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

The changes in serotonin type 3 (5-HT3) 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) did 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 gamma-aminobutyric acid (GABA). The expression of the GABA(A) receptor clustering protein gephyrin was significantly 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.