Novel targets, biomarkers, and models in the neurobiology of anxiety

• Author / Creator

  Yeung, Michelle

• Despite considerable research progress towards characterizing the neurobiology of anxiety, the focus on putative behavioral markers and the absence of a common behavioural/neurobiological signature for the different classes of anxiolytic drugs have potentially slowed research into the neural mechanisms of anxiolytic drug action. As such, current research efforts are dedicated towards identifying neural indices that yield universal signatures across all anxiolytic compounds. This, in turn, may facilitate the development of therapeutics for clinical anxiety disorders.
  The general purpose of this thesis is to identify and characterize putative compounds with anxiolytic potential and to critically evaluate an emerging neurophysiological model of anxiolytic drug action. Chapter 1 of this thesis will provide a systematic overview of current animal behavioral models of anxiety, summarize the role of several neurotransmitter systems in the biochemical basis of anxiety, describe the seminal work characterizing the neuroanatomical correlates of anxiety, characterize the role of hippocampal theta in the neurobiology of anxiety, and identify novel pharmacological targets. In chapter 2, the anxiolytic properties of somatostatin following intra-amygdala and intra-septal microinfusions and the receptor specificity of these effects will be summarized. Here, we found that a selective sst2 receptor antagonist, PRL2903 can reverse the anxiolytic effects of somatostatin in two well established behavioral models of anxiety, the elevated plus-maze and shock probe burying test. Chapter 3 will provide a critical assessment of the hippocampal theta suppression model of anxiolytic drug action. Here, we found that the bradycardic agent ZD7288 significantly suppresses reticularly activated theta frequency and produces corresponding anxiolytic effects in the elevated plus-maze. In chapter 4, three well established anxiogenic agents FG7142, yohimbine, and βCCE will be used to assess the construct validity of the theta model, (i.e. to evaluate the functional role of theta frequency in anxiety per se). Here, we found that all three anxiogenic agents reliably produced anxiogenic-like effects in the elevated plus-maze but had no effects on theta frequency. Chapter 5 of this thesis will explore the regional and functional differences of the dorsal and ventral hippocampus in relation to the theta suppression model using histamine, an important neurotransmitter in the brain. Paradoxically, we found that histamine produced marked increases to theta frequency following ventral hippocampal microinfusions while eliciting robust anxiolytic effects in the elevated plus-maze. Finally, chapter 6 will summarize the major results and conclusions of these studies, describe their limitations and propose future directions for research on novel models and mechanisms in the neurobiology of anxiety.

• Subjects / Keywords

  • Amygdala
  • Septum
  • Biomarkers
  • Animal behavior models
  • Anxiety
  • Theta
  • Hippocampus

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R33B5WG9H

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.