The effect of the μ-opioid receptor antagonist naloxone on extinction of conditioned fear in the developing rat

Kim, Jee Hyun; Richardson, Rick

doi:10.1101/lm.1282309

Cited by 37 publications

(29 citation statements)

References 40 publications

(55 reference statements)

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“…Thus, blocking endogenous μ-opioid neurotransmission enhances the acquisition of conditioned fear (43) and impairs the acquisition of extinction or learned safety (44)(45)(46). The implication of these findings is that μ-opioids are involved in reducing conditioned fear responses and enhancing fear extinction or learned safety.…”

Section: Discussionmentioning

confidence: 95%

Attachment figures activate a safety signal-related neural region and reduce pain experience

Eisenberger

Master

Inagaki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

422

355

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Although it has long been hypothesized that attachment figures provide individuals with a sense of safety and security, the neural mechanisms underlying attachment-induced safety have not been explored. Here, we investigated whether an attachment figure acts as a safety signal by exploring whether viewing an attachment figure during a threatening experience (physical pain) led to increased activity in a neural region associated with safety signaling, the ventromedial prefrontal cortex (VMPFC), and corresponding reductions in pain. Female participants in long-term romantic relationships were scanned as they received painful stimuli while viewing pictures of their partner and control images (stranger, object). Consistent with the idea that the attachment figure may signal safety, results revealed that viewing partner pictures while receiving painful stimulation led to reductions in self-reported pain ratings, reductions in pain-related neural activity (dorsal anterior cingulate cortex, anterior insula), and increased activity in the VMPFC. Moreover, greater VMPFC activity in response to partner pictures was associated with longer relationship lengths and greater perceived partner support, further highlighting a role for the VMPFC in responding to the safety value of the partner. Last, greater VMPFC activity while viewing partner pictures was associated with reduced pain ratings and reduced pain-related neural activity. An implication of these findings is that, in the same way that stimuli that historically have threatened survival (e.g., snakes, spiders) are considered to be prepared fear stimuli, attachment figures, who have historically benefited survival, may serve as prepared safety stimuli, reducing threat-or distress-related responding in their presence.functional MRI | neuroimaging | close relationship | distress ". . .for a person to know that an attachment figure is available and responsive gives him a strong and pervasive feeling of security. . ." -John Bowlby, 1988 (1) O ne of the central tenets of attachment theory is that the attachment bond-first formed between caregiver and childprovides a sense of safety and security for the child, who is not yet capable of providing or fending for him/herself (2). As suggested by Bowlby (1) above, knowing that an attachment figure is present may serve as a kind of safety signal, letting the individual know that he/she is safe and will be taken care of. Indeed, the presence versus absence of an attachment figure is known to produce quite distinct behavioral profiles in the same child-with courage and exploration seen in the caregiver's presence and timidity and fear observed in the caregiver's absence (2). Although the purpose of this attachment bond is most obvious during childhood, attachment bonds, such as those between adult romantic relationship partners, persist throughout the life cycle and may be beneficial during times of threat or danger (3).Although it makes sense that an attachment figure provides a "pervasive feeling of security," how attachment-induce...

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Section: Discussionmentioning

confidence: 95%

Attachment figures activate a safety signal-related neural region and reduce pain experience

Eisenberger

Master

Inagaki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

422

355

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“…This finding suggests that extinction involves unlearning of the original CS-US association in P17 rats; thus, subsequent re-extinction still requires the amygdala. Interestingly, a recent study demonstrated that endogenous opioids are necessary for extinction acquisition in P17 rats, as has been demonstrated in P24 rats (Kim and Richardson, 2009) and adult rats (e.g., McNally and Westbrook, 2003). Therefore, a potential neural mechanism for extinction in P17 rats may be opioid-mediated erasure of conditioned fear (for more detail, see Kim and Richardson, 2009) or opioid-induced inhibition of the amygdala (Faber and Sah, 2004); however, it is clear that more studies are necessary to delineate the processes underlying extinction early in development.…”

Section: Discussionmentioning

confidence: 95%

Fear Extinction across Development: The Involvement of the Medial Prefrontal Cortex as Assessed by Temporary Inactivation and Immunohistochemistry

Kim¹,

Hamlin²,

Richardson³

2009

J. Neurosci.

146

122

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Extinction in adult animals, including humans, appears to involve the medial prefrontal cortex (mPFC). However, the role of mPFC in extinction acrossdevelopmenthasnotyetbeenstudied.Givenseveralrecentdemonstrationsofdevelopmentaldifferencesinextinctionofconditionedfear at a behavioral level, different neural circuitries may mediate fear extinction across development. In all experiments, noise conditioned stimulus (CS) and shock unconditioned stimulus (US) were used. In experiment 1A, temporary unilateral inactivation of the mPFC during extinction training impaired long-term extinction the following day in postnatal day 24 (P24) rats but not in P17 rats. In experiment 1B, bilateral inactivationofthemPFCagainfailedtodisruptlong-termextinctioninP17rats.Inexperiment2,extinctiontrainingincreasedphosphorylatedmitogenactivated protein kinase (pMAPK) in the mPFC for P24 rats but not for P17 rats, whereas rats of both ages displayed elevated pMAPK in the amygdala. Across both ages, "not trained," "reactivated," and "no extinction" control groups expressed very low numbers of pMAPKimmunoreactive (IR) neurons across both neural structures. This result indicates that the mere conditioning experience, the exposure to the CS, or the expression of CS-elicited fear in and of itself is not sufficient to explain the observed increase in pMAPK-IR neurons in the mPFC and/or the amygdala after extinction. Together, these findings show that extinction in P17 rats does not involve the mPFC, which has important theoretical and clinical implications for the treatment of anxiety disorders in humans.

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“…Recent studies support this. Systemic [38, 39] or vlPAG microinjections [40 – 42] of MOR antagonists prevent fear extinction learning. Conversely, fear extinction learning can be facilitated by infusions of a peptidase inhibitor that reduces catabolism of vIPAG enkephalins [43].…”

Section: Introductionmentioning

confidence: 99%

Placing prediction into the fear circuit

McNally

Johansen

Blair

2011

Trends in Neurosciences

255

224

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Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here we review recent electrophysiological, molecular, and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray (PAG) region, can be linked to prediction error and expectation modulation of fear learning as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signalling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit may represent a conserved mechanism for regulating fear learning in mammals.

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The effect of the μ-opioid receptor antagonist naloxone on extinction of conditioned fear in the developing rat

Cited by 37 publications

References 40 publications

Attachment figures activate a safety signal-related neural region and reduce pain experience

Attachment figures activate a safety signal-related neural region and reduce pain experience

Fear Extinction across Development: The Involvement of the Medial Prefrontal Cortex as Assessed by Temporary Inactivation and Immunohistochemistry

Placing prediction into the fear circuit

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