Contribution of serotonin type 3 receptors in the successful extinction of cued or contextual fear conditioned responses: interactions with GABAergic signaling

Abstract

The changes in serotonin type 3 (5-HT) receptor activity influence memory and emotional regulation,the two essential components underlying the successful extinction of conditioned fear. These studies determined if blocking 5-HT3 receptors with granisetron influences the extinction of fear in male Sprague-Dawley rats. In Experiment 1, preextinction granisetron (0.5 or 1.0 mg/kg intraperitoneally) d~d not affect cued extinction learning but enhanced memory for the extinction session on retention test given 24 and 48 h later. In Experiment 2, granisetron injections given on days 1 and 4 during 6 days of extinction training reduced fear produced by contextual fear conditioning. Experiments 3 and 4 examined if 5-HT3 antagonists influence extinction memory by interactions with y-aminobutyric acid (GABA). The expression of the GABA receptor clustering protein gephyrin was significantly A elevated in the amygdala after cued fear extinction training and a subsequent extinction retention test given 24 h later. Gephyrin expression in the hippocampus but not in the amygdala or the medial prefrontal cortex was significantly reduced after contextual fear extinction sessions given 1 or 5 days after training. The current studies reveal the beneficial effects of 5-HT3 receptor activity in improving new learning associated with extinction of fearful memories and suggest that these actions could be mediated through influences on central GABAergic systems.

The 5-HT3A receptor is essential for fear extinction

“…In contrast to our findings, Park and Williams (2012) reported that systemic injection of a 5-HT 3 receptor antagonist (granisetron) facilitated the memory of cued and contextual fear extinction in rats. However, there are several points of difference between our experiments and theirs, which could account for the differences between the results obtained.…”

“…Second, the experimental paradigms differed. Park and Williams (2012) used passive avoidance paradigms to measure conditioned contextual fear, whereas we used the fear conditioning paradigms described above. These two behavioral tasks are known to be fear learning tests; however, the requirements vary across learning tasks.…”

“…Therefore, it is possible that fear learning processes (including extinction processes of learned fear) are different between the two tasks. Furthermore, as an index of conditioned fear, Park and Williams (2012) used the latency to enter the dark compartment in the passive avoidance task, whereas we have used freezing behavior in the fear conditioning test. It has been reported that different types of conditioned fear behavior (i.e., avoidance behavior of the aversive stimulus vs. freezing responses) are mediated by distinct neural systems (Killcross et al 1997).…”

“…In addition, the conditions of extinction trials are different. Park and Williams (2012) performed tone-cued extinction trials, which gave 10 presentations of the CS tone with 60-sec intertrial intervals (ITIs) within 1 d. In contrast, we performed the extinction trials over six consecutive days with 24-h ITIs. It has been reported that ITIs in extinction trials can affect the processes of fear extinction (Bouton et al 2006).…”

Corticotropin-releasing factor-related peptides, serotonergic systems, and emotional behavior

“…In addition, serotonin receptors have been implicated in playing a role in emotion-related behaviors in the hippocampus and the mPFC. Although all 5-HT receptors have been identified within the amygdala, particular attention has been paid to the 5-HT 1A and 5-HT 2C receptors (Park and Williams, 2012; Asan et al, 2013). Specifically, the 5-HT 1A receptors in the CE have been shown to be involved in the reduction of anxiety-like behaviors while 5-HT 2C receptors are associated with an increase in anxiety-like behaviors (Li et al, 2012).…”