Background
The kappa opioid receptor (KOR) system contributes to the prodepressive and aversive
consequences of stress and is implicated in the facilitation of conditioned fear and
anxiety in rodents. Here, we sought to identify neural circuits that mediate KOR system
effects on fear and anxiety in rats.
Methods
We assessed whether fear conditioning induces plasticity in KOR or dynorphin (the
endogenous KOR ligand) messenger RNA (mRNA) expression in the basolateral (BLA) and
central (CeA) nuclei of the amygdala, hippocampus, or striatum. We then assessed whether
microinfusions of the KOR antagonist JDTic (0–10 μg/side) into the BLA or CeA affect
the expression of conditioned fear or anxiety. Finally, we examined whether fear extinction
induces plasticity in KOR mRNA expression that relates to the quality of fear extinction.
Results
Fear conditioning upregulated KOR mRNA in the BLA by 65% and downregulated it in the
striatum by 22%, without affecting KOR levels in the CeA or hippocampus, or dynorphin
levels in any region. KOR antagonism in either the BLA or CeA decreased conditioned
fear in the fear-potentiated startle paradigm, whereas KOR antagonism in the BLA,
but not the CeA, produced anxiolytic-like effects in the elevated plus maze. Effective
fear extinction was associated with a 67% reduction in KOR mRNA in the BLA.
Conclusions
These findings suggest that fear conditioning and extinction dynamically regulate
KOR expression in the BLA and provide evidence that the BLA and CeA are important
neural substrates mediating the anxiolytic-like effects of KOR antagonists in models
of fear and anxiety.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Psychotomimesis mediated by kappa opiate receptors.Science. 1986; 233: 774-776
- A review of the properties of spiradoline: A potent and selective kappa-opioid receptor agonist.CNS Drugs Rev. 2003; 9: 187-198
- Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.J Pharmacol Exp Ther. 1993; 264: 489-495
- The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.J Neurosci. 2008; 28: 407-414
- Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.J Pharmacol Exp Ther. 2006; 316: 440-447
- Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats.Psychopharmacology (Berl). 2004; 172: 463-470
- Depressive-like effects of the kappa Opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens.Psychopharmacology (Berl). 2010; 210: 241-252
- Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.J Pharmacol Exp Ther. 2003; 305: 323-330
- Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system.Neuropsychopharmacology. 2006; 31: 1241-1248
- Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses.J Neurosci. 2003; 23: 5674-5683
- Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects.J Neurochem. 2004; 90: 1258-1268
- Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.J Neurosci. 2002; 22: 10883-10890
- Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.J Neurosci. 2001; 21: 7397-7403
- Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats.Neuropsychopharmacology. 2010; 35: 752-763
- Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats.J Pharmacol Exp Ther. 2007; 323: 838-845
- Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate.Neuropsychopharmacology. 2009; 34: 1339-1350
- Comparison of the kappa-opioid receptor antagonist DIPPA in tests of anxiety-like behavior between Wistar Kyoto and Sprague-Dawley rats.Psychopharmacology (Berl). 2010; 210: 295-302
- Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone.Neuropsychopharmacology. 2009; 34: 775-785
- CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior.PLoS ONE. 2009; 4: e8528
- Comorbidity of mood and anxiety disorders.Depress Anxiety. 2000; 12: 69-76
- The epidemiology of major depressive disorder: Results from the National comorbidity Survey Replication (NCS-R).JAMA. 2003; 289: 3095-3105
- Relation between anxiety and depressive disorders in childhood and adolescence.Depress Anxiety. 2001; 14: 67-78
- Causal relationship between stressful life events and the onset of major depression.Am J Psychiatry. 1999; 156: 837-841
- Biological substrates of reward and aversion: A nucleus accumbens activity hypothesis.Neuropharmacology. 2009; 56: 122-132
- Desipramine reduces stress-activated dynorphin expression and CREB phosphorylation in NAc tissue.Mol Pharmacol. 2009; 75: 704-712
- Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats.J Neurosci. 2011; 31: 3095-3103
- Distribution of dynorphin and enkephalin peptides in the rat brain.J Comp Neurol. 1986; 249: 293-336
- Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain.Neuroscience. 1996; 72: 767-783
- Opioid-receptor mRNA expression in the rat CNS: Anatomical and functional implications.Trends Neurosci. 1995; 18: 22-29
- Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: A 33P in situ hybridization study.Neuroscience. 1999; 88: 1093-1135
- Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes.Proc Natl Acad Sci U S A. 1994; 91: 8477-8481
- Stress, memory and the amygdala.Nat Rev Neurosci. 2009; 10: 423-433
- Amygdala inhibitory circuits and the control of fear memory.Neuron. 2009; 62: 757-771
- The role of neuropeptide Y in the expression and extinction of fear-potentiated startle.J Neurosci. 2008; 28: 12682-12690
- Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines.Neuropsychopharmacology. 2000; 22: 77-88
- Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats.J Neurosci. 2005; 25: 11479-11488
- Associative fear conditioning of enkephalin mRNA levels in central amygdalar neurons.Behav Neurosci. 2000; 114: 681-686
- Cholecystokinin receptor subtypes: Role in the modulation of anxiety-related and reward-related behaviours in animal models.J Psychiatry Neurosci. 2003; 28: 171-181
- Effects of substance P in the amygdala, ventromedial hypothalamus, and periaqueductal gray on fear-potentiated startle.Neuropsychopharmacology. 2009; 34: 331-340
- Regulation of cocaine reward by CREB.Science. 1998; 282: 2272-2275
- Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextual fear conditioning.J Neurosci. 2006; 26: 1616-1623
- Distinct gene expression profiles in hippocampus and amygdala after fear conditioning.Brain Res Bull. 2005; 67: 1-12
- Regulation of synaptic plasticity genes during consolidation of fear conditioning.J Neurosci. 2002; 22: 7892-7902
- Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala.Behav Neurosci. 1999; 113: 276-282
- Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala.J Neurosci. 2000; 20: RC96
- Rethinking the fear circuit: The central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning.J Neurosci. 2006; 26: 12387-12396
- Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory.Learn Mem. 2008; 15: 163-171
- Genes and mechanisms in the amygdala involved in the formation of fear memory.Ann N Y Acad Sci. 2003; 985: 92-105
- Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats.Psychopharmacology (Berl). 2009; 204: 227-239
- MAPK cascade signalling and synaptic plasticity.Nat Rev Neurosci. 2004; 5: 173-183
- Differential effects of the novel kappa Opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.Psychopharmacology (Berl). 2005; 183: 118-126
- Pharmacological properties of JDTic: A novel kappa-opioid receptor antagonist.Eur J Pharmacol. 2004; 501: 111-119
- Neuronal architecture in the rat central nucleus of the amygdala: A cytological, hodological, and immunocytochemical study.J Comp Neurol. 1986; 246: 478-499
- Cytoarchitecture of the central amygdaloid nucleus of the rat.J Comp Neurol. 1982; 208: 401-418
- The basolateral amygdaloid complex as a cortical-like structure.Brain Res. 1988; 441: 377-380
- GABAergic innervation of alpha type II calcium/calmodulin-dependent protein kinase immunoreactive pyramidal neurons in the rat basolateral amygdala.J Comp Neurol. 2002; 446: 199-218
- Mechanisms of fear extinction.Mol Psychiatry. 2007; 12: 120-150
- Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle.Neurosci Biobehav Rev. 1997; 21: 743-753
- Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala.Neuropsychopharmacology. 2006; 31: 739-750
- Neuronal competition and selection during memory formation.Science. 2007; 316: 457-460
- Molecular mechanisms underlying emotional learning and memory in the lateral amygdala.Neuron. 2004; 44: 75-91
- The role of the striatum in aversive learning and aversive prediction errors.Philos Trans R Soc Lond, B, Biol Sci. 2008; 363: 3787-3800
- Human amygdala activation during conditioned fear acquisition and extinction: A mixed-trial fMRI study.Neuron. 1998; 20: 937-945
- The indirect amygdala-dorsal striatum pathway mediates conditioned freezing: Insights on emotional memory networks.Neuroscience. 2008; 153: 84-94
- Dissociation of visual and olfactory conditioning in the neostriatum of rats.Behav Brain Res. 1989; 32: 31-42
- Mnemonic functions of dorsal striatum and hippocampus in aversive conditioning.Behav Brain Res. 2003; 142: 99-107
- Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats.Behav Neural Biol. 1991; 55: 255-269
- Interconnectivity between the amygdaloid complex and the amygdalostriatal transition area: A PHA-L study in rat.J Comp Neurol. 2001; 431: 39-58
- Properties of the pathways from the lateral amygdal nucleus to basolateral nucleus and amygdalostriatal transition area.J Neurophysiol. 2002; 87: 2593-2601
- Dynorphins are endogenous opioid peptides released from granule cells to act neurohumorly and inhibit excitatory neurotransmission in the hippocampus.Prog Brain Res. 2000; 125: 363-367
- The effects of acute stress on the regulation of central and basolateral amygdala CRF-binding protein gene expression.Brain Res Mol Brain Res. 2004; 131: 17-25
- The influence of chronic stress on multiple opioid peptide systems in the rat: Pronounced effects upon dynorphin in spinal cord.Brain Res. 1987; 413: 213-219
- Diffusion of molecules in brain extracellular space: Theory and experiment.Prog Brain Res. 2000; 125: 129-154
- Temporal and spatial control of neural effects following intracerebral microinfusion.J Drug Target. 2008; 16: 198-205
- The prefrontal cortex and flexible behavior.Neuroscientist. 2007; 13: 532-545
- Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala.Neuroscience. 2005; 132: 943-953
- Amygdala intercalated neurons are required for expression of fear extinction.Nature. 2008; 454: 642-645
- An inhibitory interface gates impulse traffic between the input and output stations of the amygdala.J Neurosci. 1999; 19: 10575-10583
- Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction.J Neurosci. 2005; 25: 502-506
- Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear.Eur J Neurosci. 2007; 26: 3631-3644
- Dynorphin, stress, and depression.Brain Res. 2010; 1314: 56-73
- Molecular mechanisms of memory acquisition, consolidation and retrieval.Curr Opin Neurobiol. 2001; 11: 180-187
- Molecular mechanisms of memory reconsolidation.Nat Rev Neurosci. 2007; 8: 262-275
- The labile nature of consolidation theory.Nat Rev Neurosci. 2000; 1: 216-219
- Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning.Eur J Neurosci. 2005; 21: 283-289
- Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature. 2000; 406: 722-726
- Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase.J Biol Chem. 2007; 282: 29803-29811
- Differential effects of mu and kappa opioid antagonists on Fos-like immunoreactivity in extended amygdala.Brain Res. 1999; 822: 34-42
- Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria.J Neurosci. 2007; 27: 11614-11623
- Activation of kappa opioid receptors decreases synaptic transmission and inhibits long-term potentiation in the basolateral amygdala of the mouse.Eur J Pain. 2009; 13: 124-129
- Characterization of neurons in the rat central nucleus of the amygdala: Cellular physiology, morphology, and opioid sensitivity.J Comp Neurol. 2006; 497: 910-927
- Synaptic properties and postsynaptic opioid effects in rat central amygdala neurons.Neuroscience. 2004; 127: 871-879
- The Rat Brain in Stereotaxic Coordinates.3rd ed. Academic Press, San Diego1996
Article info
Publication history
Published online: May 02, 2011
Accepted:
March 10,
2011
Received in revised form:
March 7,
2011
Received:
January 26,
2011
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
