Increased Fear Response to Contextual Cues in Mice Lacking the 5-HT1A Receptor

Abstract

Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice.

Behavioral evaluation of mice deficient in GABAB(1) receptor isoforms in tests of unconditioned anxiety

“…In theory, it should not necessarily be expected that conditioned and unconditioned tests of fear and anxiety should demonstrate similar phenotypes or, indeed, even to produce similar phenotypes within each of these categories (Rodgers 1997). Certainly, dissociations between aversive conditioning and exploratory anxiety has also been reported for other mutant mice, such as forebrainselective glycine transporter 1-deficient mice (Yee et al 2006) and 5-HT 1A receptor knockout mice (Klemenhagen et al 2006), although it should be noted that in each of these studies only one unconditioned anxiety paradigm was utilized. However, the differentiation between conditioned and unconditioned responses appears particularly clearly delineated with GABA B(1) isoform-deficient mice.…”

Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

“…While currently no clinical evidence has reported specific long-term therapeutic effects of CBD in PTSD patient populations, PTSD has been associated with dysregulation of 5-HT 1A expression levels in brain regions responsible for emotional memory and processing, such as the amygdala (Sullivan et al, 2013). Furthermore, preclinical evidence has shown also that genetic deletion of the 5-HT 1A receptor in mice leads to potentiated reactivity to fear-related conditioning cues (Klemenhagen et al, 2006). Future research is required to more precisely characterize the mechanisms by which CBD and 5-HT 1A receptor substrates may interact and how these processes may, in turn, regulate emotional memory formation.…”

5-Hydroxytryptamine Induces a Protein Kinase A/Mitogen-Activated Protein Kinase-Mediated and Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation in the Amygdala

“…In contrast, injection of the 5-HT 1A agonist impairs retention, and administration of the 5-HT 1A antagonist enhances the retention of passive-avoidance task (Liang, 1999;Schneider et al, 2003). In 5-HT 1A knock-out mice the fear response to contextual clues increases (Toth, 2003;Klemenhagen et al, 2006). Learned fear memory in invertebrates and vertebrates may share some common synaptic mechanism Learned fear is a form of implicit memory.…”