Single dose of
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            -dopa makes extinction memories context-independent and prevents the return of fear

Haaker, Jan; Gaburro, Stefano; Sah, Anupam; Gartmann, Nina; Lonsdorf, Tina B.; Meier, Kolja; Singewald, Nicolas; Pape, Hans‐Christian; Morellini, Fabio; Kalisch, Raffaël

doi:10.1073/pnas.1303061110

Cited by 143 publications

(187 citation statements)

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“…Interestingly however, while patients suffering from anxiety disorders show deficient CS discrimination already during fear acquisition and extinction (Duits et al, 2015;Lissek et al, 2005) and while trait anxiety has also been linked to deficits in CS-discrimination during conditioning and extinction (Haaker et al, 2013;Kindt & Soeter, 2014) the effect of state anxiety was specific to reinstatement induced ROF, as previously reported for context conditioning (Glotzbach-Schoon et al, 2015). As the effect of anxiety on fear and extinction associated processes is generally rather small and hence requires large sample sizes (Haaker et al, 2015), it remains to be investigated by future larger studies whether the effect of state 15 anxiety is indeed specific to ROF.…”

Section: Discussionmentioning

confidence: 99%

“…A major limitation to long-term remission of anxiety disorders is the high relapse rate despite of effective psychological and pharmacological interventions (Yonkers, Bruce, Dyck, & Keller, 2003). Thus, relapse prevention may represent a good intervention point for improving long-term therapeutic efficacy, which has recently become a major focus of experimental and clinical research (Fitzgerald, Seemann, & Maren, 2014;Haaker et al, 2013;Kindt, Soeter, & Vervliet, 2009;Schiller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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State anxiety modulates the return of fear

Kuhn

Mertens

Lonsdorf

2016

International Journal of Psychophysiology

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Current treatments for anxiety disorders are effective but limited by the high frequency of clinical relapse. Processes underlying relapse are thought to be experimentally modeled in fear conditioning experiments with return fear (ROF) inductions. Thereby reinstatementinduced ROF might be considered a model to study mechanisms underlying adversity-induced relapse. Previous studies have reported differential ROF (i.e. specific for the danger stimulus) but also generalized ROF (i.e. for safe and danger stimuli), but reasons for these divergent findings are not clear yet. Hence, the response pattern (i.e. differential or generalized) following reinstatement may be of importance for the prediction of risk or resilience for ROF.The aim of this study was to investigate state anxiety as a potential individual difference factor contributing to differentiability or generalization of return of fear.Thirty-six participants underwent instructed fear expression, extinction and ROF induction through reinstatement while physiological (skin conductance response, fear potentiated startle) and subjective measures of fear and US expectancy were acquired. Our data show that, as expected, high state anxious individuals show deficits in SCR discrimination between dangerous and safe cues after reinstatement induced ROF (i.e. generalization) as compared to low state anxious individuals.The ability to maintain discrimination under aversive circumstances is negatively associated with pathological anxiety and predictive of resilient responding while excessive generalization is a hallmark of anxiety disorders. Therefore, we suggest that experimentally induced ROF might prove useful in predicting relapse risk in clinical settings and might have implications for possible interventions for relapse prevention.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

State anxiety modulates the return of fear

Kuhn

Mertens

Lonsdorf

2016

International Journal of Psychophysiology

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“…Extinction LTM tests 1 and 2 were separately conducted 2 days and 14 days after extinction. After the second extinction LTM test, one shock was given to reinstate extinguished fear (Haaker et al, 2013). The reinstatement test was conducted 24 h after the reinstatement footshock.…”

Section: Contextual Fear Memorymentioning

confidence: 99%

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

Chai

Liu

Xue

et al. 2014

Neuropsychopharmacol

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Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the b-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the b-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another b-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.

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“…Increases in the availability of dopamine in the synaptic cleft result in increased receptor binding and activation of multiple intracellular signaling cascades. Drugs such as methylphenidate, methamphetamine, and L-dopa appear to promote memory and extinction through this mechanism (Abraham et al, 2012;Wood and Anagnostaras, 2009;Carmack et al, 2010;Haaker et al, 2013), raising the potential for dopaminergic compounds in treating post-traumatic stress disorder (Raczka et al, 2011;Bukalo et al, 2014). Increased availability of dopamine causes activation of D1-like and D2-like dopamine receptors, but the memory-enhancing effects of dopamine receptor activation are hypothesized to be mediated by D1/5 receptors, as antagonizing D1/5 receptors blocks methylphenidate's actions on working memory (Arnsten and Dudley, 2005), and impairs consolidation of fear or reward extinction (Hikind and Maroun, 2008;Fricks-Gleason et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

Abraham

Neve

Lattal

2016

Neuropsychopharmacol

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Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

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Single dose of l -dopa makes extinction memories context-independent and prevents the return of fear

Cited by 143 publications

References 71 publications

State anxiety modulates the return of fear

State anxiety modulates the return of fear

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

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