Habenula orphan G-protein coupled receptors in the pathophysiology of fear and anxiety.

The phasic emotion, fear, and the tonic emotion, anxiety, have been conventionally inspected in clinical frameworks to epitomize memory acquisition, storage, and retrieval. However, inappropriate expression of learned fear in a safe environment and its resistance to suppression is a cardinal feature of various fear-related disorders. A significant body of literature suggests the involvement of extra-amygdala circuitry in fear disorders. Consistent with this view, the present review underlies incentives for the association between the habenula and fear memory. G protein-coupled receptors (GPCRs) are important to understand the molecular mechanisms central to fear learning due to their neuromodulatory role. The efficacy of a pharmacological strategy aimed at exploiting habenular-GPCR desensitization machinery can serve as a therapeutic target combating the pathophysiology of fear disorders. Originating from this milieu, the conserved nature of orphan GPCRs in the brain, with some having the highest expression in the habenula can lead to recent endeavors in understanding its functionality in fear circuitry.

Habenula GPR139 is associated with fear learning in the zebrafish.

G-protein coupled receptor 139 (GPR139) is an evolutionarily conserved orphan receptor, predominantly expressing in the habenula of vertebrate species. The habenula has recently been implicated in aversive response and its associated learning. Here, we tested the hypothesis that GPR139 signalling in the habenula may play a role in fear learning in the zebrafish. We examined the effect of intraperitoneal injections of a human GPR139-selective agonist (JNJ-63533054) on alarm substance-induced fear learning using conditioned place avoidance paradigm, where an aversive stimulus is paired with one compartment, while its absence is associated with the other compartment of the apparatus. The results indicate that fish treated with 1 µg/g body weight of GPR139 agonist displayed no difference in locomotor activity and alarm substance-induced fear response. However, avoidance to fear-conditioned compartment was diminished, which suggests that the agonist blocks the consolidation of contextual fear memory. On the other hand, fish treated with 0.1 µg/g body weight of GPR139 agonist spent a significantly longer time in the unconditioned neutral compartment as compared to the conditioned (punished and unpunished) compartments. These results suggest that activation of GPR139 signalling in the habenula may be involved in fear learning and the decision-making process in the zebrafish.