Abstract
Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of κ-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 (∼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.
Footnotes
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This work was supported by the National Institute of Mental Health (Grants MH063266 to W.A.C. and MH078473 to A.T.K.) and by the National Institute on Drug Abuse (Grant DA009045 to F.I.C.). The authors disclose that W.A.C. and McLean Hospital are co-owners of a United States patent claiming the use of κ-opioid receptor antagonists in the treatment of depression.
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Carlezon WA Jr (2003) inventor; The McLean Hospital Corporation, assignee. Treatment of depression with kappa receptor antagonists. U.S. patent 6,528,518. 2003 Mar 4.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.127415.
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ABBREVIATIONS: SSRI, selective serotonin reuptake inhibitor; KOR, κ-opioid receptor; NAc, nucleus accumbens; norBNI, nor-binaltorphimine hydrochloride; 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; EPM, elevated plus maze; OF, open field; FPS, fear-potentiated startle; ANOVA, analysis of variance; CS, conditioned stimulus; ISI, interstimulus interval; CREB, cAMP response element binding protein; US, unconditioned stimulus; CeA, central nucleusofthe amygdala; BLA, basolateral amygdala.
- Received June 18, 2007.
- Accepted September 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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