Tags

Type your tag names separated by a space and hit enter

Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats.
J Pharmacol Exp Ther. 2007 Dec; 323(3):838-45.JP

Abstract

Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (approximately 24 h) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTic [(3R)-7-hydroxy-N-[(1S)-1-[[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide hydrochloride]. Rats received an i.p. injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.

Authors+Show Affiliations

Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17823306

Citation

Knoll, Allison T., et al. "Anxiolytic-like Effects of Kappa-opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats." The Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 3, 2007, pp. 838-45.
Knoll AT, Meloni EG, Thomas JB, et al. Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther. 2007;323(3):838-45.
Knoll, A. T., Meloni, E. G., Thomas, J. B., Carroll, F. I., & Carlezon, W. A. (2007). Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. The Journal of Pharmacology and Experimental Therapeutics, 323(3), 838-45.
Knoll AT, et al. Anxiolytic-like Effects of Kappa-opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats. J Pharmacol Exp Ther. 2007;323(3):838-45. PubMed PMID: 17823306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. AU - Knoll,Allison T, AU - Meloni,Edward G, AU - Thomas,James B, AU - Carroll,F Ivy, AU - Carlezon,William A,Jr Y1 - 2007/09/06/ PY - 2007/9/8/pubmed PY - 2007/12/18/medline PY - 2007/9/8/entrez SP - 838 EP - 45 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 323 IS - 3 N2 - Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (approximately 24 h) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTic [(3R)-7-hydroxy-N-[(1S)-1-[[(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide hydrochloride]. Rats received an i.p. injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/17823306/Anxiolytic_like_effects_of_kappa_opioid_receptor_antagonists_in_models_of_unlearned_and_learned_fear_in_rats_ DB - PRIME DP - Unbound Medicine ER -