Facilitation of fear extinction by novelty is modulated by ß-adrenergic and 5-HT1A serotoninergic receptors in hippocampus.

Extinction is the learned inhibition of retrieval of a previously acquired memory and is a major component of exposure therapy, which has attracted much attention because of the use in the treatment of drug addiction, phobias and particularly fear disorders such as post-traumatic stress disorder (PTSD). Exposure to a novel environment before or after extinction training can enhance the extinction of contextual fear conditioning, however the cellular and molecular substrates are still unclear. Here, we investigated the participation of H2-histaminergic, ß-adrenergic and 5-HT1A-serotonergic receptors of the hippocampus on the enhancement of extinction memory caused by novelty. The infusion into the CA1 region of the serotonin 5-HT1A-receptor agonist, 8-OH-DPAT and the ß-adrenergic blocker, Timolol, after the exposure to the novelty hindered the enhancement of extinction by novelty, while Timolol also hindered the extinction consolidation when infused post-extinction. These impairments were abolished by the coinfusion of 8-OH-DPAT plus the 5-HT1A receptor antagonist, NAN-190 and Timolol plus ß-adrenergic agonist, Isoproterenol. However, Dimaprit and Ranitidine blocked the retrieval of CFC, but did not prevented the extinction learning. Here we elucidated some of the molecular mechanisms that are involved on the enhancement of extinction by novelty, demonstrating that the ß-adrenoreceptors and 5-HT1A serotonergic receptors participate on this process alongside with dopaminergic D1 receptors previously described, while histamine H2 receptors, so ubiquitous in learning-related functions in hippocampus are not involved.

Modulation of the consolidation and reconsolidation of fear memory by three different serotonin receptors in hippocampus.

The process of memory formation is complex and highly dynamic. During learning, the newly acquired information is found in a fragile and labile state. Through a process known as consolidation, which requires specific mechanisms such as protein synthesis, the memory trace is stored and stabilized. It is known that when a consolidated memory is recalled, it again becomes labile and sensitive to disruption. To be maintained, this memory must undergo an additional process of restabilization called reconsolidation, which requires another phase of protein synthesis. Memory consolidation has been studied for more than a century, while the molecular mechanisms underlying the memory reconsolidation are starting to be elucidated. For this, is essential compare the participation of important neurotransmitters and its receptors in both processes in brain regions that play a central role in the fear response learning. With focus on serotonin (5-HT), a well characterized neurotransmitter that has been strongly implicated in learning and memory, we investigated, in the CA1 region of the dorsal hippocampus, whether the latest discovered serotonergic receptors, 5-HT5A, 5-HT6 and 5-HT7, are involved in the consolidation and reconsolidation of contextual fear conditioning (CFC) memory. For this, male rats with cannulae implanted in the CA1 region received immediately after the training or reactivation session, or 3h post-reactivation of the CFC, infusions of agonists or antagonists of the 5-HT5A, 5-HT6 and 5-HT7 receptors. After 24h, animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of the hippocampus the 5-HT5A, 5-HT6 and 5-HT7 serotonin receptors participate in the reconsolidation of the CFC memory 3h post-reactivation. Additionally, the results suggest that the 5-HT6 and 5-HT7 receptors also participate in the consolidation of the CFC memory.