How serotonin system alterations influence emotion- and cognition-related behaviors

Open Access
Gilman, Tracy Lee
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
June 28, 2013
Committee Members:
  • Dr Anne M Andrews, Dissertation Advisor/Co-Advisor
  • Kent Eugene Vrana, Committee Chair/Co-Chair
  • Sonia Angele Cavigelli, Committee Member
  • Troy Ott, Committee Member
  • David John Vandenbergh, Committee Member
  • Dr Jon E Sprague, Special Member
  • serotonin transporter
  • tryptophan hydroxylase
  • kappa opioid
  • brain development
  • anxiety-like behavior
  • conditioned place aversion
This dissertation describes research aimed at understanding how changes in brain serotonin neurotransmission influence the expression of emotion- and cognition-related behavior in mice. The serotonin-depleting effects of a novel serotonin synthesis inhibitor, PEPA, were studied in adult and postnatal mice. The effects of PEPA were compared to those resulting from administration of PCPA, which has been in use since the 1960s. Reductions in serotonin were induced during the early postnatal period in mice constitutively deficient in serotonin transporter (SERT) expression. Decreased brain serotonin levels resulting from exposure to PEPA, but not PCPA, from P4-P21 normalized increased adult anxiety-related behavior in female mice constitutively lacking SERT, presumably by reversing elevated extracellular serotonin levels during this key developmental period. Postnatal PEPA vs. PCPA had a number of other differential effects on adult social behavior and spatial learning and memory. In addition, the interactions between kappa opioid receptor (κOR) activation and differential SERT expression on dysphoria in adult mice was investigated. Dysphoria is a core component of mood disorders, in which changes in serotonin neurotransmission have been implicated. Conditioned place aversion to a κOR agonist was observed in mice lacking SERT, calling into question the requisite nature of SERT in mechanisms of kappa-mediated dysphoria. Throughout this dissertation research, drug doses and behavioral testing conditions were investigated to characterize and to improve methodologies. Investigations building on the foundation provided by this research will provide information on the roles of serotonin during developmental periods as they pertain to the expression of emotion- and cognition-related behaviors. Future studies will also be aimed at understanding how the serotonin system influences, and is modulated by, the κOR system to influence anxiety- and mood-related behavior.