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Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.
J Pharmacol Exp Ther. 2003 Apr; 305(1):323-30.JP

Abstract

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 kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-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 kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-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 kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-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 kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.

Authors+Show Affiliations

Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12649385

Citation

Mague, Stephen D., et al. "Antidepressant-like Effects of Kappa-opioid Receptor Antagonists in the Forced Swim Test in Rats." The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 1, 2003, pp. 323-30.
Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J Pharmacol Exp Ther. 2003;305(1):323-30.
Mague, S. D., Pliakas, A. M., Todtenkopf, M. S., Tomasiewicz, H. C., Zhang, Y., Stevens, W. C., Jones, R. M., Portoghese, P. S., & Carlezon, W. A. (2003). Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. The Journal of Pharmacology and Experimental Therapeutics, 305(1), 323-30.
Mague SD, et al. Antidepressant-like Effects of Kappa-opioid Receptor Antagonists in the Forced Swim Test in Rats. J Pharmacol Exp Ther. 2003;305(1):323-30. PubMed PMID: 12649385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. AU - Mague,Stephen D, AU - Pliakas,Andrea M, AU - Todtenkopf,Mark S, AU - Tomasiewicz,Hilarie C, AU - Zhang,Yan, AU - Stevens,William C,Jr AU - Jones,Robert M, AU - Portoghese,Philip S, AU - Carlezon,William A,Jr PY - 2003/3/22/pubmed PY - 2003/4/23/medline PY - 2003/3/22/entrez SP - 323 EP - 30 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 305 IS - 1 N2 - 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 kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-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 kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-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 kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-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 kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12649385/Antidepressant_like_effects_of_kappa_opioid_receptor_antagonists_in_the_forced_swim_test_in_rats_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12649385 DB - PRIME DP - Unbound Medicine ER -