Depressive-like Effects of the {kappa}-Opioid Receptor Agonist
Salvinorin A on Behavior and Neurochemistry in Rats

Carlezon Jr WA, Beguin C, Dinieri JA, Baumann MH, Richards MR,
Todtenkopf MS, Rothman RB, Ma Z, Lee DY, Cohen BM.
Harvard Medical School.
J Pharmacol Exp Ther. 2005 Oct 13


Endogenous opioids appear to play critical a 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 (5HT). 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.
Salvia divinorum
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Kappa upregulation and addiction
kappa-opioid withdrawal in Planaria
Kappa antagonists as future antidepressants?
Nalbuphine and anti-analgesia in men and women
The kappa A agonist salvinorin A induces depression
Indolomorphinan antagonists of the kappa-opioid receptor
The kappa receptor antagonist norbinaltorphimine as an antidepressant
JDTic: an antidepressant, anxiolytic kappa-selective opioid receptor antagonist

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