protein, and c-Fos within the NAc. SalvA had biphasic effects on reward: an immediate effect was to decrease the rewarding impact of ICSS, whereas a delayed effect was to increase the rewarding impact of ICSS. Repeated salvA produced a net decrease in the reward-potentiating effects of cocaine. In the NAc, both acute and repeated salvA administration increased phosphorylated ERK, whereas only acute salvA increased c-Fos and repeated salvA increased phosphorylated cAMP response element binding protein. The KOR antagonist nor-binaltorphimine (20 mg/kg) blocked the immediate and delayed effects of salvA and prolonged the duration of cocaine effects in ICSS. Repeated salvA might trigger opponent processes such that "withdrawal" from the dysphoric effects of KOR activation is rewarding and decreases the net rewarding valence of cocaine. The temporal effects of salvA on ERK signaling suggest KOR-mediated engagement of distinct signaling pathways within the NAc that might contribute to biphasic effects on reward sensitivity.
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 17
- Classic and non‐classic psychedelics for substance use disorder: A review of their historic, past and current research Addiction Neuroscience June 22, 2022
- Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects Pharmaceuticals February 3, 2021
- Effects of the 5-HT2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents. Psychopharmacology June 1, 2022
- Salvia divinorum: from Mazatec medicinal and hallucinogenic plant to emerging recreational drug. Human Psychopharmacology: Clinical and Experimental September 1, 2013
- DARK Classics in Chemical Neuroscience: Salvinorin A. ACS Chemical Neuroscience December 2, 2020
and 12 more in the library
Cites 8
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug and Alcohol Dependence November 8, 2006
- Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Biological Psychiatry February 1, 2008
- Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage July 1, 2008
- Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens. Psychopharmacology April 7, 2010
and 3 more in the library