Infralimbic D2 Receptors Are Necessary for Fear Extinction and Extinction-Related Tone Responses

doi:10.1016/j.biopsych.2010.08.014

Biological Psychiatry

Volume 68, Issue 11, 1 December 2010, Pages 1055-1060

https://doi.org/10.1016/j.biopsych.2010.08.014 Get rights and content

Background

Fear extinction is dependent on plasticity in the infralimbic prefrontal cortex, an area heavily innervated by midbrain dopaminergic inputs. Dopamine D2 receptors are concentrated in infralimbic output neurons that are involved in the suppression of conditioned fear after extinction. Here, we examined the specific role of infralimbic D2 receptors in mediating associative learning underlying fear extinction using the selective D2 antagonist raclopride.

Methods

Raclopride was administered systemically or infused into the infralimbic prefrontal cortex before fear extinction, and extinction retention was tested the following day. Rats were also prepared for single-unit recording in the infralimbic prefrontal cortex to assess the effect of raclopride on firing properties.

Results

We found that systemic injection of raclopride given before extinction impaired retrieval of extinction when rats were tested drug-free the next day but also induced catalepsy during extinction training. To determine whether impaired extinction was due to impaired motor function or disruption of extinction consolidation, we infused raclopride directly into the infralimbic prefrontal cortex. Raclopride infused immediately before extinction training did not produce motor deficits but impaired recall of extinction when tested drug-free. Furthermore, in animals that underwent extinction training, systemic raclopride reduced the tone responsiveness of infralimbic prefrontal cortex neurons in layers 5/6, with no changes in average firing rate.

Conclusions

We suggest that D2 receptors facilitate extinction by increasing the signal-to-noise of infralimbic prefrontal cortex neurons that consolidate extinction.

Section snippets

Subjects

Male Sprague-Dawley rats (270–320 g) were obtained, housed, and handled as described previously (20). Rats were restricted to 18 g of standard laboratory rat chow daily and were subsequently trained to bar press for food pellets on a variable interval schedule (VI 60 sec). Throughout behavioral experiments, rats were able to press for food to maintain a constant level of activity against which freezing could be reliably measured (20). All procedures were approved by the Institutional Animal

Systemic Blockade of Dopaminergic D2 Receptors Impairs Consolidation of Extinction Memory

We first examined whether dopamine, acting at D2 receptors, is necessary for extinction learning. Rats were fear conditioned on day 1 and were systemically injected with the D2 receptor antagonist raclopride (.3 mg/kg IP) or saline 10 min before extinction training on day 2. Rats injected with raclopride expressed significantly higher levels of freezing on average than rats injected with saline throughout the extinction session (Figure 1A). Analysis of variance revealed a main effect of group [F

Discussion

The present study demonstrates that D2 receptor signaling is necessary for extinction of conditioned fear. Blockade of D2 receptors in IL during fear extinction impairs later retrieval of extinction, implicating D2 receptor signaling in this structure. Although raclopride did not affect firing rate or bursting in IL, it attenuated extinction-related tone responses. Thus, D2 receptor signaling in IL promotes fear extinction, presumably by enabling tone responses during extinction that are

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The inability to extinguish learned fear is a hallmark of trauma- and stress-related disorders. A form of inhibitory learning called fear extinction is an effective way to treat these disorders. However, the neurobiology of fear extinction has not been clarified. The involvement of a dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens shell (AcbSh) in fear extinction has been suggested. Several neuropeptide systems, including neuropeptide S (NPS), modulate the activity of VTA dopaminergic neurons. Herein, we investigated the role of NPS in modulating the VTA-AcbSh circuit in fear extinction. While the NPS-containing neurons of the pericoerulear (periLC) area project to the VTA, the recipient cells are equipped with NPS receptors. Using a Pavlovian fear conditioning procedure, we tested the effect of NPS on fear extinction in male Wistar rats. Intra-VTA administration of NPS prior to fear extinction training facilitated the fear extinction learning and memory, however, NPS receptors antagonist had the opposite effect. Fear extinction training increased the dopamine efflux and cFOS immunoreactivity in the AcbSh area of NPS-treated rats compared with the vehicle-injected controls. We suggest that the NPS neurons of the periLC project to the VTA and might facilitate fear extinction by enhancing the activity of mesolimbic dopaminergic circuit.
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Archival ReportInfralimbic D2 Receptors Are Necessary for Fear Extinction and Extinction-Related Tone Responses

Background

Methods

Results

Conclusions

Section snippets

Subjects

Systemic Blockade of Dopaminergic D2 Receptors Impairs Consolidation of Extinction Memory

Discussion

Neuroscience

Biol Psychiatry

Brain Res Bull

Eur Neuropsychopharmacol

Neuron

Brain Res

Eur J Pharmacol

Neurosci Lett

Brain Res

Cell

Biol Psychiatry

Biol Psychiatry

Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers

Psychopharmacology (Berl)

Distinct functions of the two isoforms of dopamine D2 receptors

Nature

Selective D2 receptor actions on the functional circuitry of working memory

Science

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting

Neuropsychopharmacology

Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs

Science

Antipsychotic drug doses and neuroleptic/dopamine receptors

Nature

Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: Relevance to addiction

J Neurosci

Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation

Synapse

Neurons in medial prefrontal cortex signal memory for fear extinction

Nature

Cellular distribution of dopamine D1 and D2 receptors in rat medial prefrontal cortex

J Neurosci

Archival Report
Infralimbic D2 Receptors Are Necessary for Fear Extinction and Extinction-Related Tone Responses