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 necessary for extinction consolidation (10
Raclopride-induced impairment of fear extinction generally agrees with previous findings. Haloperidol, a predominantly D2 receptor antagonist with notable affinity for the D1 receptor, was recently shown to impair extinction when given systemically or into the nucleus accumbens (32
). In addition, lesions of the dopaminergic terminals in mPFC impair contextual fear extinction (33
). Our results implicate dopaminergic actions at the D2 receptor, and parallel the finding that D4 receptor activation in IL is also required for fear extinction (34
). Ponnusamy and colleagues (18
), however, observed accelerated extinction in mice using a different systemically-administered D2 receptor antagonist, sulpiride. The disparity with our results may be explained by the greater D2-receptor selectivity and binding strength of raclopride over sulpiride (19
). Sulpiride is known to bind non-D2 receptor sites, an effect not observed with other neuroleptics (35
). It should be noted that sulpiride did not enhance extinction of a cocaine-induced conditioned place preference (36
). Our results cannot be explained by state dependent effects as raclopride is quicky metabolized, and infusing the drug prior to extinction retrieval did not impair retrieval of extinction.
We identified IL as a site of action of raclopride in fear extinction, and observed a significant reduction in tone responses of IL neurons after systemic raclopride injections. Tone responses in IL are correlated with extinction retention (10
), and electrical stimulation designed to mimic tone responses in this region during extinction enhance extinction retention (10
). Output from IL neurons inhibits fear after extinction training by impeding amygdala output (15
). Because D2 receptors are located on IL output neurons, and conditioned responses in these neurons are observed during extinction (31
), we argue that activation of D2 receptors augments tone responsiveness during extinction learning.
In addition to direct modulation of tone responses, D2 receptor activation also stimulates mitogen-activated protein kinases (MAPKs) (38
). The MAPK signaling cascade is critical for protein synthesis, and reducing the activity of MAPK (9
) or blocking protein synthesis (41
) in IL impairs extinction retention. Thus, activation of D2 receptors on IL output neurons would facilitate consolidation of fear extinction.
Our results indicate that optimal levels of dopamine acting at D2 receptors are required for fear extinction to occur. D2 antagonists are commonly prescribed in psychiatry and are useful for the treatment of schizophrenia, a condition that is often comorbid with anxiety disorders. Our results suggest that the use of these drugs could lead to resistance to extinction, which may impede exposure therapy for anxiety disorders in patients currently using D2 receptor antagonists. Recently, it was shown that patients with schizophrenia exhibit extinction recall deficits (43
), an effect that could be attributed, in part, to the use of medications that block D2 receptors (44
). Whether chronic use of these medications reduces their potential to impair extinction learning, however, remains to be determined.