Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats

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 κ-opioid receptors) in NAc neurons, these findings raised the possibility that κ-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the κ-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at κ-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar κ-antagonists: 5′-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5′-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the κ-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the κ-agonist [5α,7α,8β]-N-methyl-N-[7-[1-pyrrolidinyl] -1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the κ-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective κ-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 κ-antagonists may have efficacy as antidepressants, but lack stimulant or rewardrelated effects.