We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at -opioid receptors) in NAc neurons, these findings raised the possibility that -receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the -antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at -receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar -antagonists: 5Ј-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5Ј-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the -antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the -agonist) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the -ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective -antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that -antagonists may have efficacy as antidepressants, but lack stimulant or rewardrelated effects.The neurobiology of depression is not understood. Because most antidepressants with clinical efficacy act upon monoamines [primarily norepinephrine (NE) and serotonin (5HT)], much research on depression has focused upon interactions between these neurotransmitters and their reuptake transporters and receptor proteins. However, recent research has become progressively focused upon the intracellular mechanisms of depression and antidepressant treatments (Manji et al., 2001;Duman, 2002;Nestler et al., 2002), with the goal of developing novel therapeutics that act faster, are more efficacious, and have fewer side effects. This approach has led to the study of brain circuits typically associated with reward-related processes, including the mesolimbic dopamine (DA) system Newton et al., 2002).The mesolimbic DA system projects from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc) of the basal forebrain, and is modulated directly and indirectly by noradrenergic and serotonergic inputs (Pasquier et al., 1977). This circuitry contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (Carlezon and Wise, 1996b;Kreek and Koob, 1998;Wise, 1998...

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.

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These data provide further evidence that stimulation of brain kappa-receptors may trigger certain depressive-like signs, and that kappa antagonists may have efficacy as antidepressants without having reward-related actions of their own.