Elsevier

Biological Psychiatry

Volume 70, Issue 5, 1 September 2011, Pages 425-433
Biological Psychiatry

Priority Communication
Kappa Opioid Receptor Signaling in the Basolateral Amygdala Regulates Conditioned Fear and Anxiety in Rats

https://doi.org/10.1016/j.biopsych.2011.03.017Get rights and content

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.

Section snippets

Rats

A total of 198 male Sprague-Dawley rats (325–375 g) (Charles River Laboratories, Raleigh, North Carolina) were used. Rats were singly housed following surgery and maintained on a 12-hour light-dark cycle with unrestricted access to food and water. Protocols were approved by McLean Hospital's Institutional Animal Care Committee and consistent with National Institutes of Health policies.

Quantitative Real-Time Reverse Transcriptase Polymerase Chain Reaction

Thirty-eight rats were used to determine if fear conditioning affects KOR or PDyn mRNA expression in the BLA,

Results

Tissue punches were obtained from the BLA, CeA, HIP, and STR, which have varying degrees of dynorphin expression (27, 29) (Figure 1A,B). Rats that received Light+Shock training displayed marked conditioned fear, as indicated by a 72% increase in startle in the presence of the light (Figure 1C). Rats exposed to Light Alone did not show altered startle in the presence of the light and had significantly lower FPS (4%) than rats receiving Light+Shock training [t(16) = 2.87, p < .05] (Figure 1C),

Discussion

Systemic administration of KOR antagonists produces anxiolytic-like effects in models of fear and anxiety (15). Here, we identify the BLA as a site of increased KOR mRNA expression following fear learning and decreased KOR mRNA expression following effective fear extinction. We also identify the BLA and CeA as regions that mediate the anxiolytic-like effects of KOR antagonists. These findings provide evidence that fear conditioning and extinction dynamically regulate KOR expression in the BLA—a

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      In contrast, changes in KOR mRNA expression in the BLA have been associated with fear-potentiated startle responses, with higher levels of fear-potentiated startle being associated with higher KOR mRNA expression (Knoll et al., 2011). Injections of the KOR antagonist, JDTic, into the BLA or CEA decreased fear-potentiated startle without affecting baseline startle (Knoll et al., 2011), potentially suggesting a role of DYN acting through KOR in the BLA (or CEA) in modulating conditioned startle responses. These results are consistent with the localization of both DYN and KOR in neurons and fibers in the BLA and CEA (Mansour et al., 1996; Mansour, Fox, Burke, et al., 1994; Mansour, Fox, Meng, et al., 1994), although DYN-containing neurons in the CL are denser than in BLA.

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