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 -opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressivelike behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective -opioid agonist, would produce depressivelike effects in the forced swim test (FST) and intracranial selfstimulation (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 depressivelike 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.Although much research on depression has focused on brain norepinephrine and serotonin (5-HT) systems, there is substantial evidence that other systems have important roles in the neurobiology of mood and affective disorders. For example, the mesolimbic dopamine (DA) systemwhich projects from the ventral tegmental area to the nucleus accumbens (NAc)-contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (see Wise, 1998;Nestler and Carlezon, 2005). It has been proposed that disruption of DA function within the NAc causes anhedonia (reduced ability to experience reward) (Wise, 1982), a hallmark sign of clinical depression. The mesolimbic DA system is modulated by noradrenergic and serotonergic inputs (Pasquier et al., 1977), as well as endogenous opioid peptides (Devine et al., 1993;Shippenberg and Rea, 1997;Svingos et al., 1999). Agents that selectively affect the function of -opioid receptors cause profound alterations in mood in humans (Pfeiffer et al., 1986;Roth et al., 2002) and motivated behaviors in laboratory animals (Shippenberg and Herz, 1987;Todtenkopf et al., 2004), suggesting that manipulations targeting brain -opioid systems might be useful in the study and treatment of depressive disorders.

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

“…Behavioral studies report that Sal A exhibits antinociceptive activity (26), is aversive in rodents (24), dose-dependently increases immobility in the forced swim test (27), is anxiolytic in the elevated plus maze test (28), and can attenuate cocaineinduced drug seeking behavior (29). In this study, we find that Colly, like Sal A, exhibits antinociception and is aversive in mice.…”

Exposure to the Selective κ-Opioid Receptor Agonist Salvinorin A Modulates the Behavioral and Molecular Effects of Cocaine in Rats

“…When considered together with previous work (Thompson et al, 2000;Carlezon et al, 2006), these findings suggest that KORs in the dorsal striatum and NAc can mediate both motivational and locomotor-stimulant effects of cocaine, respectivelyFperhaps through similar mechanisms. The aversive effects of KOR agonistsFincluding dysphoria and anhedoniaFare thought to be mediated by the NAc and typically occur within the first hour after drug administration (Shippenberg and Herz, 1988 (c) Quantification of the density of c-Fospositive nuclei in the dorsal striatum, NAc shell, and Nac core in response to a saline or cocaine (10 mg/kg, i.p.)…”

“…KOR-specific agonists have depressive-like effects in rodents and humans (Pfeiffer et al, 1986;Todtenkopf et al, 2004;Carlezon et al, 2006), suggesting that aversive states associated with cocaine withdrawal and stress might be due, in part, to activation of KORs. A substantial body of literature demonstrates that acute or repeated treatment of rats with KOR agonists reduces the behavioral effects of psychostimulants (Heidbreder et al, 1995;Gray et al, 1999;Schenk et al, 1999;Mello and Negus, 2000), although the role of endogenous dynorphin is less clear (Negus et al, 1997;Kuzmin et al, 1998).…”

Salvia divinorum Epling & Játiva (Maria Pastora) e Salvinorina A: crescente uso recreacional e potencial de abuso

“…Por outro lado, a ativação de KOP no circuito mesolímbico diminui o estímulo neuronal dopaminérgico e inibe a liberação de dopamina no núcleo accumbens (Doyon et al, 2006). O sistema mesolímbico dopaminérgico contribui de maneira muito importante para o desenvolvimento de necessidade de reforço em relação a alimentos, comportamento sexual e drogas de abuso (Carlezon et al, 2006).…”