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BEHAVIORAL PHARMACOLOGY

Depressive-Like Effects of the -Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats

Behavioral Genetics Laboratory (W.A.C., J.A.D., M.S.T.), Molecular Pharmacology Laboratory (C.B., M.R.R., B.M.C.), and Bioorganic and Natural Products Laboratory (Z.M., D.Y.-W.L.), Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; and Clinical Psychopharmacology Section (M.H.B., R.B.R.), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of -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 -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 -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.

Address correspondence to: Dr. Bill Carlezon, Department of Psychiatry, McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA 02478. E-mail: bcarlezon{at}mclean.harvard.edu

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