Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

Abstract

Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors.dopamine | inhibitory avoidance | modulation of extinction | novelty | behavioral tagging and capture F rey and Morris (1, 2) described the enhancing influence of neuronal plastic processes [long-term potentiation (LTP) or long-term depression (LTD)] generated at one set of hippocampal synapses on LTP and LTD generated at other synapses. This influence is explainable by interactions between new proteins, called plasticity-related proteins (PRPs), at the two sets of synapses; the PRPs that tag one of them can be captured by those of others and enhance their responsiveness (3-5). Many memories rely on hippocampal LTP and LTD (1, 2, 6-11), and the "synaptic tagging-and-capture" process has been applied to the explanation of interactions between concurrent memories (11-13), among which are novelty and fear acquisition (12,14) and novelty and fear extinction (15, 16). Exposure to novelty [an open field (OF) in which they had never been before] involves two consecutive processes: its detection, which is very brief (seconds), and the immediately ensuing habituation (17), which lasts much longer; both rely on hippocampal LTD (18). With a relatively restricted time window before and/or after an extinction trial, novelty can enhance the extinction of contextual fear conditioning (CFC) lastingly (15,16). This is obviously of potential importance for exposure therapy (18-21).In rodents, the exploration of a novel environment, object, ...

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

“…The distinct patterns of PKA vs PLC coupled D1/5 receptor expression (Nishi et al, 2011) might indicate that SKF 83822 (PKA-coupled D1/5R agonist) may specifically engage the cortical networks involved in fear extinction through activation of PKA-coupled D1/5 receptors, whereas SKF 83959 may primarily activate the amygdala and hippocampus without affecting fear extinction. Our studies are also in concordance with Menezes et al (2015), who demonstrated that novelty-induced enhancement of fear extinction is mediated via D1/5 receptor activation and PKA signaling.…”

“…Most of the pharmacological and behavioral evidence for a role of D1/5 receptors in aversive memory comes from studies with D1/5 receptor antagonists (Menezes et al, 2015;Holtzman-Assif et al, 2010). Fewer studies have examined whether activating D1/5 receptors could promote memory and extinction, although studies with the partial agonist SKF 38393 have demonstrated both enhancements (Fiorenza et al, 2012;Rey et al, 2014) and impairments of fear extinction retention (Borowski and Kokkinidis, 1998).…”

COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume

“…69 The VTA, which is the seat of dopaminergic cell bodies of the mesocorticolimbic dopamine system, has connections to and from the hippocampus and has been associated with facilitation of fear extinction. 70 Disturbances in this pathway have been linked to enhanced fear generalization in clinical samples. 71 One implication from these studies is that dopamine-associated hippocampal function is critical for the encoding of distinct memory representations.…”

Fear Memory

“…Two basic variants of IA are used in rats or mice: the stepdown model, in which rodents receive a footshock upon stepping down from a start platform onto a grid of electrifiable metal rods (FIGURE 3) (171,269,272,413,460), and the older, step-through model in which animals are initially placed in a usually well-lit V-shaped compartment with metal walls and step through an open door into a similar but larger compartment where the opposing walls and the floor can be electrified (290,321,322 Both have become classic, and both give basically the same results. A few scattered laboratories have used two-trial or multiple-trial IA, with no real advantage over the more usual one-trial task.…”

“…IA is by far the one in which more biochemical and pharmacological studies of memory consolidation in mammalian hippocampus in awake, behaving animals were carried out (70,72,73,105,116,183,208,264,265,267,271,272,400,401,403,405,413,563,657). Contextual and tone-conditioned fear and the LA or BLA come a distant second; Maren (379) commented on results of his own laboratory that suggest a specific role for the BLA in fear conditioning.…”