Oral Papers: Palliative Care & Oncology I
Background: Few breakthroughs in acute anxiety management have taken place in the last half-century; a panic attack in 2019 is managed as it would have been in 1969-- with a benzodiazepine. While effective, benzodiazepines are plagued by risks (e.g. confusion, ataxia, abuse), and these are amplified in the frail and elderly that consultation-liaison psychiatrists treat. A psycho-oncologist and oncologic drug developer joined forces in a preclinical project to identify new targets for anxiolytic drug development.
Methods: Three genetically identical mouse strains (N=12 females per strain) were exposed to a battery of non-traumatic but “anxiety-provoking” behavior tests. Using math modeling, researchers characterized the variability in behavior phenotypes within each strain and then carried out high throughput ribonucleic acid sequencing on amygdala extracted from the strain displaying greatest behavior variability. Bioinformatics correlated gene expression patterns with “anxiety” behaviors. Gene ontologies were carried out to corroborate this approach.
Results: Of isogenic strains, C57/BL6 displayed greatest variation in behavior. Two-hundred-two genes were identified as up- or downregulated in the amygdala of “anxious” as compared to less anxious C57/BL6 mice. Gene ontologies identified induction of pathways known to modulate anxiety: nitric oxide, opioid, and corticotropin signaling. More novel transcriptional changes included downregulation of adhesion G protein-coupled receptor L4 (ADGRL4; expression log ratio -1.033) and prolactin (expression log ratio -4.407).
Discussion: The vast majority of the most up- and down-regulated proteins in the amygdala of high “anxiety” mice were not known to have amygdalar activity. While all should be vetted, two are of greatest interest. An orphan receptor, ADGRL4 has not previously been linked to affective states.1 Future research should locate this receptor with more specificity in subregions of the amygdala and test a hypothesis that ADGRL4 agonism holds utility in the management of acute anxiety. A peptide hormone tied to pregnancy and breast-feeding and classically secreted by the anterior pituitary, prolactin is also known to be synthesized in the amygdala; its function in this brain structure is uncertain. One hypothesis is that prolactin functions as an anxiolytic in regulation of the neuroendocrine stress axis during the peripartum period.2 Replicating this protocol in postpartum females, and in males, may test this hypothesis and identify sex differences in anxiety modulation.
Conclusion/Implications: This interdisciplinary research project lays out a rationally-derived approach to identify molecular features of state anxiety and implicates biomarkers that may be targets for future anxiolytic drug development.