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

Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

doi:10.1038/npp.2016.5

Cited by 57 publications

(43 citation statements)

References 52 publications

(58 reference statements)

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“…Salience signalling and salience driven-learning have been strongly associated with dopaminergic signalling (Abraham et al, 2016) and both the amygdala and the orbitofrontal cortex receive extensive mesocortical and mesolimbic dopaminergic inputs (Meador-Woodruff et al, 1997).…”

Section: Valence-specific Effects Of Ketaminementioning

confidence: 99%

General and emotion-specific neural effects of ketamine during emotional memory formation

et al. 2017

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General and emotion-specific neural effects of ketamine during emotional memory formation, NeuroImage, http://dx.doi.org/10. 1016/j.neuroimage.2017.02.049 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractAnimal studies suggest that N-methyl-D-aspartate receptor (NMDAR) dependent signalling in limbic and prefrontal regions is critically involved in both cognitive and emotional functions. In humans, ketamine-induced transient, and disorder associated chronic NMDAR hypofunction (i.e. in schizophrenia) has been associated with deficient performance in the domains of memory and higher-order emotional functioning, as well as altered neural activity in the underlying limbicprefrontal circuits. To model the effects of NMDAR hypofunction on the integration of emotion and cognition the present pharmacological fMRI study applied the NMDAR antagonist ketamine (target plasma level = 100ng/ml) to 21 healthy volunteers in a within-subject placebo-controlled crossover 2 design during encoding of neutral, positive and negative pictures. Our results show that irrespective of emotion, ketamine suppressed parahippocampal and medial prefrontal activity. In contrast, ketamine selectively increased amygdala and orbitofrontal activity during successful encoding of negative stimuli. On the network level ketamine generally increased medial prefrontalparahippocampal coupling while specifically decreasing amygdala-orbitofrontal interplay during encoding of negative stimuli. On the behavioural level, ketamine produced generally decreased memory performance and abolished the emotional enhancement of memory after a wash-out period of 5 days. The present findings suggest that ketamine produces general as well as valencespecific effects during emotional memory formation. The pattern partly overlaps with alterations previously observed in patients with schizophrenia.

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Section: Valence-specific Effects Of Ketaminementioning

confidence: 99%

General and emotion-specific neural effects of ketamine during emotional memory formation

et al. 2017

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“…An advantage of a genetic approach to the D1 receptor is that knockouts are specific to that receptor, whereas pharmacological approaches are not specific, targeting D1 and D5 receptors. We have previously reported that pharmacological activation of the D1/5 receptor enhances fear extinction in male C57BL/6 mice (Abraham et al, 2016). To test whether this effect required D1 receptors, we examined the effects of the D1/5 agonist SKF81297 in the D1 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

“…To determine whether the previously observed enhancements of fear extinction induced by a D1/D5 agonist (Abraham et al, 2016) could be attributed to pharmacological activation of D5 receptors, we tested the effect of SKF 81297 on fear extinction in D1 KO. On Day 1, naïve subjects received a 12-min exposure to the context with four unsignaled shocks (2s, 0.35 mA), delivered at 2.5, 5, 9, and 11.5 min.…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacological approaches have found that antagonists and agonists of D1/5 receptors can modulate cocaine-induced conditioned place preference (CPP; Cervo & Samanin, 1995), fear conditioning (Inoue et al, 2000), and fear extinction (Hikind & Maroun, 2008; Abraham, et al 2016). These studies suggest that alterations in phasic signaling through D1-like receptors could have effects on fear and reward processing, but there are currently no pharmacological agents available to distinguish the contributions of D1 and D5 receptors to these behaviors.…”

mentioning

confidence: 99%

“…To determine generality of contextual learning effects, we measured cocaine conditioned place preference (CPP) in D1 KO mice (Miner et al, 1995). Finally, we used the D1 KO mice to try to isolate whether pharmacological enhancements of extinction induced by a D1/5 agonist (SKF81297; Fiorenza et al, 2012; Rey et al, 2014; Abraham et al, 2016) occur in the absence of the D1 receptor. If they do, it would suggest that D5 receptors are sufficient to mediate these pharmacological effects.…”

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confidence: 99%

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Effects of D1 receptor knockout on fear and reward learning

Abraham

Neve

Lattal

2016

Neurobiology of Learning and Memory

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Dopamine signaling is involved in a variety of neurobiological processes that contribute to learning and memory. D1-like dopamine receptors (including D1 and D5 receptors) are thought to be involved in memory and reward processes, but pharmacological approaches have been limited in their ability to distinguish between D1 and D5 receptors. Here, we examine the effects of a specific knockout of D1 receptors in associative learning tasks involving aversive (shock) or appetitive (cocaine) unconditioned stimuli. We find that D1 knockout mice show similar levels of cued and contextual fear conditioning to WT controls following conditioning protocols involving one, two, or four shocks. D1 knockout mice show increased generalization of fear conditioning and extinction across contexts, revealed as increased freezing to a novel context following conditioning and decreased freezing to an extinguished cue during a contextual renewal test. Further, D1 knockout mice show mild enhancements in extinction following an injection of SKF81297, a D1/D5 receptor agonist, suggesting a role for D5 receptors in extinction enhancements induced by nonspecific pharmacological agonists. Finally, although D1 knockout mice show decreased locomotion induced by cocaine, they are able to form a cocaine-induced conditioned place preference. We discuss these findings in terms of the role of dopamine D1 receptors in general learning and memory processes.

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Involvement of the dorsal hippocampus in expression and extinction of cocaine‐induced conditioned place preference

Hitchcock

Lattal

2018

Hippocampus

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A key aspect of substance abuse is that drug taking often occurs in a specific context. As a consequence, exposure to drug-associated contexts can trigger cravings and relapse, even after long periods of abstinence. Although many studies have demonstrated that the hippocampus is critical for developing and retrieving contextual and spatial memories, comparatively little is known about the role of the hippocampus in acquiring and inhibiting memories involving contexts and drugs of abuse. We examined the effects of hippocampal inactivation on expression of cocaine-induced conditioned place preference (CPP) after initial acquisition or extinction of CPP in C57BL/6 mice. During acquisition of CPP, distinct tactile cues were paired with cocaine (20 mg kg , intraperitoneal, CS+) and different tactile cues were paired with saline (CS-) on alternate days. Groups differed in whether the CS+ and CS- cues were presented in the same large space (one-compartment procedure) or distinct small spaces (two-compartment procedure), as previous findings demonstrate that a two-compartment configuration facilitates acquisition and attenuates extinction of a cocaine-induced CPP. Microinjection of the GABA agonist, muscimol, into the dorsal hippocampus impaired (1) retrieval of a place preference after acquisition, (2) extinction of a place preference, and (3) retrieval of extinction. These effects differed depending on the spatial configuration during acquisition or extinction, suggesting that the dorsal hippocampus may differentially modulate drug seeking during retrieval and extinction of CPP.

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

Cited by 57 publications

References 52 publications

General and emotion-specific neural effects of ketamine during emotional memory formation

General and emotion-specific neural effects of ketamine during emotional memory formation

Effects of D1 receptor knockout on fear and reward learning

Involvement of the dorsal hippocampus in expression and extinction of cocaine‐induced conditioned place preference

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