Facilitation of fear extinction by the 5‐HT_1A receptor agonist tandospirone: Possible involvement of dopaminergic modulation

Abstract

Fear extinction-based exposure treatment is an important component of psychotherapy for anxiety disorders such as posttraumatic stress disorder (PTSD). Recent studies have focused on pharmacological approaches combined with exposure therapy to augment extinction. In this study, we elucidated the therapeutic potential of the serotonin 1A (5-HT(1A) ) receptor agonist tandospirone compared with the effects of the N-methyl-D-aspartate partial agonist D-cycloserine (DCS), focusing on the possible involvement of dopaminergic mechanisms. We used a rat model of juvenile stress [aversive footshock (FS)] exposure during the third postnatal week (3wFS). The 3wFS group exhibited extinction deficit reflected in sustained fear-related behavior and synaptic dysfunction in the hippocampal CA1 field and medial prefrontal cortex (mPFC), which are responsible for extinction processes. Tandospirone administration (5 mg/kg, i.p.) before and after the extinction trials ameliorated both the behavioral deficit and synaptic dysfunction, i.e., synaptic efficacy in the CA1 field and mPFC associated with extinction training and retrieval, respectively, was potentiated in the tandospirone-treated 3wFS group. Extracellular dopamine release in the mPFC was increased by extinction retrieval in the non-FS control group. This facilitation was not observed in the 3wFS group; however, tandospirone treatment increased cortical dopamine levels after extinction retrieval. DCS (15 mg/kg, i.p.) also ameliorated the extinction deficit in the 3wFS group, but impaired extinction in the non-FS control group. These results suggest that tandospirone has therapeutic potential for enhancing synaptic efficacy associated with extinction processes by involving dopaminergic mechanisms. Pharmacological agents that target cortical dopaminergic systems may provide new insights into the development of therapeutic treatments of anxiety disorders, including PTSD.

M5 Muscarinic Receptor Gene Deletion Accelerates Extinction, But Inhibits Reinstatement of Morphine-Conditioned Reward in Mice

“…These results support a role for M5Rs in maintaining and restoring previously learned CPP, possibly through the sustained activation of dopamine neurons by M5Rs [26,[49][50][51]. Previous authors have argued that dopamine neural activity is important in the learning of extinction and spontaneous recovery in different paradigms [52,53].…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Buspirone and other 5-HT 1A R agonists are approved for the treatment of GAD, with fair response rates [50]. In preclinical studies, 5-HT 1A R agonists are anxiolytic in animal models of general anxiety [51], prevent the adverse effects of stress [52], and enhance fear extinction [53]. Both pre-and postsynaptic 5-HT 1A Rs are coupled to various members of the G i/o protein family.…”

Can fear extinction be enhanced? A review of pharmacological and behavioral findings

“…Dopamine has been implicated in many learning and memory processes, often as a mediator of memory consolidation through its role as a promoter of long-term potentiation in regions of the brain such as the mPFC (where synaptic potentiation has been found to occur and correlate with extinction learning (Saito et al, 2012)). Output neurons in the mPFC receive a large number of dopaminergic inputs from the ventral tegmental area and are thought to be involved in communicating fear inhibition learned through extinction via their excitatory projections to GABAergic interneurons in the amygdala, thereby reducing its activity and the subsequent expression of fear-related behavior.…”

“…It was found that the extinction enhancements related to an increase in mPFC dopamine release, which in turn increased mPFC activity during extinction retrieval. Importantly, there was no increase in serotonin release in the mPFC (Saito et al, 2012). Finally, and perhaps paradoxically, systemic administration of sulpiride, a dopamine D2 receptor antagonist, before extinction training resulted in enhanced extinction memory retention during subsequent tests, whereas quinpirole, a D2 agonist, resulted in diminished extinction learning.…”