Kappa opioid receptors mediate where fear is expressed following extinction training

Cole, Sindy; Richardson, Rick; McNally, Gavan P.

doi:10.1101/lm.2049511

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…However, the extended inactivation of KOR that results from the administration of these KOR antagonists makes it impossible to know from those studies if the drug treatment interfered with the acquisition or with the expression of the leaned fear response. In a third study, central administrations of norBNI after a discriminative fear conditioning procedure had no effect on subsequent expression of fear [47]. In contrast to this most recent study, we report in this paper that contextual fear expression at Day 9 was weakly attenuated in shock rats that had received a post-shock injection of 30 mg/kg norBNI.…”

Section: Discussioncontrasting

confidence: 90%

Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Rogala

et al. 2012

PLoS ONE

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Exposure of rats to footshocks leads to an enduring behavioral state involving generalized fear responses and avoidance. Recent evidence suggests that the expression of negative emotional behaviors produced by a stressor is in part mediated by dynorphin and its main receptor, the kappa opioid receptor (KOR). The purpose of this study was to determine if a subcutaneous injection of the long-acting KOR antagonist norbinaltorphimine (norBNI; 15.0 and 30.0 mg/kg) given 2 days after an acute exposure of rats to footshooks (5×2 s episodes of 1.5 mA delivered over 5 min) attenuates the expression of lasting fear and anxiety. We report that exposure of rats to acute footshock produced long-lasting (>4 weeks) fear (freezing) and anxiety (avoidance of an open area in the defensive withdrawal test). The 30 mg dose of norBNI attenuated the fear expressed when shock rats were placed in the shock context at Day 9 but not Day 27 post-shock. The same dose of norBNI had no effect on the expression of generalized fear produced when shock rats were placed in a novel chamber at Days 8 and 24. In contrast, the 30 mg dose of norBNI produced consistent anxiolytic effects in shock and nonshock rats. First, the 30 mg dose was found to decrease the latency to enter the open field in the defensive withdrawal test done 30 days after the shock exposure. Second, the same high dose also had anxiolytic effects in both nonshock and shock rats as evidence by a decrease in the mean time spent in the withdrawal box. The present study shows that systemic injection of the KOR antagonist norBNI had mixed effect on fear. In contrast, norBNI had an anxiolytic effect which included the attenuation of the enhanced avoidance of a novel area produced by a prior shock experience.

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Section: Discussioncontrasting

confidence: 90%

Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Rogala

et al. 2012

PLoS ONE

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“…Aside from alcohol dependence and withdrawal, there is emerging evidence for the role of the DYN in fear conditioning, and relapse to drugs of abuse . One study showed that nor-BNI could block fear reinstatement, while U50,488 could potentiate fear renewal (Cole et al, 2011). Another study found that the KOR antagonists nor-BNI and JDTic could attenuate conditioned fear in the fear-potentiated startle paradigm (Knoll et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Affective Cue-Induced Escalation of Alcohol Self-Administration and Increased 22-kHz Ultrasonic Vocalizations during Alcohol Withdrawal: Role of Kappa-Opioid Receptors

Berger¹,

Williams²,

McGinnis³

et al. 2012

Neuropsychopharmacol

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Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappaopioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system.

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“…The extinguished fear can relapse when the subject is presented with a conditioned stimulus (CS) in the same context in which the fear conditioning was performed (ABA renewal) or in a third context distinct from the context where the fear conditioning or extinction was carried out (ABC renewal). Although both ABA and ABC renewal demonstrate the context-dependency of extinction learning, their mechanisms and manifestations have been shown to differ clearly in several aspects [8]–[14]. The dorsal hippocampus plays a critical role in ABC renewal [15], [16], but not ABA renewal [4], [17].…”

Section: Introductionmentioning

confidence: 99%

“…The dorsal hippocampus plays a critical role in ABC renewal [15], [16], but not ABA renewal [4], [17]. In addition, blockade of kappa opioid receptor in the ventral hippocampus has a significant effect on ABA renewal, but not ABC renewal [7], [8]. Thus, it is important to study these two forms of fear renewal independently.…”

Section: Introductionmentioning

confidence: 99%

ABA Renewal Involves Enhancements in Both GluA2-Lacking AMPA Receptor Activity and GluA1 Phosphorylation in the Lateral Amygdala

et al. 2014

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Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.

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Kappa opioid receptors mediate where fear is expressed following extinction training

Cited by 15 publications

References 38 publications

Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Effects of a Post-Shock Injection of the Kappa Opioid Receptor Antagonist Norbinaltorphimine (norBNI) on Fear and Anxiety in Rats

Affective Cue-Induced Escalation of Alcohol Self-Administration and Increased 22-kHz Ultrasonic Vocalizations during Alcohol Withdrawal: Role of Kappa-Opioid Receptors

ABA Renewal Involves Enhancements in Both GluA2-Lacking AMPA Receptor Activity and GluA1 Phosphorylation in the Lateral Amygdala

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